Transcript Advances in the Treatment of RA

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.
RHEUMATOID ARTHRITIS
Worldwide Incidence and Prevalence
Prevalence (per 100)
W. Europeans/
North Americans (Whites)
0.8–1.1
Chinese
Amerindians (Chippewa, Pima)
0.3–0.4
5–8
Incidence (per 1000/year)
Women
Men
W. Europeans/
North Americans (Whites)
0.24–3.34
0.1–1.50
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?
RHEUMATOID ARTHRITIS
Genetic Factors
• 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 ARTHRITIS
Twin Studies in RA
RHEUMATOID ARTHRITIS
Shared Epitope Hypothesis
Alleles associated with RA
Lipsky PE. In: Harrison’s Principles of Internal Medicine. 2010.
Pathophysiology of Rheumatoid Arthritis
excised synovial membrane
shows many villous folds
projecting above the
synovial surface
compact nodular clusters of
lymphocytes and plasma cells
near the surface of synovial
villi.
Pathophysiology of Rheumatoid Arthritis:
knee synovitis
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: Late Destruction
A sagittal
section through
a proximal
interphalangeal
joint
demonstrates
complete bony
union of the
phalanges.
Finger joint, bony ankylosis, photomicrograph
Pathophysiology of Rheumatoid
Arthritis- Panus formation
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.
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).
RHEUMATOID ARTHRITIS
Pathogenesis of Rheumatoid Arthritis
T cell
antigen
HLA class II molecule
Antigen presenting cell
Chronic Inflammation in the
Rheumatoid Synovium
Activated T cells
Macrophage
Pannus
PMN
B cell
Cytokine
Inflamed
synovial membrane
Bone
Eroding cartilage
Cellular Interactions in the Rheumatoid Synovium
• Inflammation
• Acute phase protein synthesis
• Cachexia
IL-1
TNF
IL-6
IL-8
Antigen
Macrophage
T cell
Rheumatoid
Factor
production
B cell
differentiation
and activation
Lymphocyte
Plasma
cells
IL-2
IFN
Other cytokines
Antibody
production
RHEUMATOID ARTHRITIS
Disease Progression
Normal Knee Joint
Bone
Cartilage
Capsule
Early Rheumatoid Arthritis
Neutrophils
Synovial
Membrane
Hyperplastic
Synovial
Membrane
Synoviocytes
Capillary Formation
Hypertrophic
Synoviocyte
Established Rheumatoid Arthritis
T Cells B Cells
Neutrophils
Plasma Cell
Synovial Villi
Extensive
Angiogenesis
Eroded Bone
Pannus
RHEUMATOID ARTHRITIS
Cytokine Signaling Pathways
Involved in Inflammatory Arthritis
RHEUMATOID ARTHRITIS
Cytokine Signaling Pathways
Involved in Inflammatory Arthritis
RHEUMATOID ARTHRITIS
Cytokine Signaling Pathways
Involved in Inflammatory Arthritis
RHEUMATOID ARTHRITIS
Articular manifestations - hands
•
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 ARTHRITIS
Presenting Signs and Symptoms
– Symmetric joint pain
– Swelling of small peripheral
joints
– Morning joint stiffness of
variable duration
– Other diffuse aching
• Fatigue, malaise, and depression
may precede other symptoms
by weeks or months
Grassi W et al. Eur J Radiol. 1998;27(suppl 1):S18–S24.
RHEUMATOID ARTHRITIS
Laboratory Findings
– Chemistries normal, except slight  in albumin,  total
protein, and  iron
– Hematologic findings
• Mild anemia in 25% to 35% of patients
• Normal or slight  in white cell count
• Thrombocytosis
• eosinophilia
RHEUMATOID ARTHRITIS
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 patients
RF titers correlated with disease severity and extraarticualr 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
Rheumatoid Factor
• Methods of detection
– agglutination
IgG coated latex beads or erythrocytes
– laser nephelometry
– indirect immunofluorescence
– radioimmuno assay
– enzyme-linked immunosorbent assay
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
RHEUMATOID ARTHRITIS
Disease associated with +RF
•
Autoimmune diseases
– rheumatoid arthritis
– systemic lupus erythematosus
– scleroderma
– mixed connective tissue disease
– Sjogren’s syndrome
RHEUMATOID ARTHRITIS
Disease associated with +RF
•
Viral disease
– AIDS
– mononucleosis
– hepatitis
– influenza
RHEUMATOID ARTHRITIS
Disease associated with +RF
• Parasitic infections
– trypanosomiasis
– malaria
– Kala-azar
– schistosomiasis
– filariasis
RHEUMATOID ARTHRITIS
Disease associated with +RF
• Chronic bacterial infections
– tuberculosis
– syphilis
– leprosy
– brucellosis
– yaws
– salmonellosis
– Infective endocarditis
RHEUMATOID ARTHRITIS
Disease associated with +RF
• 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. Arthritis Rheum. 1988;31:315–324.
Must be present
for at least 6 weeks
RHEUMATOID ARTHRITIS
Radiological 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 nodules
• Nodules occur in about 20-50%
of patients with RA and are
usually associated with high
titers of rheumatoid factor.
• Subcutaneous nodules are also
seen in other conditions such as
SLE and mixed connective tissue
disease.
• Methotrexate may enhance
development.
• 2010 Rheumatoid Arthritis Classification Criteria
An American College of Rheumatology/European League Against
Rheumatism
Collaborative Initiative
Daniel Aletaha,1 Tuhina Neogi,2 Alan J. Silman,3 Julia Funovits,1 David T. Felson,2
Clifton O. Bingham, III,4 Neal S. Birnbaum,5 Gerd R. Burmester,6 Vivian P. Bykerk,7
Marc D. Cohen,8 Bernard Combe,9 Karen H. Costenbader,10 Maxime Dougados,11
Paul Emery,12 Gianfranco Ferraccioli,13 Johanna M. W. Hazes,14 Kathryn Hobbs,15
Tom 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.
RHEUMATOID ARTHRITIS
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 of
joint damage lessened with early diagnosis and treatment
Albers JMC et al. Ann Rheum Dis. 2001;60:453–458.
Grassi W et al. Eur J Radiol. 1998;27(suppl 1):S18–S24.
RHEUMATOID ARTHRITIS
Severity of Arthritis
Clinical Course of RA
4
Type 1
Type 2
Type 3
2
0
0 0.5 1
2
3
4
Years
6
8
16
Type 1 = Self-limited—5% to 20%
Type 2 = Minimally progressive—5% to 20%
Type 3 = Progressive—60% to 90%
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
TREATMENT OF RHEUMATOID ARTHRITIS
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
TREATMENT OF RHEUMATOID ARTHRITIS
Measurement of Treatment Effects
– Clinical assessment of
inflammatory synovitis
• Swollen joint count,
tender joint count
– Laboratory assessment
of inflammatory synovitis
• Acute phase reactants
(eg, ESR, CRP)

Assessment of physical function
– Stanford Health Assessment
Questionnaire (HAQ)
– Short-Form 36 Health Survey
(SF-36)

Assessment of structural joint
damage
– Radiography (ultrasound and
magnetic resonance imaging)
ACR ad hoc Committee on Clinical Guidelines. Arthritis Rheum. 1996;39:713–722.
Grassi W et al. Eur J Radiol. 1998;27(suppl 1):S18–S24.
TREATMENT OF RHEUMATOID ARTHRITIS
ACR Response Criteria
ACR20 / 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. Arthritis Rheum. 1995;38:727–735.
Felson DT et al. Arthritis Rheum. 1998;41:1564–1570.
TREATMENT OF RHEUMATOID ARTHRITIS
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 using
Ritchie 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 activity >3.7, low disease activity 2.4, remission <1.6
TREATMENT OF RHEUMATOID ARTHRITIS
EULAR Response Criteria
Decrease in DAS
Present Score
>1.2
DAS  2.4
Good
2.4 < DAS  3.7
DAS > 3.7
>0.6 to 1.2
0.6
Moderate
None
EULAR = European League Against Rheumatism; DAS = Disease activity score.
van Gestel AM et al. Arthritis Rheum. 1996;39:34–40. Copyright © 1996 American College of
Rheumatology. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.
Activated T cells
Chronic Inflammation in the
Rheumatoid Synovium
Pannus
Macrophage
& DCs
PMN
B cell
Cytokine
Inflamed
synovial membrane
Bone
Eroding cartilage
Chronic Inflammation in the
Rheumatoid Synovium
Activated T cells
Macrophage
& DCs
B cell
Cyclosporine
Azathioprine
Cyclophosphamide
PMN
Cytokine
Rituximab
Anti-cytokines
Inflamed
synovial membrane
Anti-MMPs
Eroding cartilage
Pannus
Bone
Drugs used in RA
“Symptomatic” treatment
–simple analgesics
–NSAIDs/ COX inhibitors
–(glucocorticoids)
Disease modifying agents
 Glucocoticoids
 Gold
 Antimalarials
 Sulfasalazine
 Methotrexate
 Immunosuppressives
 Anti-Cytokines
• -Halt or prevent joint
• damage
• -Preserve joint
integrity
• and function
• -Slow acting
• -Toxicity problems
Biologics
• Anti-TNF: Infliximab, Etanercept,
Humira
• Anti-IL1b
• Anti-IL-6
• Anti-CD20, rituximab
• Anti Jak-Stat signaling
• Others
TNF
osteoclasts
synoviocytes
chondrocytes
bone resorption
joint
inflammation
cartilage
degradation
bone erosion
pain/joint
inflammation
joint space
narrowing
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
Mean change from BL
12
12.6
10
*p < 0.001 vs placebo + MTX
8
6
4
1.0*
2
1.0*
1.1*
0
 0.4*
Placebo
Lipsky.NEMJ 343: 1594, . 2000.
3 mg/kg
q 8 wk
3 mg/kg
q 4 wk
10 mg/kg
q 8 wk
10 mg/kg
q 4 wk
ATTRACT Trial
Mean Improvement HAQ (102 Week)
Change in HAQ
.6
.5*
.5
.5*
.4*
.4
.4*
.3
.2
.2
.1
0
*p<.001
Placebo
Lipsky.NEMJ 343: 1594, . 2000.
3 mg/kg
q 8 wk
3 mg/kg
q 4 wk
10 mg/kg
q 8 wk
10 mg/kg
q 4 wk
• 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
80
ACR20
% patients
70
60
50
ACR50
40
30
ACR70
20
10
0
0
6
12
18
24
30
36
42
Months
Moreland. Arthritis Rheum. 2000.
Change in Total Sharp Scores and Erosions
Over Two Years
Change from baseline (mean)
Etanercept 25 mg
Methotrexate 20 mg
Total Sharp Scores
4
Erosions
4
*
3
3
2
2
1
1
0
0
0
6
12
18
24
*
0
12
18
24
Months
Months
*p = 0.001
6
*p = 0.001
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
Open-label
TCZ 8mg/kg
Double-blind
N=1196
Randomization
1:1:1
R
All other
DMARDs D/C
anti-TNF
washout
Optional
Extension Years
3–5
or double-blind
TCZ 8 mg/kg
+ MTX (n=399)
TCZ 4 mg/kg
+ MTX (n=399)
Openlabel
Placebo
+ MTX (n=392)
Day 1
Rescue
1 Year
2 Year
Screening
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
Results: Tocilizumab significantly inhibits radiographic
progression at 2 years
Placebo
+ MTX (n=393)
TCZ 8 mg/kg
+ MTX (n=398)
p≤0.0025*
1.96
p≤0.0239*
1.8
80
75
1.6
70
1.4
81%
1.2
inhibition
1.0
0.8
0.6
0.4
p≤0.0025*
0.58
p≤0.0025*
0.37
Patients without GmTSS
progression (%)
90
2.0
Mean change from
baseline in GmTSS
TCZ 4 mg/kg
+ MTX (n=398)
66
60
50
40
30
20
0.2
10
0.0
0
GmTSS = Genant-modified total Sharp score
Linear extrapolation used for missing data (post-rescue data set to missing)
* vs. placebo + MTX
83
Oral #637
Results: DAS28 remission* rates increase
over time in MTX-IR patients
TCZ
8 mg/kg + MTX (n=275)
70
TCZ
8 mg/kg + MTX (n=241)
65
60
Patients (%)
50
48
40
30
20
10
0
Week 52
*DAS28 <2.6
Last observation carried forward approach used for SJC and TJC for patients who
received rescue therapy or withdrew from that time point
Week 104
Oral #637
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)
Discontinuations due to AEs per 100 PY
SAEs per 100 PY
9,414
5.8
14.91
Serious infections per 100 PY
4.7
Deaths per 100 PY
0.53
Deaths from infection per100 PY
0.13
PY = patient-years
SAE = 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