1. Evidence-Based Care of Women
with Rheumatoid Arthritis
Marc C. Hochberg, MD, MPH
Professor of Medicine and Epidemiology and Public Health
Head, Division of Rheumatology & Clinical Immunology
University of Maryland School of Medicine
Baltimore, MD

2. Disclosures
• Dr. Hochberg receives research support
from the National Institutes of Health
• He has served as a consultant to the
following commercial entities:
– Abbott Laboratories, Amgen, Astra-Zeneca Pharmaceutical
Co., Bristol Myers Squibb Company, CORRONA,
Genentech/Roche, Merck & Co. Inc., NicOx S.A., Novartis
Pharma AG, Pfizer Inc., Pozen Inc., Theralogix LLC and
UCB Inc.

3. “So much to do; so little time.”
The White Rabbit, “Alice in Wonderland”
Slide provided by Daniel E. Furst, M.D.

4. Rheumatoid Arthritis (RA)
• A chronic, systemic inflammatory
disorder that principally affects the
synovial joints
• Characterized by a proliferative
response in the synovial membrane
leading to bone and cartilage
destruction and joint deformity
Hochberg MC, et al: Rheumatoid arthritis. Mosby/Elsevier, Philadelphia, 2009.

5. Who is Affected by RA?
• Most commonly presents
between the ages of
45 and 64 years1
• Overall lifetime risk of RA2
– 3.6% for women
– 1.7% for men
• For women with a first-
degree relative with RA,
lifetime risk of RA
approaches 18%2
1. Silman AJ and Hochberg MC. In: Rheumatoid Arthritis; 2010, 1st ed. 2. Crowson CS, et al. Arthritis
Rheum. 2011;63:633-639.

6. Common
Articular Features
• Additive, symmetric
inflammatory arthritis
– Typically involves small
joints of the hands
(PIPs, MCPs), wrists,
elbows, shoulders,
knees, ankles, and feet
(MTPs)
– DIPs, hips and spine
usually spared
DIP, distal interphalangeal; MCP, metacarpophalangeal;
MTP, metatarsophalangeal; PIP, proximal interphalangeal.

7. Characteristic Deformities
• Ulnar deviation
• Swan-neck deformity
• Boutonniere deformity

8. 8

9. 9

10. 10

11. Extra-articular Manifestations
Affected tissue or
Comments
organ
Infections Association with RA due to disease, medications; important
implications for vaccination
Cardiovascular Pericarditis, endocarditis, myocarditis, MI; association due to
underlying inflammatory disease, medications, reduced exercise,
genetics
Nervous system Depression; PML (rare but often fatal in immunosuppressed; more
common with biologics such as rituximab)
Skin Subcutaneous nodules
Pulmonary Pulmonary nodules; interstitial lung disease
Eyes Scleritis, episcleritis, retinal vasculitis
Other Secondary Sjogren’s syndrome, anemia, thrombocytosis,
vasculitis, diabetes, GI bleeding, cancer (e.g., lymphoma)
GI, gastrointestinal; MI, myocardial infarction; PML, progressive multifocal leukoencephalopathy.

12. 12

13. Natural History of RA:
Any Gender Differences?
• Baseline measures of disease activity slightly
higher in women1
– Higher swollen/tender joint count
– Higher scores for pain and fatigue
– Worse physician and patient global assessment of
disease activity
• No gender differences in treatment response2
DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; TNF, tumor necrosis factor.
1. Sokka T, et al. Arthritis Res Ther. 2009;11:R7. 2. Kristensen LE, et al. Rheumatology. 2008;47:495-499.

14. Management of RA: 2012
• Early correct diagnosis
• Prompt initiation of traditional DMARDs
– Methotrexate alone
– Triple therapy (MTX, SSZ, HCQ)
• Appropriate use of biological DMARDs
– Anti-TNF agents as 1st line biologics
– What to use in inadequate responders?
DMARD, disease-modifying antirheumatic drug; HCQ, hydroxychloroquine; MTX, methotrexate; SSZ,
sulfasalazine; TNF, tumor necrosis factor.
Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

15. Early Diagnosis of RA
• Prompt referral of patients with 1 or more
swollen joints (“early arthritis”) by the PCP to
a rheumatologist
• Evaluation by the rheumatologist to determine
correct diagnosis
• Apply 2010 ACR/EULAR Classification
Criteria to identify those with early arthritis
who do not have another diagnosis
Aletaha D, et al. Arthritis Rheum. 2010;62:2569-2581.

16. 2010 ACR/EULAR
RA Classification Criteria
• Classification as ‘definite RA’ based on:
– Confirmed presence of synovitis in at least
one joint
– Absence of an alternative diagnosis better
explaining the synovitis
Aletaha D,D et al: Arthritis Rheum 2010;62:2569-81.
*Aletaha et al. Arthritis Rheum. 2010;62:2569-2581.

17. 2010 ACR/EULAR
Classification Criteria for RA
JOINT DISTRIBUTION (0-5)
1 large joint 0
2-10 large joints
1-3 small joints (large joints not counted)
1
2
≥6 = definite RA
4-10 small joints (large joints not counted) 3
>10 joints (at least one small joint) 5
SEROLOGY (0-3) What if the score is <6?
Negative RF AND negative ACPA 0
Low positive RF OR low positive ACPA 2
Patient might fulfill the criteria…
High positive RF OR high positive ACPA 3
SYMPTOM DURATION (0-1)  Prospectively over time
<6 weeks 0 (cumulatively)
≥6 weeks 1
ACUTE PHASE REACTANTS (0-1)  Retrospectively if data on all
Normal CRP AND normal ESR 0 four domains have been
Abnormal CRP OR abnormal ESR 1 adequately recorded in the past
Aletaha D, et al. Arthritis Rheum. 2010;62:2569-2581.

18. Classification Tree
• >10 joints (≥1 small joint)
– Positive serology or duration ≥6 wks or abnormal acute
phase reactant (APR)
• 4-10 small joints
– Positive serology (if low titer, then duration ≥6 wks or
abnormal APR)
• 1-3 small joints
– Positive serology and duration ≥6 wks or abnormal APR (if
low titer, then duration ≥6 wks and abnormal APR)
• 2-10 large joints (no small joints)
– Positive serology and duration ≥6 wks and abnormal APR
Aletaha D,D et al: Arthritis Rheum 2010;62:2569-81.
*Aletaha et al. Arthritis Rheum. 2010;62:2569-2581.

19. Classification Criteria in Practice
Aletaha D,D et al: Arthritis Rheum 2010;62:2569-81.
*Aletaha et al. Arthritis Rheum. 2010;62:2569-2581.

20. Rationale for Early Institution
of Traditional DMARDs
• Early onset of functional limitation and
reduced health-related quality of life
• Early onset of joint damage
– Rate of progression of joint damage is
greater in early c/w late disease
Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

21. RA: Typical Course
• Damage occurs early in most patients
• 50% show joint space narrowing or
erosions in the first 2 years
• Disease activity and damage are
associated with functional limitation and
work disability
– By 10 years, 50% of young working
patients are “work disabled”
Aletaha D, et al. Arthritis Rheum. 2010;62:2569-2581.

22. Critical Elements of Management:
Staging RA
• Assess disease activity
• AM stiffness, synovitis (#P/T and swollen joints),
pain, ESR and/or CRP
• Document the degree of damage
• Joint space narrowing and erosions on imaging
• Functional status (HAQ-DI)
• Document extra-articular manifestations
• Nodules, sicca symptoms, vasculitis
• Assess prior Rx responses and side effects

23. Imaging Tools for Assessing Early
Joint Damage
• Plain radiographs
– Views of hands and feet at baseline visit
– Low sensitivity for early erosive disease
• Ultrasound (gray scale and power Doppler)
– Tenosynovitis common
– Correlates with active disease
• Magnetic resonance imaging
– Gadolinium enhancement for synovitis
Aletaha D, et al. Arthritis Rheum. 2010;62:2569-2581.

24. Grayscale and Power Doppler Ultrasound
Images of Synovial Hypertrophy in RA
Brown AK, et al. Nat Rev Rheumatol. 2009;5:698-706.

25. Grayscale and Ultrasonography Images
of Joint Erosion in RA
Brown AK, et al. Nat Rev Rheumatol. 2009;5:698-706.

26. MRI in Early RA
Mak W, et al. J Musculoskel Med. 2009;26:478-486.

27. Approaches to Traditional
DMARD Therapy
• Single agent (MTX as anchor drug)
– Leflunomide or SSZ in patients with a
contraindication to MTX
• Triple therapy (MTX, SSZ, HCQ)
– More efficacious than MTX alone at 6 months1
– More efficacious than MTX with either SSZ or
HCQ after 2 years2
DMARD, disease-modifying antirheumatic drug; HCQ, hydroxychloroquine; MTX, methotrexate; SSZ,
sulfasalazine.
1. O’Dell J, et al. N Engl J Med. 1996;334:1287-1291. 2. O’Dell J, et al. Arthritis Rheum. 2002;46:1164-1170.

28. Triple DMARD Therapy in RA:
ACR Responses at 2 Years
ACR, American College of Rheumatology; HCQ, hydroxychloroquine; MTX, methotrexate; SSZ, sulfasalazine.
O’Dell J, et al. Arthritis Rheum. 2002;46:1164-1170.

29. Treat to Target (T2T)
• Treatment should be targeted at achieving a
state of clinical remission
– A state of low disease activity may be an
acceptable alternative goal, particularly in patients
with established disease
• Therapy should be adjusted at least every 3
months, as needed
• Decisions should be based on validated
composite measures of disease activity
Smolen JS, et al. Ann Rheum Dis. 2010;69:631-637.

30. T2T Treatment Goals
and Decision Points
Goal DAS-28 CDAI SDAI
Low Disease
≤ 3.2 ≤ 10 ≤ 11
Activity
Clinical
≤ 2.6 ≤ 2.8 ≤ 3.3
Remission
CDAI, Clinical Disease Activity Index; DAS-28, Disease Activity Score-28; SDAI, Simplified Disease Activity
Index. JS, et al. Ann Rheum Dis. 2010;69:631-637.
Smolen

31. ACR/EULAR Definition of
Remission in RA
• Patient must satisfy all of the following:
– Tender joint count ≤ 1
– Swollen joint count ≤ 1
– C-reactive protein ≤ 1 mg/dl
– Patient global assessment ≤ 1 (0-10 scale)
• Patient must have an SDAI score ≤ 3.3
ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; SDAI, Simplified
Disease Activity Index.
Felson DT, et al. Ann Rheum Dis. 2011;70:404-413.

32. Options for Inadequate
Response to Methotrexate
• Add additional traditional DMARDs
– Azathioprine, cyclosporin, leflunomide,
sulfasalazine + hydroxychloroquine
• Add biologic DMARD
– TNF inhibitors are agents of choice for
initial biologic therapy in patients with RA
DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor.
Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

33. Current Biological Targets in RA
CTLA-4Ig / abatacept
Anti-CD20 / rituximab
Pro-inflammatory cytokines
targeted hitherto:
•TNF/ INF, ETN, ADA, GO, CP
IL- 6
•IL-1/ Anakinra
IL-6 receptor/ tocilizumab
ADA, adalimumab; CP, certolizumab pegol;
CTLA-4, cytotoxic T-lymphocyte antigen 4; IL,
interleukin; INF, interferon; ETN, etanercept; GO,
golimumab; TNF, tumor necrosis factor.
Smolen JS, et al. Nature Rev Drug Disc. 2003;2:473-488.

34. Anti-TNF Therapy in Early RA:
Swefot Trial
• 487 patients with early RA enrolled
• 145 achieved LDA with MTX
• 258 randomly assigned to either
infliximab or SSZ + HCQ added to MTX
HCQ, hydroxychloroquine; LDA, low disease activity; MTX, methotrexate; RA, rheumatoid arthritis;
SSZ, sulfasalazine; TNF, tumor necrosis factor.
van Vollenhoven RF, et al. Lancet 2009;374:459-466.

35. Swefot: Triple DMARD vs. MTX + TNFi
MTX + SSZ + HCQ (→ CsA); n=130
Early RA
MTX monotherapy
(~20 mg/wk)
A
Symptoms <1 yr 3–4 m
No other DMARD
DAS28 >3.2
MTX + IFX (→ ETN); n=128
n=487
B
Screening 3m 12 m 24 m
Randomization 1º endpoint: % pts
if DAS28 >3.2 with EULAR Good
(n=258/487) response
Patient Disposition
• 30% pts responded to the initial 3–4-month
trial of MTX monotherapy (DAS28 <3.2: 16%
remission/14% low)
• At 12 m, 75% maintained low disease activity
• Predictors of response: lower DAS, RF-
CsA, cyclosporine; DAS28, disease activity score (28 joints); HCQ, hydroxychloroquine; INF, infliximab; MTX,
methotrexate; RF, rheumatoid factor; SSZ, sulfasalazine.
van Vollenhoven R et al ACR 2008 Abstracts #717, 1003.

36. Swefot Trial Results
Response MTX + SSZ + HCQ MTX + Infliximab RR (95% CI)
EULAR Good 32 (25%) 50 (39%) 1.59 (1.10, 2.30)
EULAR Good
64 (49%) 77 (60%) 1.22 (0.98, 1.53)
or Moderate
ACR 20 37 (28%) 54 (42%) 1.48 (1.06, 2.08)
ACR 50 19 (15%) 32 (25%) 1.71 (1.02, 2.86)
ACR 70 9 (%) 15 (12%) 1.69 (0.77, 3.73)
• Frequency of adverse events similar between groups
ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; HCQ,
hydroxychloroquine; MTX, methotrexate; RR, relative risk; SSZ, sulfasalazine.
van Vollenhoven RF, et al. Lancet 2009;374:459-466.

37. Treatment of Early Aggressive RA (TEAR)
Study of Traditional vs Newer Biologics
• 755 patients with early RA (≤ 3 years)
– MTX naïve; ≥ 4 TJC/SJC; RF+ or CCP+ or ≥ 2 erosions
• Baseline characteristics
– DAS 5.8; 90% RF+; pred 42%; prior DMARD 24%
• Treatment arms
– Initial combination therapy with triple DMARDs or MTX/ETN
(n=376) or MTX monotherapy (n=379) for 24 weeks
– If DAS >3.2 with MTX alone, step up to triple therapy or MTX/ETN
• 28% achieved LDA on MTX alone
• Study endpoints
– Primary: DAS28 from weeks 48-102
– Secondary: ACR20/50/70, Xray, QOL, DAS remission
• Completers analysis: 63% @ 2 yrs
DMARD, disease-modifying antirheumatic drug; ETN, etanercept; MTX, methotrexate; RF, rheumatoid factor.
Moreland L, et al. ACR 2009; Abstract 1895.

38. TEAR Study Results
DAS28 at ACR20 ACR50 ACR70
Treatment week 102 (6 months) (6 months) (6 months)
Initial MTX/ ETN (IE) 3.0 +/- 1.4 63.6% 35.5% 13.1%
Initial Triple DMARD (IT) 2.9 +/- 1.4 64.0% 38.6% 11.4%
Step-up MTX/ETN (SE) 3.1 +/- 1.4 45.2% 22.1% 3.2%
Step-up triple DMARD (ST) 2.8 +/- 1.3 47.7% 21.5% 4.7%
6
IE IT
5
SE ST
4
DAS28
3
Step-up to multiple
2 DMARD at Week
24 if DAS28 ≥ 3.2
1
0
Week 0 Week 12 Week 24 Week 36 Week 48 Week 60 Week 72 Week 84 Week 96 Week 102
Conclusion: Early benefits to aggressive therapy, but similar outcomes
at 2 years regardless of treatment regimen
Moreland L, et al. ACR 2009; Abstract 1895.

39. Initiation of a Biologic DMARD
• Choice of agent is based on the shared decision of
the patient and rheumatologist
• TNF inhibitors are the biologic DMARDs of choice for
patients with an inadequate response to traditional
DMARDs
• Response rates generally similar across anti-TNF
agents
• Safety considerations
– Cases of tuberculosis reactivation reported for TNF-blocking
agents
– Tuberculosis reactivation risk lower with etanercept (soluble
TNF receptor) than with anti-TNF monoclonal antibodies
DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor.
Nam JL, et al. Ann Rheum Dis. 2010;69:976-986. Saillot C, et al. Ann Rheum Dis. 2011:70:266-271.

40. Numbers Needed to Treat with Biologic
DMARDs to Achieve ACR Responses
Response @ 6 months NNT (95% CI)
ACR 20 3.2 (2.4, 4.0)
ACR 50 4.2 (3.6, 4.8)
ACR 70 7.7 (6.7, 10.0)
Response @ 12 months NNT (95% CI)
ACR 20 3.0 (2.6, 3.6)
ACR 50 3.7 (3.2, 4.2)
ACR 70 5.9 (5.0, 6.7)
ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; NNT, number needed
to treat.
Nam JL, et al. Ann Rheum Dis. 2010;69:976-986.

41. Efficacy of Biologic DMARDs in Patients with
Inadequate Responses to Methotrexate
Conclusion:
consistent
trend toward
improved
response with
addition of
biologic
DMARD
Salliot C, et al. Ann Rheum Dis.

42. Cost-Effectiveness of TNF
Inhibitors in RA
Cost-effective* • In patients with an inadequate
response to MTX
Not cost-effective • As initial therapy
• In MTX- or traditional DMARD-
naïve patients
*Defined as incremental cost-effectiveness ratio (ICER) < $100,000 per quality-adjusted life year.
DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; TNF, tumor necrosis factor.
van der Velde G, et al. Arthritis Care Res. 2011;63:65-78.

43. Options for Inadequate
Responders to TNF Inhibitors
• Switch to another TNF inhibitor
• Switch to another biologic DMARD with a
different mechanism of action
– Abatacept
– Rituximab
– Tocilizumab
• Response rates generally similar between
biologic DMARDs
DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor.
Bergman GJD, et al. Semin Arthritis Rheum. 2010:39:425-441. Saillot C, et al. Ann Rheum Dis.

44. Numbers Needed to Treat for
ACR 50 Response
Biologic DMARD NNT (95% CI)
Abatacept 4 (3-5)
Certolizumab pegol 4 (3-5)
Golimumab 6 (4-13)
Rituximab 5 (4-10)
Tocilizumab 5 (3-8)
ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; NNT, number needed
to treat.
Kristensen LE, et al. Scand J Rheumatol. 2010;iFirst:1-7.

45. Role of Glucocorticoids in RA
Management
• Low-dose glucocorticoids effective for:
– Alleviating signs and symptoms
– Reducing functional limitation
– Slowing radiographic progression
• EULAR recommends that dose should be
tapered as rapidly as possible
– No good data, however, on the optimal schedule
for tapering to prevent disease flare
Gorter SL, et al. Ann Rheum Dis. 2010;69:1010-1014.

46. RA and Menopausal Status
• Contraception, fertility issues, and hormone therapy
managed by GYN and/or primary care providers
Premenopause • Recommend contraception during DMARD therapy
• No evidence of interaction between oral contraceptives
and RA
Preconception • Discontinue DMARDs at least 2 menstrual cycles before
trying to conceive
Pregnancy • Expect improvement in RA symptoms during pregnancy
followed by postpartum flare
• Avoid antirheumatic drugs with contraindications in
pregnancy (next slide)
Postmenopause • Refer for hormone therapy at the discretion of the primary
care provider or gynecologist
McNaughton S, et al. J Nurse Pract. 2008;4:370-376.

47. Antirheumatic Drug Risks During Pregnancy
FDA Pregnancy
Drug class Clinical Recommendations
Category
• First-trimester use associated with increased risk of oral cleft
Corticosteroids C
• Increased risk of adrenal insufficiency
Nonbiologic DMARDs
• No increased risk of congenital malformations
Sulfasalazine B
• Combine with folate supplements
Azathioprine D • Can be continued to maintain remission during pregnancy
• Contraindicated in pregnancy
Methotrexate X
• Discontinue 3–6 months before conception
• Contraindicated during pregnancy
Leflunomide X
• Discontinue use 2 years before pregnancy
• HCQ is compatible with pregnancy
Antimalarials C
• Risk for retinal toxicity and ototoxicity higher for chloroquine than for HCQ
Biologic DMARDs
• Anti-TNF antibodies not transferred to embryo/fetus in first trimester of
TNF inhibitors B
pregnancy
• No human pregnancy data available
Abatacept C
• Discontinue 10 weeks before planned pregnancy
• Reversible B-cell depletion or lymphopenia in the neonate
Rituximab C
• Long half-life; discontinue 1 year before planned pregnancy
• No human pregnancy data available
Tocilizumab C
• Discontinue 10 weeks before planned pregnancy
DMARD, disease-modifying antirheumatic drug; HCQ, hydroxychloroquine; TNF, tumor necrosis factor.
Hazes JMW, et al. Rheumatology. 2011;50:1955-1968.

48. Management of RA:
Summary (I)
• Early referral to rheumatology and diagnosis
are of paramount importance
• Traditional DMARDs should be initiated
promptly after diagnosis of RA
• MTX is considered the DMARD of choice
(anchor drug)
• Triple therapy can be considered as an
alternative approach
DMARD, disease-modifying antirheumatic drug; MTX, methotrexate.

49. Management of RA:
Summary (II)
• Patients with an inadequate response to MTX
should be treated with a TNF inhibitor
– Step up therapy using other traditional DMARDs
can be considered
• Patients with an inadequate response to one
TNF inhibitor may be
– Switched to another TNF inhibitor, or
– Treated with a biologic DMARD with a different
mechanism of action
DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; TNF, tumor necrosis factor.

50. Thank you