The document discusses approaches to rheumatic diseases, including criteria, biomarkers, and classification systems. It summarizes the 1977 ACR criteria for gout, the 2014 Nijmegen diagnostic rule, and the 2015 ACR/EULAR gout classification criteria. It also summarizes the 1997 ACR, 2012 SLICC, and 2015 ACR/SLICC revised criteria for systemic lupus erythematosus. Various biomarkers for osteoarthritis and rheumatoid arthritis are discussed for purposes like diagnosis, prognosis, monitoring disease activity and treatment response.

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

3. Awareness Campaign 2015
#WhenInGout

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)