Dr. Swamy Venuturupalli talks about Rheumatoid Arthritis, Early Diagnosis and Treatment at the James R. Klinenberg symposium on Rheumatic diseases in Pasadena, CA.

1. Rheumatoid Arthritis
Early Diagnosis and
Treatment
Swamy Venuturupalli MD, FACR
Clinical Chief, Division of Rheumatology, Cedars Sinai Medical Center
Associate Clinical Professor of Medicine, UCLA
Editor-in-Chief, Current Rheumatology Reviews
www.drswamy.com

2. Overview
 What is the pathogenesis of RA?
 How do you diagnose RA?
 What clinical manifestations must one be aware of?
 Is there a window of opportunity to make a difference?
 Current treatment principles:
 Medications used
 Treat to target
 When to introduce newer agents
 Complications of therapy

3. Introduction
 Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by
joint inflammation and destruction in association with serological evidence of
autoreactivity.
 Affects approximately 1% of the population and causes significant morbidity
and mortality, with accelerated atherosclerosis impairing life expectancy.
 In the past two decades, the therapy of RA has undergone revolutionary
change, reflecting a paradigm shift in treatment approach as well as the
introduction of new disease-modifying antirheumatic drugs (DMARDs), most
prominently the biological agents, including the tumor-necrosis-factor (TNF)
blockers.

4. Pathogenesis of Rheumatoid Arthritis.
Choy EH, Panayi GS. N Engl J Med 2001;344:907-916.

5. Pathogenesis of RA
2: “Trigger”
1: “Pre-articular” phase
•
Genes
Autoantibodies
•
Citrullination
•
•
•
•
•
4: Early RA phenotype
E.g:
Minor trauma
Infection
Hormones
Psychological
Progressive, erosive RA
T-cell
Immunosenescence
3: Synovitis
•
Environment
Impaired thymic
selection
•
•
•
Smoking
Infections
(gingival
disease, gut
flora changes)
Altered lymphocytesignaling thresholds
•
B S
I
O ?
M
A
R
K
E
? R
‘Good-prognosis’ RA
DMARD-responsive RA
Anti-cytokine-responsive RA
Deregulated
TLR/cytokine signaling
Anti-lymphocyte-responsive RA
Self-limiting IP
Legend:
TLR: Toll like receptor; DMARD: Disease-modifying anti-rheumatic drug; IP: Inflammatory polyarthritis
Adapted from Best Pract Res Clin Rheumatol. 2009 February; 23(1): 37–48.

6. Model for the Etiology of RA
Autoreactivity/genetics
Joint damage
Activation of
innate immunity
Periphery
DC
FL
S
Synovial
inflammation/cytokines
Adaptive Immunity
MΦ
Recruitment
autoantibodies
Migration
DC
T
T
T
T
Adapted from Vibeke Strand, Medscape.
B
Legend:
DC= dendritic cell; FLS= fibroblast-like synoviocyte; MΦ= macrophage; T= T cell

7. Severity of Arthritis
Clinical Course of RA
4
Type 1
Type 2
Type 3
3
2
1
0
0 0.5 1
2
3
4
6
8 16
Years
Type 1 = Self-limited—5% to 20%
Type 2 = Minimally progressive—5% to 20%
Type 3 = Progressive—60% to 90%
Pincus. Rheum Dis Clin North Am. 1995;21:619.

8. Clinical Spectrum of RA
Images courtesy of J. Cush, 2002.

9. Overview of joints affected
• Joints most frequently affected in RA include:
• The proximal interphalangeal
(PIP) and metacarpophalangeal
(MCP) joints of the hands
• The wrists
• The shoulders
• The elbows
• The knees
• The ankles, and
• The metarsophalangeal (MTP)
joints of the feet
• Distal interphalangeal (DIP)
joints are typically spared
in RA.

10. RA: It’s not just the joints
CVD
∧ Osteoporosis
10 Years Earlier
6-9x ∧ serious
infection rate
Joint Destruction
Disability Index
2x ∧ rate
malignancy
∧ Pulmonary
disease
∧ GI Bleeding

11. RA is a systemic disease with
extraarticular manifestations
Secondary Sjögren’s syndrome
Heart
Pericarditis
Myocarditis
Endocarditis
Valvular fibrosis
Liver
Enzyme abnormalities due to
drug reactions or Sjögren’s
syndrome
Blood / blood vessels
Mild anemia
Vasculitis
Felty’s syndrome
Eyes
Keratoconjunctivitis
Sicca syndrome
Scleritis
Episcleritis
Keratitis corneal ulceration
Choroiditis
Retinal vacuities
Episcleral nodules
Lungs
Pleuritis ± pleural effusions
Pulmonary nodules
Interstitial pulmonary fibrosis
Skin
Rheumatoid nodules
Vasculitis
Interstitial granulomatous
dermatitis
Firestein. ACP Medicine, Rheumatology II

12. Poor prognostic factors
 Extra-articular signs and symptoms (e.g. Cutaneous ulcers, vasculitic
rash, neuropathy, scleritis, subcutaneous nodules)
 Female gender
 Shared epitopes
 Poor functional status
 Involvement of multiple joints
 Early radiographic evidence of erosive changes
 Advanced age at onset of disease
 High RF titer
 Sustained elevation of acute-phase reactants (e.g. ESR)
 Low socioeconomic status/educational level
 High titre CCP antibody
 Smoking
Anaya JM, et al. Ann Rheum Dis. 1994;53:782–783; Pincus T, Callahan LF. Balliere’s Clin Rheumatol. 1992;6:161–191; Furst
DE. Rheum Dis Clin North Am. 1994;20:309–319.

13. Cardiovascular Disease (CVD) in RA
 Increased incidence of CVD and mortality in RA: 2-4 times
 Not only traditional CVD risk factors (smoking, lipids, hypertension, DM)
increased
 Inflammation involved in pathogenesis of atherosclerosis
 High index of suspicion; atypical, silent chest pain, CHF, and sudden
death common
 CVD accounts for much excess mortality in RA

14. Malignancy in RA
 2-3x lymphoproliferative disease, in particular, diffuse large B-cell lymphoma
 EBV-associated lymphomas increased in patients on methotrexate (MTX)
 Chronic inflammation may be responsible for increased lymphoma
 Lung cancer more common in RA, but may be due to cigarette smoking, a
common risk factor
 Anti-TNF medications may be associated with increased risk of lymphoma
and skin cancer

15. Diagnosing
RA

16. 1987 Revised ACR Classification of RA
Criterion
Definition
Morning stiffness
Lasting ≥ 1 hour before maximal improvement
Arthritis ≥ 3 joints
Clinical evidence of soft tissue swelling or fluid in right or left PIP, MCP,
wrist, elbow, knee, ankle, and MTP joints
Arthritis of hand joints
1 or more swollen areas in wrist, MCP, or PIP joint
Symmetric arthritis
Simultaneous involvement of same joint areas on both sides of body
(bilateral involvement of PIP, MCP, or MTP joints is acceptable without
absolute symmetry)
Rheumatoid nodules
Clinical evidence of subcutaneous nodules over bony prominences,
extensor surfaces, or in juxtaarticular regions
Serum RF
Elevated rheumatoid factor measured by any method in which positive
results are found in < 5% of normal subjects
Radiographic changes
Erosions or unequivocal body decalcification localized in or adjacent to
involved joints on posteroanterior hand and wrist radiographs
Classification of RA is fulfilled when 4 of 7 criteria are present (first 4 criteria must be present for at least 6 weeks); another
clinical diagnosis does not exclude RA.
Arnett FC et al. Arthritis Rheum. 1988;31:315-324.

17. 2010 ACR/EULAR classification criteria for RA
A score of ≥6/10 is needed to classify RA
A. Joint involvement
1 large joint
2-10 large joints
1-3 small joints (with or without involvement of large joints)
4-10 small joints (with or without involvement of large joints)
>10 joints (at least 1 small joint)
Score
0
1
2
3
5
B. Serology (at least 1 test result is needed)
Negative RF and negative ACPA
Low-positive RF or low-positive ACPA
High-positive RF or high-positive ACPA
0
2
3
C. Acute-phase reactants (at least 1 test result is needed)
Normal CRP and normal ESR
Abnormal CRP or abnormal ESR
0
1
D. Duration of symptoms
<6 weeks
≥6 weeks
0
1
Aletaha et al. Arthritis Rheum. 2010;62:2569-2581
Aletaha et al. Ann Rheum Dis. 2010; 69:1580-1588

18. Antibodies to cyclic citrullinated peptides
(anti-CCP)
 Anti-CCP has high diagnostic specificity for RA (98%)
 Found in 40% of patients who are RF negative
 Citrullination is the post-translational modification of
arginine to citrulline
 Alters the structure, antigenicity, and function of proteins
 Four candidate citrulllinated antigens have been
established: fibrinogen, vimentin, type II collagen,
-enolase
Wegener et al. Immunological Rev. 2010;233:34

19. Rheumatoid factor (RF)
 Antibody reactive against Fc fragment of IgG
 80% of RA patients are ever seropositive for RF, <50% in early RA, and is
associated with:
• More radiological abnormalities
• More disease activity
• Worse functional ability
• More extra-articular manifestations
• More treatment with second line drugs
 Not specific for RA: chronic infections, cirrhosis, malignancies, other
rheumatic diseases.

20. Radiographic
Assessment of Joint
Disease in RA

21. Early changes in RA

22. MRI SCAN OF WRIST IN EARLY RA

23. Ultrasound

24. Is there a window of
opportunity?

25. Window of opportunity
 Several studies have shown greater improvements with earlier treatment.
 Can that concept be taken to an extreme, so that these agents be started
at the earliest point in diagnosis?
 This has been codified as the “Window of opportunity hypothesis,” which
posits that, early in its course, RA displays a unique phenotype in which
immunoregulatory disturbances can be decisively or permanently blocked

26. RA Progression
Inflammation
Disability
Severity (arbitrary units)
Radiographs
0
5
10
15
20
Duration of Disease (years)
Adapted from Kirwan JR. J Rheumatol. 2001;28:881–886.
25
30

27. HAQ as a determinant of
long-term disability in RA
 HAQ has a strong, positive correlation to radiographic
damage.
 Mean HAQ scores during first 3 months of treatment
were the strongest predictor of 10-year disability
outcomes.
 HAQ>1.0, the odds ratio for disability at 10 years was 13.4
Lindqvist et al. Ann Rheum Dis. 2002;61:1055-1059
Wolfe and Hawley. J Rheumatol. 1998;25:2108-2117
Cohen et al. J Rheumatol. 2006;33:1936-1941
Drossaers-Bakker et al. Arthritis Rheum. 1999;2:1854
Welsing et al. Arthritis Rheum. 2001;44:2009-2017
Scott et al. Rheumatology. 2000;39:122-132
Aletaha et al. Arthritis Rheum. 2006;54:2784-2792

28. Relationship Between Change in CRP at
6 Months and Subsequent Change in HAQ
14
CRP reduced by < 50% in first 6
months (n = 44)
Median HAQ Score
12
10
8
CRP reduced by ≥ 50% in first
6 months (n = 31)†
6
4
CRP normalized in first
6 months (n = 34)†
2
0
Baseline
6 Months
12 Months
24 Months
†P
< .005 vs. group with < 50% reduction in CRP.
Prospective study of 109 consecutive RA patients with elevated CRP levels before steroid or
DMARD therapy. Patients were grouped according to the change in CRP seen at 6 months.
Devlin J et al. J Rheumatol. 1997;24:9-13.

29. Principles of Therapy
EARLY initiation of therapy
Treat to target
Combine medications to achieve remission

30. Treatment: The Earlier the Better
Delayed Treatment*
(median treatment lag time = 123 days; n = 109)
Early Treatment*
(median treatment lag time = 15 days; n = 97)
14
Change in Median
Sharp Score
12
10
8
6
4
2
0
0
6
12
Time (months)
*Patients were treated with chloroquine or azathioprine.
Lard LR, et al. Am J Med. 2001;111:446–451.
18
24

31. Radiographic changes in LERA (•) and VERA1 (□) patients, indicated by
the Larsen score at baseline and after 12, 24 and 36 months of follow-up.
Nell V P K et al. Rheumatology 2004;43:906-914
Rheumatology Vol. 43 No. 7 © British Society for Rheumatology 2004; all rights reserved

32. COBRA Trial
Early Intervention Yields Long-Term Benefits
Median Sharp Score
60
SSZ alone
45
30
COBRA
P < 0.03
15
0
0
1
2
3
4
5
Years of Follow-up
COBRA: Prednisolone (initially 60 mg/d, tapered in 6 weekly steps to 7.5 mg/d) +
methotrexate 7.5 mg/wk x 40 wks + sulfasalazine 2 g/d.
SSZ: Sulfasalazine 2 g/d.
Landewé RBM, et al. Arthritis Rheum. 2002;46:347–356.

33. Quantitative Measures of Disease
Activity
Patient Only
 Patient activity scale (PAS) or PASII
 Routine assessment of patient index data 3 (RAPID 3)
Patient and provider data
 Clinical disease activity index (CDAI)
Patient, provider, and lab data
 Disease activity score with the 28-joint count (DAS28)
 Simplified disease activity index (SDAI)

34. Features of Disease Activity
Measurement Tools
DAS28
 Requires assessment of 28-joint count and either ESR or CRP level
 Involves difficult calculation
CDAI
 Requires assessment of 28-joint count, physician global
assessment, and patient global assessment
 Does not require a laboratory test
SDAI
 Requires assessment of 28-joint count, physician global
assessment, and patient global assessment, plus ESR
RAPID 3
 Requires 3 measures of physical function, pain, and patient global
assessment of status
 All 3 components reported by the patient
 Involves simple addition of 3 measures

35. Assessing Disease
Activity in RA
Level of Disease Activity
Instrument
Remission
Low
Moderate
High
DAS28
(range, 0-9.4)
< 2.6
≥ 2.6 to < 3.2
≥ 3.2 to ≥ 5.1
≥ 5.1
PAS or PAS-II
(range, 0-10)
0 to 0.25
0.26 to 3.7
3.71 to < 8.0
≥ 8.0
CDAI
(range, 0-76)
≤ 2.8
> 2.8 to 10.0
> 10.0 to 22.0
> 22.0
RAPID 3
(range, 0-30)
0 to 3.0
> 3.0 to 6.0
> 6.0 to 12.0
> 12.0 to 30.0
SDAI
(range, 0-86)
≤ 3.3
> 3.3 to ≤ 11.0
> 11.0 to ≤ 26.0 > 26.0

36. BeSt: Treatment Strategies
Group 1
Monotherapy
Group 2
Step-Up Therapy
Group 3
Combo Therapy
Group 4
MTX + INF
MTX
MTX
MTX + SSZ + PRED
MTX + INF
SSZ
MTX + SSZ
MTX + CsA + PRED
SSZ
LEF
MTX + SSZ + HCQ
MTX + INF
LEF
MTX + INF
MTX + SSZ + HCQ
+ PRED
MTX + CsA + PRED
MTX + INF
Legend:
CsA = cyclosporin A; HCQ = hydroxychloroquine; INF = infliximab; LEF = leflunomide; MTX = methotrexate;
PRED = predinisone; SSZ = sulfasalazine

37. BeST Study
Treatment Strategies in Early Rheumatoid Arthritis: Clinical and
Radiological Outcomes After 2-year Follow-Up
2.5
Seq. mono n=126 1
2
Step-up combo n=121
1.5
Initial combo
w/prednisone n=133
1
Initial combo w/IFX
n=128
0.5
0
TSS change from baseline

38. Triple Therapy:
Proportion of Patients with Sustained Response
Patients with 50% improvement in
modified Paulus criteria (%)
100
All 3 drugs
80
24/31 (77%)
Sulfasalazine and
hydroxychloroquine
60
14/35 (40%)
12/36 (33%)
40
Methotrexate
20
0
0
6
12
18
24
Months
P = 0.003, triple therapy vs. other treatment arms
O'Dell. N Engl J Med. 1996.

39. Combination Methotrexate, Sulfasalazine, and
Hydroxychloroquine (FIN-RACo Study)
75%
Patients with ACR50
Responses (%)
80
70
60
Single DMARD
Combination DMARDs
60%
71%
58%
P = .028 at 1 year
P = .058 at 2 years
50
40
30
20
10
0
1 Year
2 Years
199 patients with early RA were randomly assigned to combination therapy with methotrexate 7.5 mg/week, sulfasalazine 1 g/day,
hydroxychloroquine 300 mg/day, and prednisolone 5 mg/day (with flexible dosage adjustment to achieve remission), or single DMARD
therapy with sulfasalazine 2 g/day with or without prednisolone. If necessary because of adverse events or lack of efficacy, sulfasalazine
was replaced by methotrexate and subsequently azathioprine
Mottonen T et al. Lancet. 1999;353:1568-1573.

40. Principles of Therapy
EARLY initiation of therapy
Treat to target
Combine medications to achieve remission

41. What to treat with

42. RA: Current Pharmacologic Options
• Agents that are effective in controlling the signs and symptoms of
RA, but have no effect on disease progression
– NSAIDs reduce inflammation and pain
– COX-2 inhibitors are similar to NSAIDs, but with improved GI safety and
tolerability and higher cardiac side effects
– Analgesics- these medicines do not affect inflammation, but work on
pain pathways to decrease subjective feeling of pain.
• DMARDs impact the signs, symptoms, and disease progression of
RA, as well as improve the quality of life and functionality of the
patient
• Corticosteroids have anti-inflammatory and immunoregulatory
activity, but nominal disease-modifying capability
Irvine S, et al. Ann Rheum Dis. 1999;58:510–513; Madhok R, Capell HA. Lancet 1999;353:257–258;
ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328–346; Goldbach-Mansky R, Lipsky PE.
Annu Rev Med. 2003;54:197–216.

43. T C e lls A c tiv a te M u ltip le C e llu la r P ro c e s s e s th a t
L e a d s to In fla m m a tio n a n d D e s tru c tio n
A d a p te d fro m C ho y a nd P a na y i. N E n g l J M e d 2 0 0 1 ; 3 4 4 (1 2 ): 9 0 7 – 1 6 ;
D M A R D = d ise a se -m o d ify ing a ntirhe um a tiic d rug

44. RA: Disease Modifying therapies
Traditional DMARDs
Biological DMARDS
For example
For example
 Methotrexate
 Leflunomide (Arava®)
 Sulfasalazine
(SSZ, Azulfidine®)
 Hydroxychloroquine
(HCQ, Plaquenil®)
 Azathioprine, cyc
losporine
 TNF antagonists
 Etanercept (Enbrel®)
 Adalimumab (Humira®)
 Infliximab (Remicade®)
 Certolisumab pegol (Cimzia®)
 Golimumab (Simponi®)
 Abatacept (Orencia®)
 Rituximab (Rituxan®)
 Tocilizumab (Actemra®)
 Tofacitinib (Xeljanz®)

45. Methotrexate
 Most effective single DMARD (used as baseline therapy in most patients.)
Typical dose is 15 mg/week.
 Good benefit-to-risk ratio.
 Screen Hepatitis serologies before use, ETOH
counseling, LFT, CBC, creatinine prior to use and every 2-3 months.
 Side effects include liver damage, oral and mucosal ulcers and rarely lung
toxicity. Rarely may cause bone marrow suppression.
 Must be taken with folic acid supplementation. 1mg every day except on
day of MTX.
 Avoid use with TMP/SMX: bone marrow suppression.

46. TNF antagonists
 5 currently approved agents:
 Etanercept, adalimumab, infliximab, certolizumab pegol, golimumab.
 Subcutaneous (etanercept, adalimumab, certolizumab pegol, golimumab)
and intravenous administration (infliximab and golimumab.)
 Administration in combination with MTX is superior to monotherapy.
 Time to onset: rapid (weeks)
 Adverse events:
 Infection, TB, multiple sclerosis/demyelination, lupus-like syndrome.
 Malignancy: higher rates as compared with normal population but not
higher than the background of lymphoma and solid tumors in RA
population. Increased risk of non melanotic skin cancers.
 Monitoring:
 TB screening including PPD prior to therapy.
 Periodic CBC, LFTs.
 Infection.

47. 2012 Update of the 2008 American College of Rheumatology recommendations
for the use of disease‐modifying antirheumatic drugs and biologic agents in the
treatment of rheumatoid arthritis
Arthritis Care & Research
Volume 64, Issue 5, pages 625-639, 2 APR 2012 DOI: 10.1002/acr.21641
http://onlinelibrary.wiley.com/doi/10.1002/acr.21641/full#fig1

48. British Journal of Nursing (2013) volume: 22 issue: 6 – 308, 310, 318

49. British Journal of Nursing (2013) volume: 22 issue: 6 – 308, 310, 318

50. Special situations:
Urgent issues
Fever and infections
Septic arthritis
Dyspnea and cough in a patient on MTX
Pre-op issues in long standing RA

51. Infections in RA
 Infections in RA increased (up to 6 to 9 fold)
 Immune dysfunction of RA.
 Corticosteroids, even “low dose.”
 Immunomodulatory drugs, in particular biologic therapies.
 Assessing RA patient with fever, suspected infection
 Prompt and thorough evaluation of symptoms
 Prompt initiation of antibiotics (especially for patients on biologics)
 Avoid use of trimethoprim/sulfamethoxazole
(Bactrim®, Septra®) in patients on MTX
 Usual bacterial culprits, skin and soft tissue infections, as well as rare
infections
 Opportunistic organisms (especially with biologics)
 Mycobacterial (atypical or disseminated presentation)
 Fungal (eg.
Histoplasma, Coccidioides, Cryptococcus, Aspergillus, Candi
da)
 Viral (e.g. Zoster)

53. Conclusions
 Early introduction of effective treatment with minimal delay in introduction
of combination therapy, including prednisolone or TNF blockers.
 Result-driven (for instance DAS <= 2.4 or remission) treatment.
 Tight-controlled (based on measurement of disease activity) treatment.
 New trials will help to fine tune the timing of the most effective drugs, which
include the newer biologicals.