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BIOMARKERS TO GUIDE TREATMENT IN RA

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The 1rst Kuwait-North American Update in Internal Medicine Conference 8-9 February 2014 BIOMARKERS TO GUIDE TREATMENT IN RA Henri A. M nard, MD, FRCP (C) – PowerPoint PPT presentation

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Title: BIOMARKERS TO GUIDE TREATMENT IN RA


1
The 1rst Kuwait-North American Update in
Internal Medicine Conference 8-9 February 2014
BIOMARKERS TO GUIDE TREATMENT IN RA
Henri A. Ménard, MD, FRCP (C) Professor of
Medicine McGill University McGill University
Health Center
2
Rheumatoid Arthritis (circa 1987)
  • Chronic progressively deforming polyarthritis
  • Extra-articular involvement (lung fibrosis,
    serositis, scleritis, nodules, vasculitis, sicca)
  • X-Ray joint damage in the 1st year in 30-50 of
    patients.
  • Permanent inability to work within 5 yrs in 40.
  • Life expectancy shortened by 3-14 yrs depending
    on the severity of the disease

Textbook
3
Prognosis
RA TEXTBOOK
???
EA/ERA Office
4
CLINICAL PROGRES
The ACR-EULAR 2010 Classification Criteria A
probabilistic approach to early diagnosis
5
1987 CRITERIA Mean Disease Duration 8 Years
Arthritis and Rheumatism 31315-24,1988
6
Goals 2010
  • In patients with undifferentiated arthritis
  • Identify those at high risk of chronicity and
    erosive damage
  • candidates for DMARD therapy
  • Not exclude patients later in the disease course

7
2010 ACR/EULAR RA CRITERIA Target population 1)
at least 1 joint with definite clinical synovitis
(swelling) 2) the synovitis is not better
explained by another disease Classification add
score of categories AD (6/10 is needed for a
definite RA) A. Joint involvement Sc
ore 1 large joint 0 2-10 large
joints 1 1-3 small joints (with or
without involvement of large joints)
2 4-10 small joints (with or without involvement
of large joints) 3 gt10 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 lt 6 weeks
0 gt 6 weeks
1
8
HYPOTHETICAL COURSE of RA
1987 Established RA
2010 Early RA
Inflammation
clinical threshold
Pre-RA
Auto-Ab
Time
9
POST-2010 PERSPECTIVES
  • New treatment approaches
  • New remission criteria
  • Aggressive Tx for less active disease
  • Societal cost of early Tx with biologicals
  • Need for local reference values for APR and
    Auto-Abs.
  • Extrapolation
  • Validation
  • Stratification
  • No erosions

10
EXPERT PANEL
12
12
KUWAIT
11
Biomarkers For Early Disease
  1. Clinical ACR-EULAR 2010 Criteria
  2. Serological Citrullinated Immune Systems

12
Studying Auto-Immune Systems
  • DIAGNOSIS

Auto-Abs Clinician
  • PROGNOSIS
  • MONITORING
  • TOOLS FOR BIOLOGY

Auto-Ags Biologist
  • PHYSIOPATHOLOGY
  • CLUES TO ETIOLOGY

Roadmap to Personalized Medicine
13
Rheumatoid Arthritis An In Vivo ELISA
Secondary Systems Amplification
Primary Systems Specificity
14
RA-Associated Auto-Immune Systems
  • Nucleus DNP/ssDNA/histones/macro-histone, LMG
    and HMG proteins, Ro (SS-A), hnRNP(s) A2/B1, etc
  • Cytoplasm intermediary filaments (vimentin,
    filaggrin, reticulin, fodrin), endoplasmic
    reticulum, chaperone(s), cytokeratin(s), etc
  • Extracellular Matrix Proteins collagen(s), GAGs,
    link protein(s), elastin, fibulin, keratin, etc
  • Enzymes and Inhibitors G6PI, PDI,
    calpastatin(s), follistatin-related protein,
    hyaluran synthase, enolase, aldolase, PADI4, MPO,
    etc
  • Others lactoferin, phospholipids, advance
    glycation endproducts (AGE), etc
  • Rheumatoid Factors poly-, oligo-, monoclonal Ig
    isotypes targeting Fc, Fab, idiotopes, paratopes,
    etc.

15
RA-Specific Immune Systems
  • A C P A s
  • Anti-Citrullinated PEPTIDE Antibodies.
  • Anti-Citrullinated PROTEINS Antibodies

16
Citrullination is the Enzymatic Conversion
of Arginine To Citrulline
The Antigen(s)
17
Citrullination A Mechanism To Recycle Aminoacids
3
1
2
4
5
18
Citrullination An Intracellular Agonic Event
  1. PADIs are present in most cells epithelial,
    fibroblast, osteoblast, endothelial, myeloid and
    dentritic cells but NOT IN LYMPHOID CELLS.
  2. Citrullination occurs during the calcium influx
    of early apoptosis. Vimentin is the first
    protein to be citrullinated in macrophages
    (Senshu). Cit-Vimentin the Sa antigen.
  3. Citrullination is thus a cellular agonic event, a
    NORMAL feature of inflammation and repair.

19
Citrullination Is Also A Secondary Extracellular
Event
Fibrin, Collagen, ANY PROTEIN
Exocytosis / Apoptosis
No known natural inhibitor
20
Five Points To Remember About Cit-Proteins/ACPAs
In Joints
  • Cit-proteins are found in all inflammed tissues
    and fluids, not CCP.
  • The PANNUS CITRULLINOME is mostly made of the Sa
    Ag (Ménard 1988) i.e. neo-Ags on Cit-VIMENTIN
    (Ménard 2004, Bang 2007, Tilleman 2008) generated
    during apoptosis and present in ACPA-containing
    immune complexes (Van Steendam 2008).
  • The SYNOVIAL FLUID CITRULLINOME is mostly made of
    cit-FIBRIN (Serre 2006, Pruijn 2006) generated
    extracellularly and present in ACPA-containing
    immune complexes (Zhao 2008).
  • The pannus is an ectopic lymphoid tissue
    producing RF, anti-AgN including ACPAs (Smiley
    1970, Serre 2000).
  • ACPAs are IgGs typical of a mature/ongoing
    polyclonal Ag-driven response (Ménard 1984,
    Schellekens 1998 and Ioan-Facsinay 2008, 10) .

21
Anti-CCP2 ELISA Designed For Screening
Populations
Ceiling effect
ULT
O.D.
ULN
Low Threshold
Anti-CCP2 Titer
van Venrooij W 2003
McGill anti-Sa vs Euroimmun anti-Sa 98.5
McGill anti-Sa vs Euroimmun anti-CCP2 94.2
Euroimmun anti-Sa vs Euroimmun anti-CCP2 92.5
22
Retrospective Study Scandinavian Blood Donors
SR Dahlqvist et al. AR 2003
23
Hypothetical Course of RA
1987 Established RA
2010 Early RA
Inflammation
clinical threshold
Pre-RA
Auto-Ab
Time
24
Prospective Study North American Natives
  • highest rates of RA in the world (2-4)
  • high rates of multicase families
  • predisposing HLA-DRB1 alleles very common
  • high levels of antibodies (RF, ACPA)

Ideal population to identify individuals at risk
25
Co-PI HA Ménard Montreal, Quebec
PI H El-Gabalawy, Winnipeg, Manitoba
26
Anti-Sa ELISA (2004) Design For Prognosis and
Monitoring Individual RA Patients
ULT
ULT
O.D.
ULN
ULN
Anti-Sa titer
Anti-CCP Titer
McGill anti-Sa vs Euroimmun anti-Sa 98.5
McGill anti-Sa vs Euroimmun anti-CCP2 94.2
Euroimmun anti-Sa vs Euroimmun anti-CCP2 92.5
27
Anti-Sa / anti-CCP2 In NAN A Prospective Study
Anti-CCP2 ELISA
9
20
79
RA
FDR
UNRELATED
0
0
51
Anti-Sa ELISA
Ioan-Facsinay A et al. (El Gabalawy H, Ménard H)
AR 2008
28
Baseline AutoAbs And Erosions After 3 years
Prospective Early RA Sherbrooke Cohort
Very Erosive (14) (n)
Erosive ( 5) (n)
Titers at Inclusion (n)
29.3 (41) 40.7 (46) 38.1 (8) 32.6 (38)
42.9 (60) 55.8 (63) 42.9 (9) 58.7
(54) plt0.05
RF (n253) Neg (140) Pos (113)
Low (21) Moderate/High (92)
31.4 (49) 39.2 (38) 36,4 (4) 39.5
(34)
42.9 (67) 57.7 (56) 54.5 (6)
58.1 (50) plt0.05
Anti-CCP2 (n253) Neg (156) Pos (97)
Low (11) Moderate/High (86)
29.2 (57) 51.7 (30) plt0.005
33.3 (6) 60.0 (24) plt0.0005
41.0 (80) 74.1 (43) plt0.0001
66.7 (12) 77.5 (31) plt0.0001
Anti-Sa (n253) Neg (195) Pos (58)
Low (18) Moderate/High (40)
Guzian C et al. (Boire G, Ménard H) ART 2010
29
Examples of Anti-CCP2 in Non-Rheumatoid Patients
  • Idiopathic inflammatory myopathy (Rheumatology
    (Oxford) 2009) from a Tertiary Care Center in
    Barcelona. 13 positive anti-CCP (75 mod-high
    titers). No arthritis, no AKA.
  • 25 positive anti-CCP in SLE from low to high
    titers. (Unpublished Ménard and Van Venroij). No
    arthritis, no anti-Sa.
  • Chronic infections like HIV (South Africa), Tb
    (India) No arthritis. Anti-CCP positive, anti-Sa
    status unknown,
  • RA-like conditions HVB or HVC with cryo, CPPD
    with hemochromatosis, Psoriatic Arthritis, IBD
    Arthritis. Some anti-CCP pos but anti-Sa always
    negative.

30
MONITORING RA WITH ANTI-Sa
CSR Clinical Serological Remission
Anti-CCP2 never changed significantly
Rotman J (Ménard HA) European Workshop Rheum Res
Toulouse 2008
31
Summary Of ACPA in Pre-RA
  • Anti-CCP and RF are present up to 15 years before
    disease onset
  • The higher the anti-CCP titres the shorter the
    time to disease onset (retrospective data).
  • Anti-Sa Abs define a sub-group of RA patients
    with higher titres of anti-CCP and higher Ig
    isotype usage MORE SEVERE
  • Anti-Sa Abs are strictly RA disease-associated,
    not anti-CCP.

32
Clinical Summary of ACPA Literature In Early and
Established RA
  • SPECIFICITY (85-100)
  • anti-Sa gtgt CCP gt MCV
  • SENSITIVITY 40 to 80 depending on test and
    patients i.e. phase of disease, age at onset,
    treatment.
  • anti-CCP MCV gt anti-Sa
  • For SCREENING
  • anti-CCP gt MCV gtgt Sa
  • more sensitive, less specific.
  • for DIAGNOSIS
  • anti-Sagtgt CCP gt MCV
  • for MONITORING
  • anti-Sa gtgt MCV gtgt CCP 0
  • ACPA are highly correlated with RF
  • 80-90 ACPA also have RF
  • 50-85 RF also have ACPA
  • 25-30 RF(-) have ACPA
  • Same in children with adult form

33
Interpretation Of The Clinical Data
ARTHRITIS
NEPHRITIS
RA
SLE
Anti-CCP
Anti-Sa
ANA
Anti-dsDNA
It is not one or the other, it is one and the
other. Ménard HA. Nature Clin Practice
Rheumatol 2007.
34
SHUKRAN ALA ALDAWAH
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