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What’s New?
APPROACH TO
RHEUMATIC DISEASES
CRITERIA, BIOMARKERS, ETC.
Sidney Erwin T. Manahan, MD FPCP FPRA
26 February 2016
DISCLOSURE
• Part of the speakers bureau for Pfizer
(Celebrex, Lyrica)
• Previously part of the speakers bureau
for Ajanta Pharma (Atenurix) and
Menarini (Ketesse)
• Received honoraria for previous
participation in clinical trials from
Roche, Wyeth and Parexel
• Received education support from
Pfizer
Awareness Campaign 2015
#WhenInGout
1977 ACR Criteria for
Acute Arthritis of GOUT
• >1 attack of acute arthritis
• Max inflammation within 24 hrs
• Attack of monoarthritis
• Joint redness
• Painful or swollen MTP1
• Unilateral attack involving the
tarsal jt
• Suspected tophus
• Hyperuricemia
• Assymmetric swelling within a
joint (XR)
• Subcortical cyst without erosions
(XR)
• Negative SF culture aspirated
during an acute episode of
arthritis
URATE CRYSTALS in joint fluid or from a tophus
OR
Any SIX (6) of the following criteria:
2014 Diagnostic Rule for GOUT
(NIJMEGEN SCORE)
FEATURES Score
Male Sex 2
Previous arthritis attack (patient reported) 2
Onset within 1 day 0.5
Joint Redness 1
Involvement of the 1st MTP (podagra) 2.5
Hypertension or >1 CV disease 1.5
Serum uric acid >5.88mg/dl 3.5
< 4 points
NON-GOUT
>4 and <8 points
UNCERTAIN
> 8 points
GOUT
Kienhorst LB, Janssens HJ, Fransen J, et al. Rheumatology (Oxford) 2014; 16 Epub.
2015 GOUT Classification Criteria
( AC R/ E U L AR )
• Joint Involvement
• Characteristics
• Typical Episodes
• Evidence of Tophus
• Serum Uric Acid
• Synovial Fluid Urate
• Imaging
• Radiographs
Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
2015 GOUT Classification Criteria
( AC R/ E U L AR )
• JOINT INVOLVEMENT
• Characteristics
• Typical Episodes
• Evidence of Tophus
• Serum Uric Acid
• Synovial Fluid Urate
• Imaging
• Radiographs
• MTP1 (2)
• Ankle/ midfoot (1)
• Other joints (0)
Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
2015 GOUT Classification Criteria
( AC R/ E U L AR )
• Joint Involvement
• CHARACTERISTICS
• Typical Episodes
• Evidence of Tophus
• Serum Uric Acid
• Synovial Fluid Urate
• Imaging
• Radiographs
DURING THE ACUTE
ATTACK
• Great difficulty using the joint
• Can’t bear touch or pressure
• Erythema
• All 3 are present (3)
• Only 2 are present (2)
• Only 1 is present (1)
• None are present (0)
Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
2015 GOUT Classification Criteria
( AC R/ E U L AR )
• Joint Involvement
• Characteristics
• TYPICAL EPISODES
• Evidence of Tophus
• Serum Uric Acid
• Synovial Fluid Urate
• Imaging
• Radiographs
THE TYPICAL GOUT ATTACK
• Maximal pain <24h
• Resolution <14 days
• Asymptomatic in between
• Recurrent attacks (2)
• One typical attack (1)
• No typical attack (0)
Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
2015 GOUT Classification Criteria
( AC R/ E U L AR )
• Joint Involvement
• Characteristics
• Typical Episodes
• EVIDENCE OF TOPHUS
• Serum Uric Acid
• Synovial Fluid Urate
• Imaging
• Radiographs
TOPHUS
• Present (4)
• Absent (0)
Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
2015 GOUT Classification Criteria
( AC R/ E U L AR )
• Joint Involvement
• Characteristics
• Typical Episodes
• Evidence of Tophus
• SERUM URIC ACID
• Synovial Fluid Urate
• Imaging
• Radiographs
URATE LEVELS (mg/dl)*
• <4 (-4)
• 4 - <6 (0)
• 6 - <8 (2)
• 8- <10 (3)
• >10 (4)
* Highest measurement, OFF urate
lowering therapy, >4 weeks from
an episode
Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
2015 GOUT Classification Criteria
( AC R/ E U L AR )
• Joint Involvement
• Characteristics
• Typical Episodes
• Evidence of Tophus
• Serum Uric Acid
• SYNOVIAL FLUID
URATE
• Imaging
• Radiographs
• NEGATIVE for MSU (-4)
• NOT DONE (0)
• POSITIVE for MSU
(SUFFICIENT CRITERION)
Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
2015 GOUT Classification Criteria
( AC R/ E U L AR )
• Joint Involvement
• Characteristics
• Typical Episodes
• Evidence of Tophus
• Serum Uric Acid
• Synovial Fluid Urate
• IMAGING
• Radiographs
IMAGING CRITERIA
• Double contour sign on US OR
urate deposition on DECT in an
affected joint
• Present (4)
• Absent / Not Done (0)
Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
2015 GOUT Classification Criteria
( AC R/ E U L AR )
• Joint Involvement
• Characteristics
• Typical Episodes
• Evidence of Tophus
• Serum Uric Acid
• Synovial Fluid Urate
• Imaging
• RADIOGRAPHS
GOUT EROSION
• Cortical break with
sclerotic margin and
overhanging edge on
hands or feet images
• Present (4)
• Absent (0)
Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
2015 GOUT Classification Criteria
( AC R/ E U L AR )
ENTRY CRITERIA
• >1 episode of joint or
bursal swelling, pain or
tenderness
SUFFICIENT CRITERIA
• Demonstration of MSU
crystals in synovial fluid or
tophus
THRESHOLD SCORE
• >8 classifies a patient as
having gout
Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
CRITERIA SET SENSITIVITY SPECIFICITY
ACR / EULAR 0.92 0.89
ACR/ EULAR (Clinical) 0.85 0.78
ACR 1977 (survey) 0.84 0.62
Rome 0.97 0.78
New York 1.00 0.78
Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
Comparison of
Criteria for GOUT
AIDS in Diagnosing Gout
Goutclassificationcalculator.auckland.ac.nz
1997 ACR CLASSIFICATION CRITERIA FOR
SYSTEMIC LUPUS ERYTHEMATOSUS
• Serositis
• Oral Ulcers
• Arthritis
• Photosensitivity
• Blood
• Renal
• ANA
• Immunologic
• Neurologic
• Malar rash
• Discoid rash
2012 SLICC CLASSIFICATION CRITERIA FOR
SYSTEMIC LUPUS ERYTHEMATOSUS
• Acute cutaneous LE
• Chronic cutaneous LE
• Oral ulcer
• Alopecia
• Synovitis
• Serositis
• Renal
• Neurologic
• Hemolytic anemia
• Leucopenia/ lymphopenia
• Thrombocytopenia
• ANA
• Anti-dsDNA
• Anti-Sm
• aPL antibodies
• Low complement
• Direct Coomb’s test
CLINICAL IMMUNOLOGIC
Petri M, Orbai AM, Alarcon GS, et al. Arth & Rheum 2012; 64 (8): 2677-86.
AT LEAST 4 CRITERIA
(1 Needs to be IMMUNOLOGIC)
Biopsy proven LUPUS NEPHRITIS and ANA or anti-DNA
2015 ACR/ SLICC Revised Criteria for
SYSTEMIC LUPUS ERYTHEMATOSUS
• ACUTE CUTANEOUS LE
– Malar rash (2)
– SCLE rash (1)
– Urticarial vasculitis (1)
– Photosensitivity (1)
• DISCOID LE (1)
• ALOPECIA (1)
• ORAL ULCERS (1)
• JOINT DISEASE (1)
• SEROSITIS (1)
• PSYCHOSIS OR SEIZURES OR
ACUTE CONFUSION STATE (1)
• KIDNEY
– Proteinuria or casts (1)
– Biopsy proven LN (2)
• HEMOLYTIC ANEMIA (1)
• THROMBOCYTOPENIA (1)
• LEUCOPENIA/ LYMPHOPENIA
(1)
• LOW TITER ANA (1)
• HIGH TITER ANA – homo/ rim
(2)
• Positive ANTI-DSDNA (2)
• Positive ANTI-SM (2)
• APL antibodies (1)
• LOW COMPLEMENT (1)
?
Salehi-Abari I. Autoimmune Dis Ther Approaches Open Access 2015; 2:114
2015 ACR/ SLICC Revised Criteria for
SYSTEMIC LUPUS ERYTHEMATOSUS
HOW WERE THE CRITERIA CREATED?
?
“You should know that after many years of
visiting the patients with SLE and studying the
literatures and evaluating of the classification
criteria of SLE in every each one of the
patients who have had a diagnosis of SLE
upon clinical/ laboratory judgement, this new
criteria can easily be created.”
Salehi-Abari I. Autoimmune Dis Ther Approaches Open Access 2015; 2:114
BIOMARKERS
in Rheumatic Diseases
DRUG DEVELOPMENT
• Identify responders
• Assess patient response
Bay-Jensen AC, Reker D, Kjelgaard-Petersen CF, et al. Osteoarth and Cart 2016; 24: 9-20. Karsdal MA, Henriksen K, Leeming DJ, et al.
Biomarkers 2009; 14: 181-202. Bauer DC, Hunter DJ, Abramson SB, et al. Osteoarth and Cart 2006; 14: 723-7.
DIAGNOSIS
PROGNOSIS MONITORING
BIPED Classification of OA Biomarkers
Burden of Disease ADAMTS4
ADAMTS5
ARGS
Autotaxin
C Col 10*
CCL3
CCL4
CD14*
CGRP
COMP*
CRPM
FGF21*
MMP1/3
Sclerostin
TNF-
Investigative C2C* CD14*
Prognosis
Predictive
CD163* hmwAPN* Leptin*
Efficacy
Diagnostic BDNF* Fib3-2*
Bay-Jensen AC, Reker D, Kjelgaard-Petersen CF, et al. Osteoarth and Cart 2016; 24: 9-20.
Utility of OA Biomarkers
Now you know, so what?
Biomarkers in Rheumatoid Arthritis
Poor Prognostic Features
• Functional disability
• Extra-articular disease
• Erosions
• ACPA Positivity
• RF Positivity
2010 ACR Classification Criteria
• Joint Involvement
• Acute Phase Reactants
• Duration of Symptoms
• Serology
– Rheumatoid Factor (RF)
– Anti- Cyclic Citrullinated Protein Antibodies (ACPA)
Monitoring in Rheumatoid Arthritis
Parameters ACR DAS28 SDAI CDAI RAPID
Pt Function + +
Pt Pain + +
Pt Global + + + +
MD Global + + +
Tender joints + + + +
Swollen joints + + + +
ESR or CRP + + +
ACR – ACR 20/50/70; DAS28 – Disease Activity Score 28 joints; SDAI – Simplified Disease Activity
Index; CDAI – Clinical Disease Activity Index; RAPID – Routine Assessment of Patient Index Data
Hobbs KF, Cohen MD. Rheumatol 2012; 51: vi21-vi27.
Targets in Rheumatoid Arthritis
Tool Remission Low Moderate High
DAS28 <2.6 2.6-3.2 3.3-5.1 >5.1
SDAI <3.3 3.4-11 12-26 >26
CDAI <2.8 2.9-10 11-22 >22
RAPID <3 3-<6 6-12 >12
Hobbs KF, Cohen MD. Rheumatol 2012; 51: vi21-vi27.
Does Remission ENSURE
Better Outcomes?
Patients who meet established
criteria for CLINICAL
REMISSION may experience
progressive structural damage.
Brown AK, Conaghan PG, Karim Z, et al. Ann Rheum Dis 2008; 58: 2958-67
Brown AK, Quinn MA, Karim Z, et al. Ann Rheum Dis 2006; 54: 3761-73
Cohen G, Gossec L., Dougados M, et al. Ann Rheum Dis 2007; 66: 358-363
Lillegraven S, Prince FH, Shadick NA, et al. Ann Rheum Dis 2012; 71:861-6
Molenaar ET, Voskuyl AE, Dirant HS, et al. Arthritis and Rheum 2004: 36-42
Developing the BIOMARKERS
Study Biomarker Patients Samples Objectives
SCREEN 130 20 20 Candidate identification
I 113 128 128 Prioritization
II 75 320 320 Prioritization
III 65 85 255 Prioritization
IV 16 119 119
New marker evaluation,
prioritization
Pilot >25 24 107 Assessment of capabilities
Training 25 708 708
Analytical validation,
development of algorithm
Centola M, Cavet G, Shen Y, et al. PLoS ONE 2013; 8(4): e60635
Biomarkers in Rheumatoid Arthritis
IL-6 Leptin
TNF R1 VEGF-A
EGF VCAM-1
SAA
YKL-40
MMP-1
MMP-3
Resistin
CRP
Biomarkers in Rheumatoid Arthritis
IL-6 Leptin
TNF R1 VEGF-A
EGF VCAM-1
SAA
YKL-40
Predicted
TJC
MMP-1
MMP-3
Resistin
CRP
Biomarkers in Rheumatoid Arthritis
IL-6 Leptin
TNF R1 VEGF-A
EGF VCAM-1
SAA
YKL-40
MMP-1
MMP-3
Resistin
Predicted
TJC
Predicted
SJC
CRP
Biomarkers in Rheumatoid Arthritis
IL-6 Leptin
TNF R1 VEGF-A
EGF VCAM-1
SAA
YKL-40
MMP-1
MMP-3
Resistin
Predicted
TJC
Predicted
SJC
Patient
Global CRP
Biomarkers in Rheumatoid Arthritis
IL-6 Leptin
TNF R1 VEGF-A
EGF VCAM-1
SAA
YKL-40
MMP-1
MMP-3
Resistin
Predicted
TJC
Predicted
SJC
Patient
Global CRP
MULTI-BIOMARKER DISEASE ACTIVITY SCORE
Computing the MBDA Score
Centola M, Cavet G, Shen Y, et al. PLoS ONE 2013; 8(4): e60635
Targets in Rheumatoid Arthritis
Tool Remission Low Moderate High
DAS28 <2.6 2.6-3.2 3.3-5.1 >5.1
SDAI <3.3 3.4-11 12-26 >26
CDAI <2.8 2.9-10 11-22 >22
RAPID <3 3-<6 6-12 >12
MBDA <25 26-29 30-44 >44
Hobbs KF, Cohen MD. Rheumatol 2012; 51: vi21-vi27.
Validation of the MBDA Score
Biomarker
Measure
Clinical Measure
Pearson’s
Correlation
P-value N
SEROPOSITIVE
MBDA Score SDAI 0.55 <0.001 148
CDAI 0.48 <0.001 148
RAPID3 0.47 <0.001 92
SERONEGATIVE
MBDA Score SDAI 0.29 <0.001 139
CDAI 0.21 0.02 139
RAPID3 0.26 0.003 127
Curtis JR, van der Helm-van Mil AH, Knevel R, et al. Arthritis Care & Res 2012; 64 (12): 1794-1803.
Monitoring with the MBDA Score
Clinical Outcome Δ MBDA Score
Change in disease activity (Spearman’s)
Baseline to FinalVisit
Δ DAS28 CRP 0.51 (P<0.001)
ACR-N ResponseCriteria 0.45 (P=0.002)
Discrimination of clinically defined response (AUROC)
Baseline to FinalVisit
Δ DAS28 CRP 0.77 (P=0.002)
ACR50 ResponseCriteria 0.69 (P=0.03)
Baseline toWeek 2
Δ DAS28 CRP 0.72 (P=0.02)
ACR-N ResponseCriteria 0.65 (P=0.11)
Curtis JR, van der Helm-van Mil AH, Knevel R, et al. Arthritis Care & Res 2012; 64 (12): 1794-1803.
How the MBDA Score Compares
% with Good Radiographic Outcome (ΔSHS <3)
Test for Remission Remission Non-Remission P-value
DAS28 CRP<2.32 80 (66/83) 71 (134/188) 0.18
MBDA<25 93 (40/43) 70 (160/228) 0.001
ACR/ EULAR 83 (25/30) 73 (175/241) 0.27
Van der Helm-van Mil AHM, Knevel R, Cavet G, et al. Rheumatology 2013; 52: 839-46.
Which was better at predicting
RADIOGRAPHIC PROGRESSION?
7
20
15
27
18
24
43
37
0
5
10
15
20
25
30
35
40
45
50
MBDA DAS28 CRP
RiskofRadiographicProgression
Remission
Low
Moderate
High
Van der Helm-van Mil AHM, Knevel R, Cavet G, et al. Rheumatology 2013; 52: 839-46.
RR 6.1
RR 1.8
P<0.05
When MBDA and DAS28 DIFFER
58
20
11
87
47
33
0
10
20
30
40
50
60
70
80
90
100
ΔSHS>0 ΔSHS>3 ΔSHS>5
RiskofRadiographicProgression
DAS28 CRP Remission
DAS 28 CRP Remission, High MBDA
Van der Helm-van Mil AHM, Knevel R, Cavet G, et al. Rheumatology 2013; 52: 839-46.
RR 1.5
(1.16, 1.85)
RR 2.28
(1.13, 3.68)
RR 3.07
(1.08, 5.47)
MBDA Score in the CAMERA Study
MBDA
Score
DAS28 CRP
Baseline At 6 Months
Low Moderate High Low Moderate High
Low 0 1 4 9 3 2
Moderate 0 8 5 7 7 4
High 0 15 40 2 4 10
K (95% CI) 0.23 (-0.03, 0.48) 0.32 (0.11, 0.53)
Weighted K 0.20 (0.01, 0.39) 0.39 (0.02, 0.76)
Pearson Correlation (r) = 0.72 (p <0.001)
AUROC = 0.86 (p <0.001)
Bakker MF, Cavet G, Jacobs JWG, et al. Ann Rheum Dis 2012; 71: 1692-97.
Baseline = 66%
AT 6 MONTHS = 54%
MBDA Score in the SWEFOT Trial
Baseline
MBDA
Score
Baseline DAS28 ESR
Low
<3.2
Moderate
>3.2-5.1
High
>5.1
TOTAL
Low
(<30)
0 0/3 0/2 0/5
Moderate
(30-44)
0 1/14 0/15 1/29
High
(>44)
0 9/51 33/150 42/201
TOTAL 0 10/68 33/167 43/235
Hambardzumyan K, Bolce R, Saevasdottir S, et al. Ann Rheum Dis 2015; 74:1102-09.
NUMERATORS – no of patients with radiographic progression (change in SHS >5)
DENOMINATORS – no o f patients meeting MBDA and DAS Scores
15% 20%
3%
21%
MBDA Score in the SWEFOT Trial
The MBDA Score at baseline was a strong predictor of radiographic
progression at 1 year among patients with early RA
Hambardzumyan K, Bolce R, Saevasdottir S, et al. Ann Rheum Dis 2015; 74:1102-09.
80
20
0
66
14
3
46
33
21
0
10
20
30
40
50
60
70
80
90
No Change in SHS Change in SHS >3 Change in SHS >5
%ofPatients
Low (<30) Moderate (30-44) High (>44)
RADIOGRAPHIC PROGRESSION:
DAS28 CRP x MBDA Score
7
16
0
20
22
7
44
28
50
0
10
20
30
40
50
60
<2.6 >2.6-<4.1 >4.1
RiskofRadiographicProgression
(ΔSHS>3)
DAS 28 CRP
Low
Moderate
High
MBDA Score
Wanying L, Sasso EH, van der Helm-can Mil AHM, et al. Rheumatology 2016; 55:357-366
MOLECULAR REMISSION
CLINICAL REMISSION
Targets in Rheumatoid Arthritis
Tool Remission Low Moderate High
DAS28 <2.6 2.6-3.2 3.3-5.1 >5.1
SDAI <3.3 3.4-11 12-26 >26
CDAI <2.8 2.9-10 11-22 >22
RAPID <3 3-<6 6-12 >12
MBDA <25 26-29 30-44 >44
Hobbs KF, Cohen MD. Rheumatol 2012; 51: vi21-vi27.
Using MBDA Score in Undiff Arthritis
100
80
60
40
20
MBDAScore
RA-RA
n=81
UA-RA
n=16
UA-UA
n=29
p=0.001 p=0.132
Maijer K, Wanying L, Sasso EH, et al. Ann Rheum Dis 2015; 74 (11): 2097-99
MBDA Score in JIA
Patients 31 children with JIA with mean duration of 5
years (RF+ / RF- /oligoarticular)
Comparison MBDA vs JADAS
Methodology Cross sectional observational study
Results • Moderate correlation between MBDA and
JADAS (r=0.68)
• Similar biomarker profile between those
with CID and controls
• Difference between CID/ controls and
active disease seen in SAA, CRP, IL6 and
MMP3
Ringold S, Lu L, Wallace CA, et al. Arthritis Rheum 2014l 66 (S3): S10-S11.
Tailoring First Line Biologic Therapy
from the Italian BiologicsTherapy (ITABIO) Board
“Any biologic may be used in the
absence of driving factors in RA.”
High Infection Risk or +LTBI
Abatacept
Tocilizumab
Etanercept
High ACPA or RF
Tocilizumab
Abatacept
High CV Risk
Etanercept
Anti-TNF inhibitors
Cost Effectivess
Etanercept
bs Infliximab
Cantini F, Nannini C, Cassara E, et al. Semin Arthritis Rheum 2015; S0049-0172.
Tailoring First Line Biologic Therapy
from the Italian BiologicsTherapy (ITABIO) Board
Anterior Uveitis / IBD
Mabs Anti-TNF
Inhibitors
High Infection Rate or +TB
Ustekinumab
Etanercept
Enthesitis, Dactylitis, Severe Skin
or Joint Symptoms
Anti-TNF inhibitors
Ustekinumab
Metabolic Syndrome or
High CV Disease Risk
Etanercept
Cantini F, Nannini C, Cassara E, et al. Semin Arthritis Rheum 2015; S0049-0172.
Spondyloarthritis / Psoriatic Arthritis
SUMMARY
• Reviewed the latest criteria on gout
and lupus
• Describe the state of biomarker
studies in OA
• Discuss the use of MBDA in RA
• Enumerated recommendations from
the ITABIO Board on tailoring first line
biologic therapy in RA/ SpA/ PsA
SLIDES would be made available
(for viewing) SOON at
RheumatologyWebsite (rheumatology.org.ph)
PersonalWebsite (phrheumajr.wordpress.com)

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Updates to the Approach to Rheumatic Disease

  • 1. What’s New? APPROACH TO RHEUMATIC DISEASES CRITERIA, BIOMARKERS, ETC. Sidney Erwin T. Manahan, MD FPCP FPRA 26 February 2016
  • 2. DISCLOSURE • Part of the speakers bureau for Pfizer (Celebrex, Lyrica) • Previously part of the speakers bureau for Ajanta Pharma (Atenurix) and Menarini (Ketesse) • Received honoraria for previous participation in clinical trials from Roche, Wyeth and Parexel • Received education support from Pfizer
  • 4. 1977 ACR Criteria for Acute Arthritis of GOUT • >1 attack of acute arthritis • Max inflammation within 24 hrs • Attack of monoarthritis • Joint redness • Painful or swollen MTP1 • Unilateral attack involving the tarsal jt • Suspected tophus • Hyperuricemia • Assymmetric swelling within a joint (XR) • Subcortical cyst without erosions (XR) • Negative SF culture aspirated during an acute episode of arthritis URATE CRYSTALS in joint fluid or from a tophus OR Any SIX (6) of the following criteria:
  • 5. 2014 Diagnostic Rule for GOUT (NIJMEGEN SCORE) FEATURES Score Male Sex 2 Previous arthritis attack (patient reported) 2 Onset within 1 day 0.5 Joint Redness 1 Involvement of the 1st MTP (podagra) 2.5 Hypertension or >1 CV disease 1.5 Serum uric acid >5.88mg/dl 3.5 < 4 points NON-GOUT >4 and <8 points UNCERTAIN > 8 points GOUT Kienhorst LB, Janssens HJ, Fransen J, et al. Rheumatology (Oxford) 2014; 16 Epub.
  • 6. 2015 GOUT Classification Criteria ( AC R/ E U L AR ) • Joint Involvement • Characteristics • Typical Episodes • Evidence of Tophus • Serum Uric Acid • Synovial Fluid Urate • Imaging • Radiographs Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
  • 7. 2015 GOUT Classification Criteria ( AC R/ E U L AR ) • JOINT INVOLVEMENT • Characteristics • Typical Episodes • Evidence of Tophus • Serum Uric Acid • Synovial Fluid Urate • Imaging • Radiographs • MTP1 (2) • Ankle/ midfoot (1) • Other joints (0) Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
  • 8. 2015 GOUT Classification Criteria ( AC R/ E U L AR ) • Joint Involvement • CHARACTERISTICS • Typical Episodes • Evidence of Tophus • Serum Uric Acid • Synovial Fluid Urate • Imaging • Radiographs DURING THE ACUTE ATTACK • Great difficulty using the joint • Can’t bear touch or pressure • Erythema • All 3 are present (3) • Only 2 are present (2) • Only 1 is present (1) • None are present (0) Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
  • 9. 2015 GOUT Classification Criteria ( AC R/ E U L AR ) • Joint Involvement • Characteristics • TYPICAL EPISODES • Evidence of Tophus • Serum Uric Acid • Synovial Fluid Urate • Imaging • Radiographs THE TYPICAL GOUT ATTACK • Maximal pain <24h • Resolution <14 days • Asymptomatic in between • Recurrent attacks (2) • One typical attack (1) • No typical attack (0) Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
  • 10. 2015 GOUT Classification Criteria ( AC R/ E U L AR ) • Joint Involvement • Characteristics • Typical Episodes • EVIDENCE OF TOPHUS • Serum Uric Acid • Synovial Fluid Urate • Imaging • Radiographs TOPHUS • Present (4) • Absent (0) Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
  • 11. 2015 GOUT Classification Criteria ( AC R/ E U L AR ) • Joint Involvement • Characteristics • Typical Episodes • Evidence of Tophus • SERUM URIC ACID • Synovial Fluid Urate • Imaging • Radiographs URATE LEVELS (mg/dl)* • <4 (-4) • 4 - <6 (0) • 6 - <8 (2) • 8- <10 (3) • >10 (4) * Highest measurement, OFF urate lowering therapy, >4 weeks from an episode Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
  • 12. 2015 GOUT Classification Criteria ( AC R/ E U L AR ) • Joint Involvement • Characteristics • Typical Episodes • Evidence of Tophus • Serum Uric Acid • SYNOVIAL FLUID URATE • Imaging • Radiographs • NEGATIVE for MSU (-4) • NOT DONE (0) • POSITIVE for MSU (SUFFICIENT CRITERION) Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
  • 13. 2015 GOUT Classification Criteria ( AC R/ E U L AR ) • Joint Involvement • Characteristics • Typical Episodes • Evidence of Tophus • Serum Uric Acid • Synovial Fluid Urate • IMAGING • Radiographs IMAGING CRITERIA • Double contour sign on US OR urate deposition on DECT in an affected joint • Present (4) • Absent / Not Done (0) Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
  • 14. 2015 GOUT Classification Criteria ( AC R/ E U L AR ) • Joint Involvement • Characteristics • Typical Episodes • Evidence of Tophus • Serum Uric Acid • Synovial Fluid Urate • Imaging • RADIOGRAPHS GOUT EROSION • Cortical break with sclerotic margin and overhanging edge on hands or feet images • Present (4) • Absent (0) Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
  • 15. 2015 GOUT Classification Criteria ( AC R/ E U L AR ) ENTRY CRITERIA • >1 episode of joint or bursal swelling, pain or tenderness SUFFICIENT CRITERIA • Demonstration of MSU crystals in synovial fluid or tophus THRESHOLD SCORE • >8 classifies a patient as having gout Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98.
  • 16. CRITERIA SET SENSITIVITY SPECIFICITY ACR / EULAR 0.92 0.89 ACR/ EULAR (Clinical) 0.85 0.78 ACR 1977 (survey) 0.84 0.62 Rome 0.97 0.78 New York 1.00 0.78 Neogi T, Jansen TLTA, Dalbeth N, et al. Ann Rheum Dis 2015; 74: 1789-98. Comparison of Criteria for GOUT
  • 17. AIDS in Diagnosing Gout Goutclassificationcalculator.auckland.ac.nz
  • 18. 1997 ACR CLASSIFICATION CRITERIA FOR SYSTEMIC LUPUS ERYTHEMATOSUS • Serositis • Oral Ulcers • Arthritis • Photosensitivity • Blood • Renal • ANA • Immunologic • Neurologic • Malar rash • Discoid rash
  • 19. 2012 SLICC CLASSIFICATION CRITERIA FOR SYSTEMIC LUPUS ERYTHEMATOSUS • Acute cutaneous LE • Chronic cutaneous LE • Oral ulcer • Alopecia • Synovitis • Serositis • Renal • Neurologic • Hemolytic anemia • Leucopenia/ lymphopenia • Thrombocytopenia • ANA • Anti-dsDNA • Anti-Sm • aPL antibodies • Low complement • Direct Coomb’s test CLINICAL IMMUNOLOGIC Petri M, Orbai AM, Alarcon GS, et al. Arth & Rheum 2012; 64 (8): 2677-86. AT LEAST 4 CRITERIA (1 Needs to be IMMUNOLOGIC) Biopsy proven LUPUS NEPHRITIS and ANA or anti-DNA
  • 20. 2015 ACR/ SLICC Revised Criteria for SYSTEMIC LUPUS ERYTHEMATOSUS • ACUTE CUTANEOUS LE – Malar rash (2) – SCLE rash (1) – Urticarial vasculitis (1) – Photosensitivity (1) • DISCOID LE (1) • ALOPECIA (1) • ORAL ULCERS (1) • JOINT DISEASE (1) • SEROSITIS (1) • PSYCHOSIS OR SEIZURES OR ACUTE CONFUSION STATE (1) • KIDNEY – Proteinuria or casts (1) – Biopsy proven LN (2) • HEMOLYTIC ANEMIA (1) • THROMBOCYTOPENIA (1) • LEUCOPENIA/ LYMPHOPENIA (1) • LOW TITER ANA (1) • HIGH TITER ANA – homo/ rim (2) • Positive ANTI-DSDNA (2) • Positive ANTI-SM (2) • APL antibodies (1) • LOW COMPLEMENT (1) ? Salehi-Abari I. Autoimmune Dis Ther Approaches Open Access 2015; 2:114
  • 21. 2015 ACR/ SLICC Revised Criteria for SYSTEMIC LUPUS ERYTHEMATOSUS HOW WERE THE CRITERIA CREATED? ? “You should know that after many years of visiting the patients with SLE and studying the literatures and evaluating of the classification criteria of SLE in every each one of the patients who have had a diagnosis of SLE upon clinical/ laboratory judgement, this new criteria can easily be created.” Salehi-Abari I. Autoimmune Dis Ther Approaches Open Access 2015; 2:114
  • 22. BIOMARKERS in Rheumatic Diseases DRUG DEVELOPMENT • Identify responders • Assess patient response Bay-Jensen AC, Reker D, Kjelgaard-Petersen CF, et al. Osteoarth and Cart 2016; 24: 9-20. Karsdal MA, Henriksen K, Leeming DJ, et al. Biomarkers 2009; 14: 181-202. Bauer DC, Hunter DJ, Abramson SB, et al. Osteoarth and Cart 2006; 14: 723-7. DIAGNOSIS PROGNOSIS MONITORING
  • 23. BIPED Classification of OA Biomarkers Burden of Disease ADAMTS4 ADAMTS5 ARGS Autotaxin C Col 10* CCL3 CCL4 CD14* CGRP COMP* CRPM FGF21* MMP1/3 Sclerostin TNF- Investigative C2C* CD14* Prognosis Predictive CD163* hmwAPN* Leptin* Efficacy Diagnostic BDNF* Fib3-2* Bay-Jensen AC, Reker D, Kjelgaard-Petersen CF, et al. Osteoarth and Cart 2016; 24: 9-20.
  • 24. Utility of OA Biomarkers Now you know, so what?
  • 25. Biomarkers in Rheumatoid Arthritis Poor Prognostic Features • Functional disability • Extra-articular disease • Erosions • ACPA Positivity • RF Positivity 2010 ACR Classification Criteria • Joint Involvement • Acute Phase Reactants • Duration of Symptoms • Serology – Rheumatoid Factor (RF) – Anti- Cyclic Citrullinated Protein Antibodies (ACPA)
  • 26. Monitoring in Rheumatoid Arthritis Parameters ACR DAS28 SDAI CDAI RAPID Pt Function + + Pt Pain + + Pt Global + + + + MD Global + + + Tender joints + + + + Swollen joints + + + + ESR or CRP + + + ACR – ACR 20/50/70; DAS28 – Disease Activity Score 28 joints; SDAI – Simplified Disease Activity Index; CDAI – Clinical Disease Activity Index; RAPID – Routine Assessment of Patient Index Data Hobbs KF, Cohen MD. Rheumatol 2012; 51: vi21-vi27.
  • 27. Targets in Rheumatoid Arthritis Tool Remission Low Moderate High DAS28 <2.6 2.6-3.2 3.3-5.1 >5.1 SDAI <3.3 3.4-11 12-26 >26 CDAI <2.8 2.9-10 11-22 >22 RAPID <3 3-<6 6-12 >12 Hobbs KF, Cohen MD. Rheumatol 2012; 51: vi21-vi27.
  • 28. Does Remission ENSURE Better Outcomes? Patients who meet established criteria for CLINICAL REMISSION may experience progressive structural damage. Brown AK, Conaghan PG, Karim Z, et al. Ann Rheum Dis 2008; 58: 2958-67 Brown AK, Quinn MA, Karim Z, et al. Ann Rheum Dis 2006; 54: 3761-73 Cohen G, Gossec L., Dougados M, et al. Ann Rheum Dis 2007; 66: 358-363 Lillegraven S, Prince FH, Shadick NA, et al. Ann Rheum Dis 2012; 71:861-6 Molenaar ET, Voskuyl AE, Dirant HS, et al. Arthritis and Rheum 2004: 36-42
  • 29. Developing the BIOMARKERS Study Biomarker Patients Samples Objectives SCREEN 130 20 20 Candidate identification I 113 128 128 Prioritization II 75 320 320 Prioritization III 65 85 255 Prioritization IV 16 119 119 New marker evaluation, prioritization Pilot >25 24 107 Assessment of capabilities Training 25 708 708 Analytical validation, development of algorithm Centola M, Cavet G, Shen Y, et al. PLoS ONE 2013; 8(4): e60635
  • 30. Biomarkers in Rheumatoid Arthritis IL-6 Leptin TNF R1 VEGF-A EGF VCAM-1 SAA YKL-40 MMP-1 MMP-3 Resistin CRP
  • 31. Biomarkers in Rheumatoid Arthritis IL-6 Leptin TNF R1 VEGF-A EGF VCAM-1 SAA YKL-40 Predicted TJC MMP-1 MMP-3 Resistin CRP
  • 32. Biomarkers in Rheumatoid Arthritis IL-6 Leptin TNF R1 VEGF-A EGF VCAM-1 SAA YKL-40 MMP-1 MMP-3 Resistin Predicted TJC Predicted SJC CRP
  • 33. Biomarkers in Rheumatoid Arthritis IL-6 Leptin TNF R1 VEGF-A EGF VCAM-1 SAA YKL-40 MMP-1 MMP-3 Resistin Predicted TJC Predicted SJC Patient Global CRP
  • 34. Biomarkers in Rheumatoid Arthritis IL-6 Leptin TNF R1 VEGF-A EGF VCAM-1 SAA YKL-40 MMP-1 MMP-3 Resistin Predicted TJC Predicted SJC Patient Global CRP MULTI-BIOMARKER DISEASE ACTIVITY SCORE
  • 35. Computing the MBDA Score Centola M, Cavet G, Shen Y, et al. PLoS ONE 2013; 8(4): e60635
  • 36. Targets in Rheumatoid Arthritis Tool Remission Low Moderate High DAS28 <2.6 2.6-3.2 3.3-5.1 >5.1 SDAI <3.3 3.4-11 12-26 >26 CDAI <2.8 2.9-10 11-22 >22 RAPID <3 3-<6 6-12 >12 MBDA <25 26-29 30-44 >44 Hobbs KF, Cohen MD. Rheumatol 2012; 51: vi21-vi27.
  • 37. Validation of the MBDA Score Biomarker Measure Clinical Measure Pearson’s Correlation P-value N SEROPOSITIVE MBDA Score SDAI 0.55 <0.001 148 CDAI 0.48 <0.001 148 RAPID3 0.47 <0.001 92 SERONEGATIVE MBDA Score SDAI 0.29 <0.001 139 CDAI 0.21 0.02 139 RAPID3 0.26 0.003 127 Curtis JR, van der Helm-van Mil AH, Knevel R, et al. Arthritis Care & Res 2012; 64 (12): 1794-1803.
  • 38. Monitoring with the MBDA Score Clinical Outcome Δ MBDA Score Change in disease activity (Spearman’s) Baseline to FinalVisit Δ DAS28 CRP 0.51 (P<0.001) ACR-N ResponseCriteria 0.45 (P=0.002) Discrimination of clinically defined response (AUROC) Baseline to FinalVisit Δ DAS28 CRP 0.77 (P=0.002) ACR50 ResponseCriteria 0.69 (P=0.03) Baseline toWeek 2 Δ DAS28 CRP 0.72 (P=0.02) ACR-N ResponseCriteria 0.65 (P=0.11) Curtis JR, van der Helm-van Mil AH, Knevel R, et al. Arthritis Care & Res 2012; 64 (12): 1794-1803.
  • 39. How the MBDA Score Compares % with Good Radiographic Outcome (ΔSHS <3) Test for Remission Remission Non-Remission P-value DAS28 CRP<2.32 80 (66/83) 71 (134/188) 0.18 MBDA<25 93 (40/43) 70 (160/228) 0.001 ACR/ EULAR 83 (25/30) 73 (175/241) 0.27 Van der Helm-van Mil AHM, Knevel R, Cavet G, et al. Rheumatology 2013; 52: 839-46.
  • 40. Which was better at predicting RADIOGRAPHIC PROGRESSION? 7 20 15 27 18 24 43 37 0 5 10 15 20 25 30 35 40 45 50 MBDA DAS28 CRP RiskofRadiographicProgression Remission Low Moderate High Van der Helm-van Mil AHM, Knevel R, Cavet G, et al. Rheumatology 2013; 52: 839-46. RR 6.1 RR 1.8 P<0.05
  • 41. When MBDA and DAS28 DIFFER 58 20 11 87 47 33 0 10 20 30 40 50 60 70 80 90 100 ΔSHS>0 ΔSHS>3 ΔSHS>5 RiskofRadiographicProgression DAS28 CRP Remission DAS 28 CRP Remission, High MBDA Van der Helm-van Mil AHM, Knevel R, Cavet G, et al. Rheumatology 2013; 52: 839-46. RR 1.5 (1.16, 1.85) RR 2.28 (1.13, 3.68) RR 3.07 (1.08, 5.47)
  • 42. MBDA Score in the CAMERA Study MBDA Score DAS28 CRP Baseline At 6 Months Low Moderate High Low Moderate High Low 0 1 4 9 3 2 Moderate 0 8 5 7 7 4 High 0 15 40 2 4 10 K (95% CI) 0.23 (-0.03, 0.48) 0.32 (0.11, 0.53) Weighted K 0.20 (0.01, 0.39) 0.39 (0.02, 0.76) Pearson Correlation (r) = 0.72 (p <0.001) AUROC = 0.86 (p <0.001) Bakker MF, Cavet G, Jacobs JWG, et al. Ann Rheum Dis 2012; 71: 1692-97. Baseline = 66% AT 6 MONTHS = 54%
  • 43. MBDA Score in the SWEFOT Trial Baseline MBDA Score Baseline DAS28 ESR Low <3.2 Moderate >3.2-5.1 High >5.1 TOTAL Low (<30) 0 0/3 0/2 0/5 Moderate (30-44) 0 1/14 0/15 1/29 High (>44) 0 9/51 33/150 42/201 TOTAL 0 10/68 33/167 43/235 Hambardzumyan K, Bolce R, Saevasdottir S, et al. Ann Rheum Dis 2015; 74:1102-09. NUMERATORS – no of patients with radiographic progression (change in SHS >5) DENOMINATORS – no o f patients meeting MBDA and DAS Scores 15% 20% 3% 21%
  • 44. MBDA Score in the SWEFOT Trial The MBDA Score at baseline was a strong predictor of radiographic progression at 1 year among patients with early RA Hambardzumyan K, Bolce R, Saevasdottir S, et al. Ann Rheum Dis 2015; 74:1102-09. 80 20 0 66 14 3 46 33 21 0 10 20 30 40 50 60 70 80 90 No Change in SHS Change in SHS >3 Change in SHS >5 %ofPatients Low (<30) Moderate (30-44) High (>44)
  • 45. RADIOGRAPHIC PROGRESSION: DAS28 CRP x MBDA Score 7 16 0 20 22 7 44 28 50 0 10 20 30 40 50 60 <2.6 >2.6-<4.1 >4.1 RiskofRadiographicProgression (ΔSHS>3) DAS 28 CRP Low Moderate High MBDA Score Wanying L, Sasso EH, van der Helm-can Mil AHM, et al. Rheumatology 2016; 55:357-366
  • 46. MOLECULAR REMISSION CLINICAL REMISSION Targets in Rheumatoid Arthritis Tool Remission Low Moderate High DAS28 <2.6 2.6-3.2 3.3-5.1 >5.1 SDAI <3.3 3.4-11 12-26 >26 CDAI <2.8 2.9-10 11-22 >22 RAPID <3 3-<6 6-12 >12 MBDA <25 26-29 30-44 >44 Hobbs KF, Cohen MD. Rheumatol 2012; 51: vi21-vi27.
  • 47. Using MBDA Score in Undiff Arthritis 100 80 60 40 20 MBDAScore RA-RA n=81 UA-RA n=16 UA-UA n=29 p=0.001 p=0.132 Maijer K, Wanying L, Sasso EH, et al. Ann Rheum Dis 2015; 74 (11): 2097-99
  • 48. MBDA Score in JIA Patients 31 children with JIA with mean duration of 5 years (RF+ / RF- /oligoarticular) Comparison MBDA vs JADAS Methodology Cross sectional observational study Results • Moderate correlation between MBDA and JADAS (r=0.68) • Similar biomarker profile between those with CID and controls • Difference between CID/ controls and active disease seen in SAA, CRP, IL6 and MMP3 Ringold S, Lu L, Wallace CA, et al. Arthritis Rheum 2014l 66 (S3): S10-S11.
  • 49. Tailoring First Line Biologic Therapy from the Italian BiologicsTherapy (ITABIO) Board “Any biologic may be used in the absence of driving factors in RA.” High Infection Risk or +LTBI Abatacept Tocilizumab Etanercept High ACPA or RF Tocilizumab Abatacept High CV Risk Etanercept Anti-TNF inhibitors Cost Effectivess Etanercept bs Infliximab Cantini F, Nannini C, Cassara E, et al. Semin Arthritis Rheum 2015; S0049-0172.
  • 50. Tailoring First Line Biologic Therapy from the Italian BiologicsTherapy (ITABIO) Board Anterior Uveitis / IBD Mabs Anti-TNF Inhibitors High Infection Rate or +TB Ustekinumab Etanercept Enthesitis, Dactylitis, Severe Skin or Joint Symptoms Anti-TNF inhibitors Ustekinumab Metabolic Syndrome or High CV Disease Risk Etanercept Cantini F, Nannini C, Cassara E, et al. Semin Arthritis Rheum 2015; S0049-0172. Spondyloarthritis / Psoriatic Arthritis
  • 51. SUMMARY • Reviewed the latest criteria on gout and lupus • Describe the state of biomarker studies in OA • Discuss the use of MBDA in RA • Enumerated recommendations from the ITABIO Board on tailoring first line biologic therapy in RA/ SpA/ PsA
  • 52. SLIDES would be made available (for viewing) SOON at RheumatologyWebsite (rheumatology.org.ph) PersonalWebsite (phrheumajr.wordpress.com)

Notas del editor

  1. <=4 NOT GOUT in 95% >=8 GOUT in 87% >4-<8 UNCERTAIN
  2. Draining OR chalk-like subcutaneous nodule under transparent skin, often with overlying vascularity over joints, ears, olecranon bursae, finger pads, tendons
  3. In order to make a diagnosis of knee OA – we look into the patient’s background risks for developing the condition, we look for signs and symptoms suggesting the diagnosis and request for radiographs to looks for features supporting the diagnosis of OA. Past criteria for OA have focused on a constellation of symptoms, PE findings and radiographic changes in order to make a diagnosis.
  4. The 2010 EULAR Criteria is different in that it focuses on risk factors and clinical features to make the diagnosis. How do we diagnose then? In adults >45 complaining of knee pain, a diagnosis of knee osteoarthritis can be made with 99% probability if all symptoms and signs are present In adults > 40 years with knee pains, a diagnosis of knee OA can be confidently made if all symptoms AND at least one physical examination finding is present ALSO, a confident diagnosis of knee OA can be made even without radiographic evaluation (which can still be ordered but whose purpose will be for anatomic evaluation) and even if an ordered radiograph turns out normal.
  5. The 2010 EULAR Criteria is different in that it focuses on risk factors and clinical features to make the diagnosis. How do we diagnose then? In adults >45 complaining of knee pain, a diagnosis of knee osteoarthritis can be made with 99% probability if all symptoms and signs are present In adults > 40 years with knee pains, a diagnosis of knee OA can be confidently made if all symptoms AND at least one physical examination finding is present ALSO, a confident diagnosis of knee OA can be made even without radiographic evaluation (which can still be ordered but whose purpose will be for anatomic evaluation) and even if an ordered radiograph turns out normal.
  6. The US FDA and EMA have recently published guidelines recommending a higher level of integration of biomarkers in development and testing of new drugs – to advance decision making on dosing, time, treatment effect, risk/ benefit analysis and personalized medicine. Why biomarkers in drug development? To identify a subpopulation of responsive subjects that will provide the best evidence for rejecting the null hypothesis of no treatment effect and thereby demonstrate the efficacy and safety of a drug candidate. To assess individual patient’s response to treatment – clinicians will be able to conclude whether treatment has the desired effect or not.
  7. For 2014/ 2015, most biomarkers in OA studied were either biomarkers of joint tissue turnover and biomarkers of the inflammatory status. But more than the nature of biomarkers, most investigators were interested in the utility of these tests and their potential impact in influencing management. BIPED Classification - evaluation and qualification of the utility of biomarkers. (* tested in large studies) S ADAMTS4 – found in early OA > intermediate and late OA while S ADAMTS5 was higher in intermediate and late OA than early OA and controls. SF ARGS in acute knee injury. S/ SF were increased following knee injury. C2C P/ SF Autotaxin – severity of RKOA and WOMAC scores. S C Col 10 – elevated in KL 2 vs KL 0 and those with above normal hsCRP. CCL 3 severity of KOA. CCL 4 associated with severity of RKOA. CRGP – correlated with KL score, total WOMAC. S COMP increased in severity of hand OA but no correlation with RHOA. CRPM – correlated with degree of central sensitization. S FGF21 – correlated with radiographic bone loss. MMP1 and MMP3 correlated with intermediate and late OA but not with early OA and controls. Sclerostin – negative correlation with RKOA. Increased SF TNF alpha, SPARC and IL-8 were associated with osteochondral fractures. P/ SF CD14 – associated with JSN and osteophytosis and osteophyte progression. Also seen to correlate with severity of knee pain. CD163 – osteophyte progression. S HMWAPN associated with progression of RHOA. Leptin (Elderly Boston Study Population), high leptin level were associated with increased risk for OA – suggesting that part of the BMI risk factor is mediated through leptin concentrations. BDNF – correlated with RKOA and WOMAC severity. Fib3-2 (in the PROOF study), high levels of Fibulin 3 epitopes were highly associated with clinical KOA among middle aged and obese women.
  8. Not all assessments use the same set of paramters Some assessments like RAPID emphasize patient reported outcomes (PROs) Others use a combination of patient reported outcomes, physician assessments and laboratory tests OBVIOUSLY, not included are imaging modalities There are concerns about inter- and intra- observer variation. Some problems are observed. The joint counts for example – may pose a challenge – swollen – obesity OR tender points OR swelling in OA OR fibrous thickening ACR – reflects visit to visit changes in disease activity DAIs – represents single point in time assessment ACR 20/50/70, DAS 28 and Health Assessment Questionnaires are required by regulatory and licensing agencies for product approval in the US
  9. The target in treating RA is remission. No cure is available. Remission offers the possibility of better QOL and minimal disability
  10. Staged approach used in biomarker discovery and prioritization and algorithm development
  11. The target in treating RA is remission. No cure is available. Remission offers the possibility of better QOL and minimal disability
  12. MBDA had significant correlation with DAS28 CRP in distinguishing low/ remission disease activity vs moderate/ high disease activity. It was an independent predictor of disease activity measures. MBDA scores went down from 53 (SD 18) to 39 (SD 16). MBDA scores in the intensive treatment group went down from 53 (17) to 35 (14) while the usual care group it went down from 55 (20) to 56 (19).
  13. Numerators = number of patients with radiographic progression Denominators = no of patients meeting MBDA and DAS scores Agreement between MBDA Score and DAS28 ESR seen in 70% of cases
  14. The target in treating RA is remission. No cure is available. Remission offers the possibility of better QOL and minimal disability
  15. Systematic review of the literature to identify English-language articles on the variables influencing the first-line biologic choice, including the efficacy and safety of the drug, the route of administration, the availability of response predictorbiomarkers, the need of monotherapy, the patient socio-economic status, lifestyle, cultural level, personality, fertility and childbearing potential in women, the presence of comorbidities, the host-related risk factors for infection and latent tuberculosis infection (LTBI) reactivation, the cardiovascular (CV) risk, and costs