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Patient profiling and predictors of response and non-response to RA therapies

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Title: Patient profiling and predictors of response and non-response to RA therapies


1
Patient profiling and predictors of response and
non-response to RA therapies
  • Workshop 3 Chairs
  • Edward Keystone Professor of Medicine,
    University of Toronto, Toronto, Canada
  • John IsaacsProfessor of Clinical Rheumatology,
    Newcastle University, UK

2
Overview of Workshop 3
  • We will explore the use of biomarkers in patient
    profiling and prediction of response/non-response
    to RA therapies
  • How far have we come in the use of biomarkers for
    clinical diagnosis and prognosis of RA?
  • Is there any evidence that biomarkers can predict
    responsiveness to biologic therapies?
  • Can registry data identify prognostic factors for
    clinical remission?
  • How close are we to personalised medicine in
    RA?
  • Talk-show format with the Chairman as host
    and a panel of expert guests who will present
    their evidence
  • Discussion using question cards or microphones

Please note that there will be a time limitation
for the question session in order to finish each
workshop on time for the live-link summary
transmission
3
Patient profiling and predictors of response and
non-response to RA therapies
  • Introduction Session Chair Edward Keystone
  • Use of biomarkers in clinical diagnosis and
    prognosis in RA Eugen Feist
  • Biomarkers and predictors of responsiveness to
    biologics in RA John Isaacs
  • Registry evidence the Italian experience
    Gianfranco Ferraccioli
  • The demand for personalised healthcare
    Identifying theB-cell patient Philippe
    Dieudé
  • Summary Session Chair John Isaacs

4
Patient profiling and predictors of response and
non-response to RA therapies
  • Dr Edward Keystone
  • Professor of MedicineUniversity of
    TorontoToronto, Canada

5
Patient RB
  • 41 years old
  • School teacher
  • No background medical problems
  • Family history
  • Mother had osteoarthritis

6
History of joint symptoms
  • Left knee intermittent pain and swelling for
    the past 3 years
  • Swelling of the wrists and finger joints
  • EMS x 4.5 hours
  • Rx Diclofenac 50 mg tid

7
Rheumatology specialist unit referral _at_ 3 years
  • On examination
  • Mild generalised hypermobility
  • Finger joint tenderness, but no swelling
  • Left knee tenderness (medial colateral ligament)
  • Bilateral pes planus

8
Investigations and management
  • X-rays no erosions on hands and feet
  • Rheumatoid factor negative
  • ANA negative

9
Pre-rheumatoid arthritis clinic referral
  • Anti-CCP antibody
  • Using CCP2 lt7 normal 710 equivocal gt10
    abnormal
  • This patient's result was equivocal on two
    occasions (9)
  • Later, when she developed definite synovitis the
    result was 14
  • Ultrasound power Doppler

10
Summary
  • Potentially inflammatory symptoms
  • Subsequent synovitis on physical examination
    confirmed by
  • Equivocal and then positive CCP
  • Power Doppler signal MCPs on ultrasound

11
Whats the evidence?
  • When asked how confident I am about this
    patients diagnosis

12
VERY
13
Whats the evidence?
  • When asked how confident I am about this
    patients prognosis

14
I HAVE NO IDEA!
15
Use of biomarkers in clinical diagnosis and
prognosis of RA
  • Dr Eugen Feist
  • Department of Rheumatology and Clinical
    Immunology Charité Universitätsmedizin,
    Berlin, Germany

16
Goal Early diagnosis and stratification
Clinical Examination
Novel Markers
Improved Imaging
ACPA
Ubiquitous
Profiling
Nienhuis et al., ARD 1964 Young et al., Br Med.
J 1979 Schellekens et al., JCI 1998
17
Anti-CCP antibodies precede disease onset
Half of patients were IgM-RF and/or anti-CCP 4.5
years (median) before the onset of disease
(0.113.8 years)
50
IgM-RF Anti-CCP IgM-RF or anti-CCP
40
30
Sensitivity (percentage positivity)
20
10
0
Years before symptoms 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1
Number of samples 3 14 25 27 40 51 67 79 89 99 115 99 120 120 130
Nielen et al. Arthritis Rheum 200450380-86
Anti-CCP, anti-cyclic citrullinated peptide
18
Half of patients with undifferentiated arthritis
develop confirmed RA at 1 year
Test Anti-CCP 1 Anti-CCP 2
Patients (n) 1327 2017
Mean disease duration at baseline, months 16 5
Median duration of follow-up, months 12 (1224) 12 (1236)
Patient anti-CCP at baseline, 23 23
Patients with confirmed RA at end of follow-up, 45 51
Patient anti-CCP at diagnosis, 46 51
Odds ratio 20 25
Avouac et al. Ann Rheum Dis 200665845851
19
Structural comparison of CCP and mutated
citrullinated vimentin (MCV)
CCP synthetic peptides of app. 20 AA (1 - 2
potential epitopes)
Human Vimentin recombinant protein of 54 kD and
app. 45 arginins modified by enzymatic
deimination and mutation e.g. STRSVSSSSYXXMFR TYS
LGSALRPSTSXSLYASSPXR GPGTASRPSSSR
X Citrullination (Arg--gtCitr) R
g/c-Transversion (Gly--gtArg) X
g/c-Transversion (Gly--gtArg) and citrullination
(Arg--gtCitr) G,T New tryptic cleavage site
caused by g/c-Transversion
Bang et al., Arthritis Rheum 2007
20
Comparison of autoantibodies against
citrullinated antigens
Anti-MCV ELISA Anti-CCP ELISA
RA (n 1151) positive 950 831
Healthy (n232) positive 4 8
Specificity () 98 96
Sensitivity () 82 72
Correlation to DAS28 (ESR) 0.4038 (P lt0.0001) 0.0968 (P 0.1873)
Bang et al., Arthritis Rheum 2007
21
Anti-MCV in early RA Higher sensitivity and
extended prognostic value
  • 273 patients with early RA
  • Anti-MCV Sensitivity 70.7 Specificity 95
  • Anti-CCP Sensitivity 57.9 Specificity 96
  • Anti-MCV predictive for high disease activity

10
7.5

SJC
5



p lt 0.01 p lt 0.001

2.5
0
0
3 months
1 year
2 years
3 years
5 years
Mathsson et al., Arthritis Rheum 2008
22
Anti-MCV in early RA Higher sensitivity and
extended prognostic value
TJC
DAS28
10
8
6
6
5
4
4




3
2
2
0
1
0
3 months
1 year
2 years
3 years
5 years
3 months
1 year
2 years
3 years
5 years
0
P lt 0.05 P lt 0.01
Mathsson et al. Arthritis Rheum 200858(1)3645.
23
Anti-MCV appears to perform better than anti-CCP
in identifying poor radiological prognosis in
early RA
Increase in Larsen score (2 years) p-value
RF 7.25 0.0258
RF- 6.25 0.0258
Anti-CCP 7.375 0.0126
Anti-CCP- 6.25 0.0126
Anti-MCV 7.5 0.0034
Anti-MCV- 5.25 0.0034
Mann-Whitney U test
Mathsson et al., Arthritis Rheum 2008
24
Decrease in anti-CCP titres reported to be
associated with treatment efficacy
Evolution of anti-CCP titres in
adalimumab-treated patients
NS
ND
P0.001
NS
Anti-CCP titre
Atzeni, et al. Arthritis Res Ther. 20068(1)R3.
25
Analytic precision and diagnostic performance of
different anti-CCP assays
Manufacturer Cut-off (units) Sensitivity (95 CI) Sensitivity (95 CI) Specificity (95 CI) Specificity (95 CI)
Aesku 68 60 0.4970.696 89.1 0.8390.930
Astra 11 61 0.5070.706 92.6 0.8800.957
Axis-Shield 5 71 0.6000.787 97 0.9570.996
Eurodiagnostica 25 75 0.6530.831 97 0.9360.989
Euroimmun 5 73 0.6320.813 98.5 0.9570.997
Genesis 6.2 61 0.5070.706 94.6 0.9040.972
Inova 2 20 66 0.5580.751 97 0.9360.989
Inova 3.0 20 73 0.6320.813 96 0.9130.982
Inova 3.1 50 74 0.6420.822 89.6 0.8450.934
Orgentec 20 72 0.6210.805 93.1 0.8860.961
Phadia 10 74 0.6420.822 98.5 0.9570.996
Bizzaro et al., Clin Chem 2007
26
Novel rapid point of care tests
  • Comparison of CCPoint and standard CCP2-ELISA in
    109 RA, 351 non-RA, 420 HD
  • CCPoint test was fast, valid and reliable
    (sensitivity specificity 95)
  • Comparison of RheumaChec and standard MCV-ELISA
    in 80 RA, 83 non-RA and 200 HD
  • Sensitivity of MCV patients in whole blood 70.2
    (serum 94.7) and specificity 98.9

Snijders GF et al., Scand J Rheumatol 2008
27
Autoantibodies as prognostic markers in RA
RF
CCP/MCV
App. 70
Erosive manifestation
Seropositive
App. 30
Mild manifestation
Seronegative
28
Summary
  • Anti-CCP antibodies precede RA occurrence
  • Citrullination modifies potential autoantigens
    and likely plays an important role in the
    pathogenesis of RA
  • Detection of anti-CCP significantly improves the
    diagnosis of early RA
  • Anti-CCP and anti-MCV immunoassays provide a
    comparable diagnostic sensitivity and specificity

29
What does this mean for Eds patient?
  • Anti-CCP provides a high diagnostic probability
    in an RF-negative patient with undifferentiated
    arthritis

30
(No Transcript)
31
Biomarkers and predictors of responsiveness to
biologics in RA
  • Professor John Isaacs
  • Professor of Clinical RheumatologyNewcastle
    UniversityNewcastle, UK

32
What evidence is available that response to
therapy can be predicted?
  • TNF inhibitors
  • Rituximab

33
Predictors of responsiveness to TNF inhibitors
  • Clinical factors
  • Serological biomarkers
  • Genetic biomarkers

34
Clinical factors that predict responsiveness to
TNF inhibitors
  • n2879 (1267 ETA, 1612 INF)
  • Poorer response
  • higher baseline HAQ
  • current smoker (INF, OR 0.77 CI 0.600.99)
  • Better response
  • current use of NSAIDs
  • current use of MTX (ETA, OR 1.82 CI 1.382.40)

35
RF, anti-CCP and genetic variants Association
with response to TNF inhibitors
  • n642 (278 ETA, 296 INF, 68 ADA)
  • RF and anti-CCP negativity associated with better
    response
  • SE, PTPN22 status not associated with response
  • Females less likely to achieve remission

Potter C et al. Ann Rheum Dis. 20096869-74.
Epub 2008 Mar 28
36
Autoantibodies in TNF inhibitor treated RA
patients
Predictor n () Mean DAS score (SD) Mean DAS score (SD) Association
Predictor n () Baseline Improvement Association
RF -ve 59 (11) 6.72 (1) 3.03 (1.7) p0.02
RF ve 462 (89) 6.59 (1) 2.43 (1.5) p0.02
Anti-CCP -ve 96 (18) 6.61 (1) 2.90 (1.6) p0.02
Anti-CCP ve 425 (82) 6.61 (1) 2.40 (1.5) p0.02
Analyses were performed in 521 patients for whom
serum samples were available. p-values stated are
for linear regression, adjusted for concurrent
DMARD, gender, baseline HAQ and DAS28 score.
Potter C et al. Ann Rheum Dis. 20096869-74.
Epub 2008 Mar 28
37
Response to TNF inhibitors may decline with
increasing anti-CCP titre
  • 236 etanercept patients
  • CCP ve lt50 u/mL CCP ve gt50 u/mL lt1600
    u/mL CCP high ve gt1600 u/mL
  • CCP high 27 of population

Etanercept EULAR responses according to CCP status
90
80
70
60
Patients ()
EULAR no response
50
EULAR response
40
30
20
10
0
CCP -ve
CCP ve
CCP high ve
Drynda S et al. ACR 2008
38
Genetic factors in anti-TNF treatment response
Candidate genes Studies
TNF 15 studies mostly -308 SNP
SE and extended MHC 6 studies
TNFR2 5 studies exon 6 Met196Arg SNP
TNFR1 1 study exon 1 Pro12Pro SNP
Fc?R3a 2 studies Val158Phe SNP
Other cytokines/receptors 1 or 2 studies each
  • Results are inconsistent and inconclusive
  • Small sample sizes and limited power (n50300)
  • Varied designs (e.g. TNF inhibitor, disease,
    outcome)
  • Investigate individual polymorphisms

39
Example TNF-308 promoter SNP
Study Samples Drug Outcome (month(s)) Association
Miceli-Richard et al 2008 354 French ADA ACR (3) Haplotype
Ongaro et al 2008 105 Italian All 3 ACR (3, 6, 12) No
Pinto et al 2008 113 Spanish INF DAS28 (8) No
Guis et al 2007 86 French ETA DAS28 (6, 12) Yes
Cuchacovich et al 2006 70 Chilean ADA Both (2, 4, 6) No
Lee et al 2006 311 Mixed All 3 Both (mixed) Yes
Seitz et al 2006 86 Swiss All 3 DAS28 (6) Yes
Marotte et al 2006 198 French INF ACR (8) No
Maxwell et al 2008 1041 British INF, ETA DAS28 (6) Yes
Performed multivariate and haplotype analyses
Meta-analysis incorporating 6 additional
studies Study involved RA, PsA and AS
40
Predictors of responsiveness to rituximab
  • Serological biomarkers learnings from
  • The DANCER study
  • The REFLEX study

41
Dose-ranging Assessment iNternational Clinical
Evaluation of Rituximab in RA (DANCER)
Emery et al 2006. Arth Rheum 2005541390-400
42
DANCER study ACR responses at 6 months RF
ve vs RF -ve patients, ITT
Roche, data on file
43
DANCER study Placebo-adjusted ACR responses at
6 months RF ve vs RF -ve patients
RF positive
RF negative
Roche, data on file
44
A Randomised Evaluation oF Long-term Efficacy of
rituXimab in RA (REFLEX)
Cohen S et al. Arthritis Rheum 2006542793-806
45
REFLEX study ACR responses at Week 24 in RFve
vs RF-ve patients (ITT)
RF positive (ITT) RF negative (ITT)
plt0.0001
54
plt0.0009
41
plt0.0001
29
NS
19
plt0.0001
17
p0.045
13
12
9
6
5
2
0
ACR20 ACR50 ACR70
ACR20 ACR50 ACR70
ACR20 ACR50 ACR70
ACR20 ACR50 ACR70
Placebo (n160)
Rituximab 1000 mg x 2 (n160)
Rituximab 1000 mg x 2 (n64)
Placebo (n41)
Cohen et al, 2006 Smolen et al. 2006
46
REFLEX study Placebo-adjusted ACR responses at
Week 24 in RFve vs RF-ve patients (ITT)
RF positive (ITT) RF negative (ITT)
Patients ()
Rituximab 1000 mg x 2 (n234)
Rituximab 1000 mg x 2 (n64)
Cohen et al, 2006 Smolen et al. 2006
47
REFLEX study ACR responses at Week 24 according
to RF and anti-CCP status
RF and/or anti-CCP positive
RF negative and anti-CCP negative
Patients ()
ACR20 ACR50 ACR70
ACR20 ACR50 ACR70
ACR20 ACR50 ACR70
ACR20 ACR50 ACR70
Placebo (n107)
Rituximab (n157)
Rituximab (n29)
Placebo (n16)
Tak et al, ACR 2006
48
REFLEX study Placebo-adjusted ACR responses at
Week 24 according to RF and anti-CCP status
RF and/or anti-CCP positive
RF negative and anti-CCP negative
Patients ()
Rituximab (n157)
Rituximab (n29)
Cohen et al, 2006 Smolen et al. 2006
49
REFLEX Study 56 week radiographic outcomes
seropositive subgroups
RF and/or anti-CCP positive
RF negative and anti-CCP negative
P0.0085
P0.0225
P 0.0018
Roche, data on file
50
Summary
  • Conflicting reports of association between TNF
    polymorphisms and clinical response to TNF
    inhibitors
  • Rituximab shows consistent association with RF
    and/or anti-CCP as the biomarkers predictive of
    clinical response
  • RA patients who are seropositive (RF and/or
    anti-CCP) appear to have an enriched response to
    rituximab

51
The FUTURE
  • Data from SERENE, MIRROR and IMAGE studies of
    rituximab will provide an additional opportunity
    to assess serological biomarker association with
    clinical response
  • Further studies of biomarkers with the range of
    biological therapies are warranted to fully
    assess their potential role in predicting response

52
What does this mean for Eds patient?
  • Seropositivity suggests a better outcome with
    rituximab

53
(No Transcript)
54
Registry evidence the Italian experience
  • Professor Gianfranco Ferraccioli
  • Professor of RheumatologyDirector Division of
    RheumatologySchool of MedicineCatholic
    University of the Sacred HeartRome, Italy

55
Evidence for prognostic factors for clinical
remission
  • This presentation will review
  • Remission data across countries
  • Evidence from databases
  • The Italian experience GISEA and other studies

GISEA,Gruppo Italiano per lo Studio delle Early
Arthritis
56
Treatment of RA aims at
REMISSION
What are the clinical predictors of response to
therapy and remission?
  • Baseline patient characteristics

57
Remission and RA Data for patients receiving
usual care (conventional DMARDs) in 24 countries
5,848 patients receiving usual care at 67 sites
in 24 countries
25
ACR
19.6
DAS28
20
Remission ()
CDAI
13.8
15
8.6
10
5
0
Sokka T et al. Arthritis Rheum 2008582642-51
58
Prognostic factors of clinical remission on
DMARDs The Quest-RA study
No. patients 5848 Clinical evidence in database No. patients 5848 Clinical evidence in database No. patients 5848 Clinical evidence in database
Baseline variables OR (95 CI)
Sex, female 0.47 (0.390.55)
Disease duration 0.98 (0.970.99)
No. comorbidities 0.76 (0.700.82)
Sokka T et al. Arthritis Rheum 2008582642-51
59
Treatment of RA aims at
REMISSION
What are the clinical predictors of response to
rescue therapy for DMARDs failure, and remission?
  • Baseline patient characteristics
  • Biomarkers

60
Prognostic factors for clinical remission with
TNF inhibitors The GISEA study
Mancarella L et al. J Rheumatol 2007341670-73
GISEA,Gruppo Italiano per lo Studio delle Early
Arthritis
61
Characteristics of 591 patients with RA at
baseline
Variables Variables
Women () 404 (67)
Age (years) 53.3 12.7
Age at diagnosis (years) 41.5 13.7
Duration of disease (years) 11.6 7.6
Swollen joints (n) 10.4 7.1
Tender joints (n) 17.1 9.4
HAQ score 1.63 0.6
DAS28 5.9 1.2
ESR (mm/h) 41.2 25.0
Patients taking steroids 49
(median mg, range) 5 (17.5)
CRP positivity 72.4
RF positivity ( patients) 79
CRPgt5 mg/L RFgt20 IU/ml. DAS, Disease Activity Score ESR, erythrocyte sedimentation rate HAQ, Health Assessment Questionnaire RF rheumatoid factor. CRPgt5 mg/L RFgt20 IU/ml. DAS, Disease Activity Score ESR, erythrocyte sedimentation rate HAQ, Health Assessment Questionnaire RF rheumatoid factor.
Mancarella L et al. J Rheumatol 2007341670-73
62
Characteristics of patients at baseline
according to RF status
Variables RF positivity RF negativity p-value
(n467) (n124)
Sex, women 66 70
Age (years) 53.6 12.9 53.1 12.8 0.63
Age at diagnosis (years) 41.8 13.5 41.1 15.0 0.73
Duration of disease (years) 11.8 7.5 12.0 8.1 0.87
Swollen joints (n) 10.6 7.4 9.3 6.1 0.15
Tender joints (n) 17.4 9.5 15.4 8.8 0.05
HAQ score 1.7 0.7 1.5 0.6 0.04
DAS28 6.0 1.2 5.7 1.1 0.02
ESR (mm/h) 41.5 4.5 39.9 7.2 0.40
CRP (mg/L) 22.6 24.8 19.6 22.9 0.06
C-reactive protein positivity CRPgt5 mg/L
Mancarella L et al. J Rheumatol 2007341670-73
63
Prognostic factors for clinical remission with
TNF inhibitors
No. patients 591 Clinical evidence in database No. patients 591 Clinical evidence in database No. patients 591 Clinical evidence in database
Baseline variables OR (95 CI)
Age (53 years) 0.64 (0.440.94)
HAQ score (1.63) 0.56 (0.380.83)
RF (positivity) 0.61 (0.390.96)
Sex (female/male) 24 vs 36 p0.03
  • Hosmer-Lemeshow test p0.935. Hosmer-Lemeshow
    test p0.554.

Mancarella L et al. J Rheumatol 2007341670-73
64
Significantly better EULAR responses on
follow-up in RF-negative patients
EULAR response RF-positive patients RF-negative patients p-value
n () n ()
Good 164 (37) 60 (50) 0.01
Moderate 241 (37) 45 (54) 0.001
Remission 112 (24) 43 (36) 0.03

Mancarella L et al J Rheumatol 2007341670-73
65
Is there a correlation between RF isotype and
clinical response to TNF inhibitors?
Bobbio-Pallavicini F et al. Ann Rheum Dis
200766302-7
66
Investigation of a correlation between RF
isotype and clinical response to TNF inhibitors
  • 132 patients
  • Advanced RA, DMARD-IR
  • Treated with
  • infliximab (n63)
  • etanercept (n35)
  • adalimumab (n34)
  • 1 year follow-up
  • 126 evaluable for clinical response
  • IgM, IgA and IgG rheumatoid factors and anti-CCP
    antibodies assessed

Bobbio-Pallavicini F et al. Ann Rheum Dis
200766302-7
67
Trend for higher levels of RF and anti-CCP
titres in non-responders to TNF inhibitors
Responders (n83) Non-responders (n43) p-value
RF (nephelometry), positive 83.13 (69/83) 83.72 (36/43) 1
Level 86 (15268.4) 97 (28338) 0.769
IgM RF, positive 78.31 (65/83) 83.72 (36/43) 0.638
Level 41.5 (22.1120) 67.6 (32.9295) 0.035
IgA RF, positive 61.44 (51/83) 69.76 (30/43) 0.434
Level 24.8 (10.290.8) 130.4 (13.8276.7) 0.003
IgG RF, positive 57.83 (48/83) 69.76 (30/43) 0.246
Level 24.3 (7.294.9) 46.1 (13.2210.6) 0.057
Anti-CCP, positive 72.28 (60/83) 81.39 (35/43) 0.285
Level 25.27 (2.9374.27) 35.28 (7.32114.99) 0.233
The negative RF samples were included and
counted with the measured values.
Bobbio-Pallavicini F et al. Ann Rheum Dis
200766302-7
68
High IgA RF levels are associated with poor
clinical response to TNF inhibitors
Percentage of responders
Bobbio-Pallavicini F et al. Ann Rheum Dis
200766302-7
69
Take home messages
  • Prognostic factors and predictive factors for
    clinical response and remission have been
    identified
  • Predictive factors have been delineated both in
    RCTs and in real world patients treated with TNF
    inhibitors
  • Baseline predictors HAQ, gender
  • Biomarker predictors RF, RF/CCP and high IgA
    RF levels predict a poor response to TNF
    inhibitors

Mancarella L et al J Rheumatol 2007
3416701673 Bobbio-Pallavicini et al. Ann
Rheum Dis 200766302-307 Potter C, et al Ann
Rheum Dis. 2009 Jan68(1)69-74. Epub 2008 Mar 28.
70
What does the future hold?
  • Biomarkers that can predict clinical response to
    TNF inhibitors still remain to be defined in well
    controlled, prospectively assessed cohorts of
    patients
  • Greater knowledge of predictive factors in our
    patients will enable us to develop better
    personalised treatment strategies
  • Appropriate tailored treatment will reduce
    treatment failure and stop disease progression
    more quickly

71
Conclusions
  • Biomarkers and clinical markers should be studied
    more and more to help the clinicians to tailor
    their therapeutic strategy in daily practice
  • Clinical scores and possibly some biomarkers
    could be adopted to target the therapeutic
    intervention
  • The therapeutic algorithm still needs to be fully
    defined according to the targets to treat in
    subsets of RA patients

72
Acknowledgements
  • Bari
  • Ferrara
  • Modena
  • Padova
  • Perugia
  • Ancona
  • Roma
  • Brescia
  • Milano 1
  • Milano 2
  • Verona
  • Pavia
  • LAquila
  • Palermo
  • Genova
  • Siena

73
What does this mean for Eds patient?
  • Seropositivity suggests a lower probability of a
    response to a TNF inhibitor

74
(No Transcript)
75
The demand for personalised healthcare
Identifying the B cell patient
  • Dr Philippe Dieudé
  • Rheumatology Department, University Bichat
    Hospital, Paris, France

76
Background
  • CTDs and autoimmune diseases (AIDs) share a
    common genetic background
  • HLA II
  • Non-HLA genes PTPN22, IRF5, STAT4, BANK1and
    more
  • A common genetic background could lead to an
    overlap of different autoimmune phenotypes
  • Frequency of overlap syndrome in other AIDs
  • Sjögren 25
  • Type 1 diabetes 5-20
  • SSc 23

Alarcon Segovia M. Curr Rheumatol Rep
20046(3)171-4 Hemminki K Arthritis Rheum 2009
(3)661-668 Garcia-Carrasco M. Medicine
(Baltimore) 2002 81 (4)270-280 Somers EC.
Epidemiology 200617(2)202-217 Liao KP.
Arthritis Rheumatism 2009 60(3)653-660 Avouac
J. Arthritis Rheumatism 2008 58
(9-suppl) S826
77
Objectives
  • To determine
  • Frequency of overlap syndrome in the RA
    population
  • Whether overlap syndromes are restricted to a
    particular RA subset

78
Study 1 Frequency of an  enriched 
immunological phenotype in the RA population
  • Prospective study
  • 6 months /114 patients with RA (ACR 1987
    criteria)
  • Screening of all RA patients for an  enriched 
    immunological phenotype
  • Anti-CCP, RF
  • Anti-SSA,anti-SSB
  • AI Thyroiditis
  • Anti-parietal cells
  • Anti-smooth muscle
  • Anti-DNAn
  • ACA, anti-Topo I, anti-RNP

Non-RA specific autoantibodies
79
Frequency of non-RA specific autoantibodies in
the RA population
80
Characteristics of the 55 patients with RA with
enriched immunological phenotype
Characteristic Value
Female, 82
Mean (SD) age, years 53.8 (12.3)
Mean (SD) disease duration, years 10.4 (8.2)
Erosive disease, 78
Anti-CCP, 100
RF, 85
81
Immunological phenotypes in RA patients

80.8
30.7
15.4
11.5
82
RA phenotype according to non-RA- specific
autoantibody status
83
Frequency of overlapping autoimmune diseases
38
Frequency of overlapping AID in the global RA
sample 18
84
Study 2 Screening patients with RA for
overlapping autoimmune diseases
  • Prospective study (18 months)
  • 334 patients with RA
  • 2 Rheumatology Departments (Cochin Bichat
    University Hospital, Paris)
  • 117 patients included (35)
  • RA ACR 1987 criteria
  • Diagnosis criteria for another AID
  • 21 currently treated with rituximab

85
Characteristics of the 117 patients with RA with
overlapping AID
Characteristic Value
Female, 88
Mean (SD) age, years 56.7 (11.3)
Mean (SD) disease duration, years 14.3 (9.7)
Erosive disease, 78
Anti-CCP, 92
RF, 88
86
Distribution of overlapping AID in the RA
population

87
Distribution of overlapping AID in the RA
population
88
RA phenotype according to the overlap syndrome
Plt0.001
Plt0.004
89
Summary
  • Co-occurrence of other AIDs with RA is frequent
    (1835)
  • A particular RA phenotype
  • No statistical significant difference between RA
    patients with overlapping AIDs and those without
  • Erosions
  • Mean age at onset
  • Mean disease duration
  • Significant difference
  • Anti-CCP and RF positive status
  • High anti-CCP production

90
Questions and Perspective (1)
  • Do these RA patients have a  strong  B
    cell-driven disease?
  • Anti-CCP and RF
  • High anti-CCP production
  • Other autoantibodies

91
Questions and Perspective (2)
  • Influence of anti-CCP status in RTX response?
  • Unclear
  • Which isotype?
  • Low anti-CCP IgM patients responded better to RTX
  • Anti-CCP IgM production is related to CD20-,
    CD79a B cell
  • Re-analyse RTX responses according to
  • Anti-CCP status
  • Qualitative anti-CCP status (isotype)
  • Quantitative anti-CCP status

Tak PP.et al Arthritis Rheum 2006 54 Supl9 S368
Teng YKO et al. Arthritis Rheum 2007
56(12)3909-3918)
92
Questions and Perspective (3)
  • Is rituximab more efficient in this particular RA
    patient segment?
  • Our studies were not designed to detect such
    effect
  • Re-analyse RTX response according to
  • Enriched immunological phenotype
  • Overlapping AIDs
  • Personal experience of overlapping AIDs with RA
  • All were responders (EULAR)
  • 79 received a 2nd course of RTX, 54 a 3rd
    course

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What does this mean for Eds patient?
  • There is not enough biomarker data for this
    patient to suggest an overlapping AID

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Patient profiling and predictors of response and
non-response to RA therapies
  • Workshop Summary
  • John Isaacs
  • Professor of Clinical Rheumatology, Newcastle
    University, UK

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Exploring the use of biomarkers in patient
profiling and prediction of response/non-response
to RA therapies
97
How far have we come in the use of biomarkers for
clinical diagnosis and prognosis of RA?
Conclusions
  • Anti-CCP antibodies can be detected prior to RA
    occurrence
  • Detection of anti-CCP significantly improves the
    diagnosis of early RA
  • Citrullination modifies potential autoantigens
    and plays an important role in the pathogenesis
    of RA
  • Anti-CCP and anti-mutated citrullinated vimentin
    (MCV) immunoassays have comparable diagnostic
    sensitivity and specificity

98
Is there any evidence that biomarkers can predict
responsiveness to biologic therapies?
Conclusions
  • Conflicting reports of association between TNF
    polymorphisms and clinical response to TNF
    inhibitors
  • Rituximab shows consistent association with RF
    and/or anti-CCP as the biomarkers predictive of
    clinical response
  • RA patients who are seropositive (RF and/or
    anti-CCP) appear to have an enriched response to
    rituximab

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REFLEX study Placebo-adjusted ACR responses at
Week 24 according to RF and anti-CCP status
RF and/or anti-CCP positive
RF negative and anti-CCP negative
Patients ()
Rituximab (n157)
Rituximab (n29)
Cohen et al, 2006 Smolen et al. 2006
100
REFLEX Study 56 week radiographic outcomes
seropositive subgroups
RF and/or anti-CCP positive
RF negative and anti-CCP negative
P0.0085
P0.0225
P 0.0018
Roche, data on file
101
Can RCT and registry data identify prognostic
factors for clinical remission? Conclusions
  • Yes prognostic for clinical response and
    remission have been identified, but require
    further investigation
  • TNF inhibitors
  • Baseline predictors HAQ, gender
  • Biomarker predictors RF, RF/CCP and high IgA
    RF levels predict a poor response to TNF
    inhibitors
  • Biomarkers that can predict good clinical
    response to TNF inhibitors still remain to be
    defined

102
Prognostic factors for clinical remission with
TNF inhibitors
No. patients 591 Clinical evidence in database No. patients 591 Clinical evidence in database No. patients 591 Clinical evidence in database
Baseline variables OR (95 CI)
Age (53 years) 0.64 (0.440.94)
HAQ score (1.63) 0.56 (0.380.83)
RF (positivity) 0.61 (0.390.96)
Sex (female/male) 24 vs 36 p0.03
  • Hosmer-Lemeshow test p0.935. Hosmer-Lemeshow
    test p0.554.

Mancarella L et al. J Rheumatol 2007341670-73
103
Significantly better EULAR responses on
follow-up in RF-negative patients
EULAR response RF-positive patients RF-negative patients p-value
n () n ()
Good 164 (37) 60 (50) 0.01
Moderate 241 (37) 45 (54) 0.001
Remission 112 (24) 43 (36) 0.03

Mancarella L et al J Rheumatol 2007341670-73
104
High IgA RF levels are associated with poor
clinical response to TNF inhibitors
Percentage of responders
Bobbio-Pallavicini F et al. Ann Rheum Dis
200766302-7
105
How close are we to personalised medicine in
RA? Conclusions
  • Studies have shown
  • Co-occurrence of other autoimmune diseases (AIDs)
    in patients with RA is frequent (1835)
  • More common in a particular RA subset anti-CCP
    and RF

106
Frequency of overlapping autoimmune diseases
38
Frequency of overlapping AID in the global RA
sample 18
107
RA phenotype according to the overlap syndrome
Plt0.001
Plt0.004
108
Take home message
  • Biomarkers will become increasingly important in
    the management of the patient with synovitis
  • Diagnosis
  • Prognosis
  • Treatment

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