Rheumatoid Arthritis - Epidemiology, pathogenesis and clinical manifestations Dror Mevorach, M.D....

Rheumatoid Arthritis - Epidemiology, pathogenesis and clinical manifestations

Dror Mevorach, M.D.November, 2013

RHEUMATOID ARTHRITIS

Overview– Chronic inflammatory disease of

unknown etiology– Complex, multifactorial pathogenesis– Fluctuating clinical course– Characterized by

• Progressive destruction of synovial joints with loss of cartilage and bone

• Damaged ligaments and tendons• Loss of physical function and quality of life

• Premature death

RHEUMATOID ARTHRITIS Epidemiology

– Affects approximately 1% (0.3%-1.5%) of the global adult population

– Occurs 2 to 3 times more often in women than in men

– Estimated annual incidence Males: 0.1–0.2 per 1000 Females: 0.2–0.4 per 1000

– Monozygotic twins concordance of 15%-30%.– R.R of 2.5 of monozygotic compared to

dizygotic twins.– Incidence largely consistent racially and

geographically– Increases with age, peaks between the ages of

45 and 65 years.


Worldwide Incidence and Prevalence

Prevalence (per 100)Prevalence (per 100)W. Europeans/W. Europeans/ 0.8–0.8–1.1 North Americans (Whites)North Americans (Whites)

ChineseChinese 0.3–0.4–0.4Amerindians (Chippewa, Pima)Amerindians (Chippewa, Pima) 5–85–8

W. Europeans/W. Europeans/ 0.24–3.34 0.24–3.340.1–1.50 0.1–1.50 North Americans (Whites)North Americans (Whites)

WomenWomen Men Men Incidence (per 1000/year)Incidence (per 1000/year)

RHEUMATOID ARTHRITIS Etiology and Pathogenesis

• Suspected infectious agents– Bacteria (Mycoplasma, Mycobacteria,

enteric bacteria)– Viruses (HTLV, Retrovirus, Herpesvirus,

Epstein-Barr virus, rubella, parvovirus)

• Defective recognition of autoantigen– Pregnancy induced remission linked to

maternal-fetal HLA mismatch? Hormones?

• Strong association with class II major histocompatibility complex human leukocyte antigen on chromosome 6– HLA-DR4 - N European and Americans– HLA-DR1 - Italian, Israeli Jewish, some

Hispanics– HLA-DR14 - Yakima Indians

– DRB1*04 (DR4) alleles are markers for severe, erosive RA

RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS Genetic Factors Genetic Factors

RHEUMATOID ARTHRITIS Twin Studies in RA

Lipsky PE. In: Harrison’s Principles of Internal Medicine. 2010.

RHEUMATOID ARTHRITIS Shared Epitope Hypothesis

Alleles associated with RA

Pathophysiology of Rheumatoid Arthritis

compact nodular clusters of lymphocytes and plasma cells near the surface of synovial villi.

excised synovial membrane shows many villous folds projecting above the synovial surface

Hyperplastic, hypertrophic synoviocytes with occasional multi-nucleated giant cells. The enlarged villi are diffusely infiltrated by lymphocytes and plasma cells. Moderate capillary proliferation is seen.

Pathophysiology of Rheumatoid Arthritis: knee synovitis

Pathophysiology of Rheumatoid Arthritis: Late Destruction

Finger joint, bony ankylosis, photomicrograph

A sagittal section through a proximal interphalangeal joint demonstrates complete bony union of the phalanges.

Pathophysiology of Rheumatoid Pathophysiology of Rheumatoid Arthritis- Panus formationArthritis- Panus formation

Typical pannus formation. Fibrovascular tissue protrudes from the inflamed synovium into the articular cartilage. Note the inflammatory exudate in the subchondral bone (hematoxylin-eosin, medium power).

A portion of the fibrous tissue extends over the surface of the cartilage, which shows death of chondrocytes and loss of basophilia of the matrix.

RHEUMATOID ARTHRITIS Pathogenesis of Rheumatoid Arthritis

antigen

HLA class II molecule

Antigen presenting cell

T cell

Chronic Inflammation in the Rheumatoid Synovium

Pannus

PMN

Cytokine

Bone

Activated T cells

Macrophage

B cell

Inflamed synovial membrane

Eroding cartilage

Cellular Interactions in the Rheumatoid Synovium

• Inflammation•Acute phase protein synthesis•Cachexia Antigen

Plasmacells

Antibodyproduction

B celldifferentiationand activation

Lymphocyte

Macrophage

IL-2IFNOther cytokines

IL-1TNFIL-6IL-8

T cell

RheumatoidFactor

production


Disease Progression

Capillary Formation

HyperplasticSynovialMembrane

HypertrophicSynoviocyte

Neutrophils

T CellsT Cells B CellsB Cells

Early Rheumatoid Arthritis

Established Rheumatoid Arthritis

Synovial Villi

ExtensiveAngiogenesis

Plasma Cell

PannusEroded Bone

Neutrophils

Capsule

Bone

Synovial Membrane

Synoviocytes

Normal Knee Joint

Cartilage

RHEUMATOID ARTHRITIS Cytokine Signaling Pathways

Involved in Inflammatory Arthritis

• Joints are warm, swollen noticed in superficial joints. Usually symmetrical.

• Frequently seen in wrists, MCPs, PIPs & DIPs

• Compression of peripheral nerves – carpal tunnel syndrome, ulnar nerve (Guyon’s canal)

RHEUMATOID ARTHRITIS Articular manifestations - hands

• Tenosynovitis may result in rheumatoid nodules – might interfere with finger flexion.

RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS Articular manifestationsArticular manifestationsRHEUMATOID ARTHRITIS Articular manifestations - hands


Presenting Signs and Symptoms

– Symmetric joint pain– Swelling of small peripheral

joints– Morning joint stiffness of

variable duration– Other diffuse aching• Fatigue, malaise, and

depressionmay precede other symptomsby weeks or months

Grassi W et al. Grassi W et al. Eur J RadiolEur J Radiol. 1998;27(suppl 1):S18–S24.. 1998;27(suppl 1):S18–S24.


Laboratory Findings

– Chemistries normal, except slight in albumin, totalprotein, and iron

– Hematologic findings• Mild anemia in 25% to 35% of patients• Normal or slight in white cell count• Thrombocytosis• eosinophilia


Laboratory Findings

– Anti-cyclic citrullinated protein (CCP) predicts RA development in patients with polyarthritis. Low sensitivity, high specificity

– Rheumatoid factor positive in up to 80% of patientsRF titers correlated with disease severity and extra-articualr manifestations.Some patients convert from RF/- TO RF/+ (as the disease progresses).

– Acute phase reactants (ESR, CRP, PLTs) in almost all patientsat some point, correlates with synovitis.Other Acute phase reactants: C3 C4

– hypergammaglobulinemia

RHEUMATOID ARTHRITIS Rheumatoid Factor

• Most common autoantibody in RA

– Binds to the Fc portion of IgG molecule

– Usually an IgM antibody– Less often an IgG or IgA

antibody• Detected in 70-80% of

RA patients• High titer predicts

adverse outcome– Erosive arthritis,

vasculitis

• Methods of detection– agglutination

IgG coated latex beads or erythrocytes– laser nephelometry– indirect immunofluorescence– radioimmuno assay– enzyme-linked immunosorbent assay

Rheumatoid Factor

RHEUMATOID ARTHRITIS Disease associated with +RF

• Autoimmune diseases• Infectious diseases (viral, bacterial,

parasitic infections• other hyper--globulinemic states• Malignant conditions• Aging (up to 3% of the elderly population


• Autoimmune diseases– rheumatoid arthritis– systemic lupus erythematosus– scleroderma– mixed connective tissue disease– Sjogren’s syndrome


• Viral disease– AIDS– mononucleosis– hepatitis– influenza


• Parasitic infections– trypanosomiasis– malaria– Kala-azar– schistosomiasis– filariasis


• Chronic bacterial infections– tuberculosis– syphilis– leprosy– brucellosis– yaws– salmonellosis– Infective endocarditis


• other hyper--globulinemic states– hyper--globulinemic purpura– Cryoglobulinemia (>90%)– chronic liver disease– Sarcoidosis– Sjogren syndrome– other chronic pulmonary diseases

RHEUMATOID ARTHRITIS Diagnosis of Rheumatoid Arthritis

American College of Rheumatology Criteria

At least 4 of the following criteria

– Morning stiffness >1 hour– Arthritis of 3 joint areas– Arthritis of hand joints– Symmetric arthritis– Rheumatoid nodules– Serum rheumatoid factor– Radiographic changes

Arnett FC et al. Arnett FC et al. Arthritis RheumArthritis Rheum. 1988;31:315–324.. 1988;31:315–324.

Must be presentfor at least 6 weeks

RHEUMATOID ARTHRITISRHEUMATOID ARTHRITIS

Radiological FeaturesRadiological Features

Progressive MCP erosion

Thinning of the radial

side of the cortex with

minimal disturbance of

underlying trabeculae

and minimal joint

space narrowing. A

marginal erosion (C)

appears on the radial

aspect of the

metacarpal head.

There is loss of bone

substance and joint

space narrowing.

Subcutaneous nodulesSubcutaneous nodules

• Nodules occur in about 20-50% Nodules occur in about 20-50%

of patients with RA and are of patients with RA and are

usually associated with high usually associated with high

titers of rheumatoid factor. titers of rheumatoid factor. • Subcutaneous nodules are also Subcutaneous nodules are also

seen in other conditions such as seen in other conditions such as

SLE and mixed connective tissue SLE and mixed connective tissue

disease.disease. • Methotrexate may enhance

development.

• 2010 Rheumatoid Arthritis Classification CriteriaAn American College of Rheumatology/European League Against

RheumatismCollaborative Initiative

Daniel Aletaha,1 Tuhina Neogi,2 Alan J. Silman,3 Julia Funovits,1 David T. Felson,2Clifton O. Bingham, III,4 Neal S. Birnbaum,5 Gerd R. Burmester,6 Vivian P. Bykerk,7Marc D. Cohen,8 Bernard Combe,9 Karen H. Costenbader,10 Maxime Dougados,11Paul Emery,12 Gianfranco Ferraccioli,13 Johanna M. W. Hazes,14 Kathryn Hobbs,15Tom W. J. Huizinga,16 Arthur Kavanaugh,17 Jonathan Kay,18 Tore K. Kvien,19

Timothy Laing,20 Philip Mease,21 Henri A. Menard,22 Larry W. Moreland,23 Raymond L. Naden,24 Theodore Pincus,25 Josef S. Smolen,1 Ewa Stanislawska-Biernat,26 Deborah Symmons,27Paul P. Tak,28 Katherine S. Upchurch,18 Jirˇi Vencovsky’,29

Frederick Wolfe,30 and Gillian Hawker31

• Table 3. The 2010 American College of Rheumatology/European League Against Rheumatism classification. criteria for rheumatoid arthritis Score

• Target population (Who should be tested?): Patients who 1) have at least 1 joint with definite clinical synovitis (swelling)*2) with the synovitis not better explained by another disease†

• Classification criteria for RA (score-based algorithm: add score of categories A–D;a score of 6/10 is needed for classification of a patient as having definite RA)‡

• † Differential diagnoses vary among patients with different presentations, but may include conditions such as systemic lupus erythematosus, psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses to consider, an expert rheumatologist should be consulted.

• ‡ Although patients with a score of 6/10 are not classifiable as having RA, their status can be reassessed and the criteria might be fulfilled cumulatively over time.

• Table 3. The 2010 American College of Rheumatology/European League Against Rheumatism classification. criteria for rheumatoid arthritis Score

• A. Joint involvement§-1 large joint. 0-large joints 1-3 small joints (with or without involvement of large joints)# 2-10 small joints (with or without involvement of large joints) 3-10 joints (at least 1 small joint)** 5• B. Serology (at least 1 test result is needed for classification)††-Negative RF and negative ACPA 0-Low-positive RF or low-positive ACPA 2-High-positive RF or high-positive ACPA 3• C. Acute-phase reactants (at least 1 test result is needed for classification)‡‡-Normal CRP and normal ESR 0-Abnormal CRP or abnormal ESR 1• D. Duration of symptoms§§-6 weeks 0-6 weeks 1

• * The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of rheumatoid arthritis (RA) with a history compatible with prior fulfillment of the 2010 criteria should be classified as having RA. Patients with longstanding disease, including those whose disease is inactive (with or without treatment) who, based on retrospectively available data, have previously fulfilled the 2010 criteria should be classified as having RA.

• § Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment. Categories of joint distribution are classified

according to the location and number of involved joints, with placement into the highest category possible based on the pattern of joint involvement.

• . “Large joints” refers to shoulders, elbows, hips, knees, and ankles.

• # “Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.

• ** In this category, at least 1 of the involved joints must be a small joint.


Prognostic factors– Clinical course unpredictable but mostly progressive– Unfavorable prognostic markers

– Male sex – Eosinophilia– Low socioeconomic status – Elevated ESR or CRP– Subcutaneous nodules – High RF factor titer – Systemic signs – Antinuclear antibodies– Persistent synovitis – Cryoglobulins– Thrombocytosis – Shared epitope (?)– Disease activity reduced faster and radiographic evidence

ofjoint damage lessened with early diagnosis and treatment

Albers JMC et al. Albers JMC et al. Ann Rheum DisAnn Rheum Dis. 2001;60:453–458.. 2001;60:453–458.Grassi W et al. Grassi W et al. Eur J RadiolEur J Radiol. 1998;27(suppl 1):S18–S24. . 1998;27(suppl 1):S18–S24.

RHEUMATOID ARTHRITIS Clinical Course of RA

Type 1 = Self-limited—5% to 20%Type 2 = Minimally progressive—5% to 20%Type 3 = Progressive—60% to 90%

0

2

4

0 0.5 1 2 3 4 6 8 16

Type 1

Type 2

Type 3

Years

Severi

ty o

f A

rthri

tis

Rheumatoid Arthritis: Typical Course

• Damage occurs early in most patients – 50% show joint space narrowing or

erosions in the first 2 years.– By 10 years, 50% of young working

patients are disabled.• Death comes early

– Multiple causes– Compared to general population

• Women lose 10 years, men lose 4 years

TREATMENT OF RHEUMATOID ARTHRITIS

Goals of Therapy

– Relieve symptoms, including fatigue, pain, swelling, and stiffness

– Prevent joint destruction, loss of joint function, deformity, disability, and early death

– Preserve quality of life– Achieve clinical remission


General Approach– Start treatment early to prevent joint damage– Institute general therapeutic measures: education,

exercise, rest, joint protection, physical therapy– Prescribe medications for symptom relief – Prescribe DMARDs to prevent joint damage

and induce remission. Low dose steroids, Biologics– Consider surgery in selected cases


Measurement of Treatment Effects

– Clinical assessment ofinflammatory synovitis• Swollen joint count,

tender joint count– Laboratory assessment

of inflammatory synovitis• Acute phase reactants

(eg, ESR, CRP)

ACR ad hoc Committee on Clinical Guidelines. ACR ad hoc Committee on Clinical Guidelines. Arthritis RheumArthritis Rheum. 1996;39:713–722.. 1996;39:713–722.Grassi W et al. Grassi W et al. Eur J RadiolEur J Radiol. 1998;27(suppl 1):S18–S24.. 1998;27(suppl 1):S18–S24.

Assessment of physical functionAssessment of physical function– Stanford Health Assessment Stanford Health Assessment

Questionnaire (HAQ)Questionnaire (HAQ)– Short-Form 36 Health SurveyShort-Form 36 Health Survey

(SF-36)(SF-36) Assessment of structural jointAssessment of structural joint

damagedamage– Radiography (ultrasound and Radiography (ultrasound and

magnetic resonance imaging)magnetic resonance imaging)


ACR Response CriteriaACR20 / ACR50 / ACR70

• 20% / 50% / 70% improvement in– Swollen joint count– Tender joint count– Improvement in at least 3 of the following 5 measures

• Patient’s global assessment of disease activity• Physicians’ global assessment of disease activity• Patient’s assessment of pain• Acute-phase reactant (ESR, CRP)• Disability (HAQ)

Felson DT et al. Felson DT et al. Arthritis RheumArthritis Rheum. 1995;38:727–735.. 1995;38:727–735.Felson DT et al. Felson DT et al. Arthritis RheumArthritis Rheum. 1998;41:1564. 1998;41:1564––1570.1570.


Disease Activity Score (DAS)Assessment of Improvement or Response

• DAS = 0.54 • (RAI) + 0.065 • (sw) + 0.33•Ln(ESR) + 0.0072•GH

– RAI = number of tender joints (t) calculated usingRitchie Articular Index

– Number of swollen joints (sw)– Erythrocyte sedimentation rate (ESR, mm/hour)– General health status (GH) using a 100-mm

visual analog scale (VAS)

High disease activityHigh disease activity >3.7, low>3.7, low disease activitydisease activity 2.4,2.4, remissionremission <1.6<1.6


EULAR Response Criteria

van Gestel AM et al. van Gestel AM et al. Arthritis RheumArthritis Rheum. 1996;39:34–40. Copyright © 1996 American College of . 1996;39:34–40. Copyright © 1996 American College of Rheumatology. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.Rheumatology. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

>1.2>1.2 >0.6 to >0.6 to 1.21.2 0.60.6

DAS DAS 2.4 2.4

2.4 < DAS 2.4 < DAS 3.7 3.7

DAS > 3.7DAS > 3.7

Decrease in DASDecrease in DAS

Good

Moderate

None

Present ScorePresent Score

EULAR = European League Against Rheumatism; DAS = Disease activity score.EULAR = European League Against Rheumatism; DAS = Disease activity score.


Pannus

PMN

Cytokine

Bone

Activated T cells

Macrophage& DCs

B cell


Eroding cartilage


Pannus

PMN

Cytokine

Bone

Activated T cells

Macrophage& DCs

B cell


Eroding cartilage

CyclosporineAzathioprineCyclophosphamide

Rituximab

Anti-cytokines

Anti-MMPs

Anti-signaling

Drugs used in RA

“Symptomatic” treatment

–simple analgesics

–NSAIDs/ COX inhibitors

–(glucocorticoids)

Disease modifying agents• -Halt or prevent joint• damage• -Preserve joint

integrity• and function• -Slow acting• -Toxicity problems

Glucocoticoids

Gold

Antimalarials

Sulfasalazine

Methotrexate

Immunosuppressives

Anti-Cytokines

• Anti-TNF: Infliximab, Etanercept, Humira

• Anti-IL1b• Anti-IL-6• Anti-CD20, rituximab• Anti Jak-Stat signaling• Others

Biologics

TNF

osteoclastsosteoclasts synoviocytessynoviocytes chondrocyteschondrocytes

bonebone resorptionresorption

bonebone erosionerosion

jointjoint inflammationinflammation

cartilagecartilage degradationdegradation

jointjoint spacespace narrowingnarrowing

painpain//jointjoint inflammationinflammation

Role of TNFa in RA

• Up-regulation of-TNF receptor expression in synoviocytes, chondrocytes and osteoclasts

• Induction of secretion of serine proteases (matrix metalloproteinases, MMP’s)

• TNFa – modulates angiogenesis

• Up-regulation of adhesion molecules (ICAM-1, VCAM etc.)

Infliximab (cA2): A Chimeric anti-human TNFa Monoclonal Antibody

V region:A2- A mouse anti-human TNFa monoclonal antibody + constant part: A human IgG1-k

cA2 (Infliximab): chimeric (human-mouse) anti-human TNFa neutralizing antibody

Mouse(Binding site for TNF)

Human (IgG1)

ATTRACT Trial Mean Change in Total Modified Sharp Score

Lipsky.NEMJ 343: 1594, . 2000.

Mean

Mean c

han

ge

ch

an

ge f

rom

from

BL

BL

12.612.6

1.0*1.0* 1.0*1.0* 1.1*1.1*

0.4*0.4*00

22

44

66

88

PlaceboPlacebo 3 3 mg/kgmg/kgq 8 wkq 8 wk

3 3 mg/kgmg/kgq 4 wkq 4 wk



**pp < 0.001 vs placebo + < 0.001 vs placebo + MTXMTX

1010

1212

Lipsky.NEMJ 343: 1594, . 2000.

ATTRACT TrialMean Improvement HAQ (102 Week)

Ch

an

ge in

HA

QC

han

ge in

HA

Q

00

.1.1

.5*.5* .5*.5*

.2.2

.4*.4*

*p<.001

.2.2

.3.3

.4.4

.5.5

.6.6

PlaceboPlacebo 3 3 mg/kgmg/kgq 8 wkq 8 wk




.4*.4*

• Anti-immunoglobulin antibodies-anti-idiotype, anti-allotype

–5-30% after a single dose up to 50% in repeated dosing Allergic reactions, anaphylaxsis

• Need for concomitant methotrexate therapy• Infections• Malignancies• Cost $12,000 year

Etanercept: A Recombinant sTNF-R:Fc Fusion Protein

Recombinant human TNF-receptor p75-two chains

+

Fc of a human IgG1

TNFR:Fc- Etanercept aTNF neutralizing protein

ACR Responses

00

1010

2020

3030

4040

5050

6060

7070

8080

00 66 1212 1818 2424 3030 3636 4242

MonthsMonths

%

% p

atie

nts

pat

ien

ts

ACR20ACR20

ACR50ACR50

ACR70ACR70

Moreland. Arthritis Rheum. 2000.

*p = 0.001

0

1

2

3

4

0 6 12 18 24

Months

Cha

nge

from

bas

elin

e (m

ean)

*

Erosions

Months

*p = 0.001

0

1

2

3

4

0 6 12 18 24

Etanercept 25 mg

Methotrexate 20 mg

Total Sharp Scores

*

Change in Total Sharp Scores and Erosions Over Two Years

Genovese. Arthritis Rheum. 2000.

LITHE: Tocilizumab inhibits radiographic progression and improves physical function in rheumatoid arthritis patients at 2 yrs with increasing clinical

efficacy over time

R Fleischmann1, R Burgos-Vargas2, P Ambs3, E Alecock4, J Kremer5

1Metroplex Clinical Research Center, Dallas, TX, USA; 2Hospital General de México, Mexico; 3Roche, Basel, Switzerland, 4Roche, Welwyn, UK, 5Albany Medical College, Albany, NY, USA

LITHE: Study design

All other

DMARDs D/C anti-TNF

washout

Screening1 Year

Placebo + MTX (n=392)

TCZ 8 mg/kg + MTX (n=399)

N=1196Randomization1:1:1

Day 1

Double-blind

Open-labelTCZ 8mg/kgor double-blind


Rescue 1: Patients who failed to respond to treatment at 16 weeks were offered rescue therapy with tocilizumab (blinded dose)Rescue 2: Patients who failed to respond to Rescue 1 were offered a second step of tocilizumab rescue therapy at any time between Week 28 and Week 52 (Rescue 2)Double-blind therapy in Year 2: Patients who responded to treatment at Weeks 48 and 52 (>70% reduction in swollen joint count [SJC] and tender joint count [TJC]) could remain on their blinded therapy

Rescue 2 Year

R

Optional Extension Years 3–5

Open-

label

Results: Tocilizumab significantly inhibits radiographic progression at 2 years

Placebo + MTX (n=393)


Pat

ient

s w

ithou

t G

mT

SS

pr

ogre

ssio

n (%

)

p≤0.0025*

Mea

n ch

ange

fro

m

base

line

in G

mT

SS

p≤0.0025*


GmTSS = Genant-modified total Sharp scoreLinear extrapolation used for missing data (post-rescue data set to missing)* vs. placebo + MTX

p≤0.0025*

p≤0.0239*

Oral #637

1.96

0.58

0.37

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

66

75

83

0

10

20

30

40

50

60

70

80

90

81%inhibition

Results: DAS28 remission* rates increase over time in MTX-IR patients

Pat

ient

s (%

)

TCZ8 mg/kg + MTX (n=275)

TCZ8 mg/kg + MTX (n=241)

*DAS28 <2.6Last observation carried forward approach used for SJC and TJC for patients who received rescue therapy or withdrew from that time point Oral #637

48

65

0

10

20

30

40

50

60

70

Week 52 Week 104

SAFETY:

LONG TERM SAFETY – 2.4 YEARS

SIE. CV events, lipid profile, liver enzymes

Results: Overall safety profile

All patients receiving ≥1 dose of tocilizumab (n=4,009)

Total treatment exposure (PY) 9,414

Discontinuations due to AEs per 100 PY 5.8

SAEs per 100 PY 14.91

Serious infections per 100 PY 4.7

Deaths per 100 PY 0.53

Deaths from infection per100 PY 0.13

PY = patient-yearsSAE = serious adverse event Oral #1955

Summary

• ACTEMRA demonstrates high DAS28 remission rate across all patients types

• long-term treatment with Actemra is associated with ongoing improvements in the clinical signs and symptoms of RA

• Laboratory abnormalities were consistent with the mechanism of action of tocilizumab and could be effectively managed: lipids, cytopenias

• The safety profile of Actemra in long-term follow-up was consistent with that seen in 24-week controlled studies

Oral #1955

Rheumatoid Arthritis - Epidemiology, pathogenesis and clinical manifestations Dror Mevorach, M.D....

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Transcript of Rheumatoid Arthritis - Epidemiology, pathogenesis and clinical manifestations Dror Mevorach, M.D....