Evidence-Based Care of Women     with Rheumatoid Arthritis              Marc C. Hochberg, MD, MPHProfessor of Medicine and...
Disclosures• Dr. Hochberg receives research support  from the National Institutes of Health• He has served as a consultant...
“So much to do; so little time.”                           The White Rabbit, “Alice in Wonderland”Slide provided by Daniel...
Rheumatoid Arthritis (RA)        • A chronic, systemic inflammatory          disorder that principally affects the        ...
Who is Affected by RA?   • Most commonly presents     between the ages of     45 and 64 years1   • Overall lifetime risk o...
Common      Articular Features      • Additive, symmetric        inflammatory arthritis            – Typically involves sm...
Characteristic Deformities• Ulnar deviation• Swan-neck deformity• Boutonniere deformity
8
9
10
Extra-articular Manifestations    Affected tissue or                       Comments    organ    Infections              As...
12
Natural History of RA:                Any Gender Differences?       • Baseline measures of disease activity slightly      ...
Management of RA: 2012       • Early correct diagnosis       • Prompt initiation of traditional DMARDs            – Methot...
Early Diagnosis of RA       • Prompt referral of patients with 1 or more         swollen joints (“early arthritis”) by the...
2010 ACR/EULAR              RA Classification Criteria      • Classification as ‘definite RA’ based on:           – Confir...
2010 ACR/EULAR              Classification Criteria for RA   JOINT DISTRIBUTION (0-5)   1 large joint                     ...
Classification Tree      • >10 joints (≥1 small joint)           – Positive serology or duration ≥6 wks or abnormal acute ...
Classification Criteria in PracticeAletaha D,D et al: Arthritis Rheum 2010;62:2569-81.*Aletaha et al. Arthritis Rheum. 201...
Rationale for Early Institution            of Traditional DMARDs       • Early onset of functional limitation and         ...
RA: Typical Course       • Damage occurs early in most patients             •   50% show joint space narrowing or         ...
Critical Elements of Management:            Staging RA• Assess disease activity  •   AM stiffness, synovitis (#P/T and swo...
Imaging Tools for Assessing Early                Joint Damage       • Plain radiographs             – Views of hands and f...
Grayscale and Power Doppler Ultrasound         Images of Synovial Hypertrophy in RABrown AK, et al. Nat Rev Rheumatol. 200...
Grayscale and Ultrasonography Images                  of Joint Erosion in RABrown AK, et al. Nat Rev Rheumatol. 2009;5:698...
MRI in Early RAMak W, et al. J Musculoskel Med. 2009;26:478-486.
Approaches to Traditional                   DMARD Therapy        • Single agent (MTX as anchor drug)              – Leflun...
Triple DMARD Therapy in RA:             ACR Responses at 2 YearsACR, American College of Rheumatology; HCQ, hydroxychloroq...
Treat to Target (T2T)        • Treatment should be targeted at achieving a          state of clinical remission           ...
T2T Treatment Goals                       and Decision Points        Goal                           DAS-28                ...
ACR/EULAR Definition of                 Remission in RA      • Patient must satisfy all of the following:            – Ten...
Options for Inadequate             Response to Methotrexate       • Add additional traditional DMARDs             – Azathi...
Current Biological Targets in RA                 CTLA-4Ig / abatacept                Anti-CD20 / rituximab        Pro-infl...
Anti-TNF Therapy in Early RA:                 Swefot Trial        • 487 patients with early RA enrolled        • 145 achie...
Swefot: Triple DMARD vs. MTX + TNFi                                                         MTX + SSZ + HCQ (→ CsA); n=130...
Swefot Trial Results    Response            MTX + SSZ + HCQ           MTX + Infliximab           RR (95% CI)    EULAR Good...
Treatment of Early Aggressive RA (TEAR)        Study of Traditional vs Newer Biologics       • 755 patients with early RA ...
TEAR Study Results                                                    DAS28 at             ACR20          ACR50           ...
Initiation of a Biologic DMARD        • Choice of agent is based on the shared decision of          the patient and rheuma...
Numbers Needed to Treat with Biologic      DMARDs to Achieve ACR Responses        Response @ 6 months                     ...
Efficacy of Biologic DMARDs in Patients with                Inadequate Responses to Methotrexate                          ...
Cost-Effectiveness of TNF                    Inhibitors in RA       Cost-effective*                     • In patients with...
Options for Inadequate          Responders to TNF Inhibitors        • Switch to another TNF inhibitor        • Switch to a...
Numbers Needed to Treat for            ACR 50 Response       Biologic DMARD                                            NNT...
Role of Glucocorticoids in RA                  Management        • Low-dose glucocorticoids effective for:             – A...
RA and Menopausal Status        • Contraception, fertility issues, and hormone therapy          managed by GYN and/or prim...
Antirheumatic Drug Risks During Pregnancy                        FDA Pregnancy      Drug class                      Clinic...
Management of RA:                         Summary (I)        • Early referral to rheumatology and diagnosis          are o...
Management of RA:                         Summary (II)        • Patients with an inadequate response to MTX          shoul...
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  • Patients with American College of Rheumatology (ACR) 20%, 50%, and 70% responses at 2 years, by treatment group. MTX = methotrexate; HCQ = hydroxychloroquine; SSZ = sulfasalazine; NS = not significant. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party.
  • Note: If possible, please add a title to this slide: “Biologics Sites of Action”
  • Two head-to-head treatment arms A Traditional: MTX + SSZ 1000 mg BID + HCQ 400 mg qd; minor adjustments allowed with intolerance B Biologic: infliximab 3 mg/kg (frequency, not dose increase, allowed) given at 0, 2, 6, and then q 8 wks. Could be replaced with etanercept 50 mg/wk Two arms well-matched at baseline Primary = EULAR good response Secondaries = EULAR moderate response, ACR20, 50, 70 responses, etc Imaging data to come
  • KEY POINTS ABSTRACT Purpose: No direct data compares triple DMARD (methotrexate [MTX], sulfasalazine [SSZ], hydroxychloroquine [HCQ]) to MTX + anti-TNF therapy (etanercept) in patients with early RA. The relative benefit of a strategy of either combination vs MTX monotherapy with step-up after 6 months is also uncertain. The TEAR trial evaluates both issues. Methods: The investigator-initiated, multi-center, randomized TEAR trial began in 2004 and enrolled 755 participants to compare immediate (I) vs step-up (S) strategy with MTX, etanercept (E) and triple DMARD (T) in 4 arms: immediate MTX + E (IE) or triple therapy (IT); step-up from MTX to MTX+E (SE) or to T (ST). In SE/ST, if DAS28 ≥ 3.2 at 6 months of MTX, patients were blindly stepped-up to IE/IT. Inclusion criteria: disease duration ≤ 3yrs, diagnosis by ACR criteria; RF+, CCP+ or ≥ 2 radiographic erosions; ≥ 4 tender and 4 swollen joints; MTX naïve. The primary endpoint was mean DAS28 from weeks 48-102. Other endpoints: ACR 20, 50, 70; discontinuation for lack of efficacy, DAS28 remission, QOL and Radiographic progression. Results:   Subjects were 72% female; 80% Caucasian, 11% African American; with a mean age at entry of 49±13 yrs, with 3.6±6.5 months since diagnosis, 90% RF+. The mean DAS28 at entry 5.8±1.1; 28 joint count: 14.3±6.8 painful and 12.8±6.0 swollen joints. As shown in the Table, during the second year of treatment, patients randomized to S arms had clinical responses that were not statistically different than those who received I combination therapy, regardless of treatment arm (p-values: I vs S: 0.95, E vs T: 0.23). There were significant differences in the outcome of ACR response at 6 months between treatment arms: patients initially receiving IE or IT were significantly more likely to achieve an ACR 20/50/70 response at 6 months than those randomized to step-up arms (all p < 0.0001), regardless of treatment (E vs T).   Conclusions:      A 2-year double-blinded trial of early RA patients found no differences in the mean levels of DAS28 during weeks 48-102 among patients randomized to etanercept or triple DMARD, regardless of whether they received immediate combination treatment or MTX monotherapy with a step-up. At 6 months immediate combination treatment with either strategy was more effective than MTX monotherapy; however, there were no significant differences in groups at 2 years. Initial use of MTX monotherapy with the addition of SSZ/HCQ or etanercept, if necessary after 6 months, is a reasonable therapeutic strategy for early RA.  
  • KEY POINTS ABSTRACT Purpose: No direct data compares triple DMARD (methotrexate [MTX], sulfasalazine [SSZ], hydroxychloroquine [HCQ]) to MTX + anti-TNF therapy (etanercept) in patients with early RA. The relative benefit of a strategy of either combination vs MTX monotherapy with step-up after 6 months is also uncertain. The TEAR trial evaluates both issues. Methods: The investigator-initiated, multi-center, randomized TEAR trial began in 2004 and enrolled 755 participants to compare immediate (I) vs step-up (S) strategy with MTX, etanercept (E) and triple DMARD (T) in 4 arms: immediate MTX + E (IE) or triple therapy (IT); step-up from MTX to MTX+E (SE) or to T (ST). In SE/ST, if DAS28 ≥ 3.2 at 6 months of MTX, patients were blindly stepped-up to IE/IT. Inclusion criteria: disease duration ≤ 3yrs, diagnosis by ACR criteria; RF+, CCP+ or ≥ 2 radiographic erosions; ≥ 4 tender and 4 swollen joints; MTX naïve. The primary endpoint was mean DAS28 from weeks 48-102. Other endpoints: ACR 20, 50, 70; discontinuation for lack of efficacy, DAS28 remission, QOL and Radiographic progression. Results:   Subjects were 72% female; 80% Caucasian, 11% African American; with a mean age at entry of 49±13 yrs, with 3.6±6.5 months since diagnosis, 90% RF+. The mean DAS28 at entry 5.8±1.1; 28 joint count: 14.3±6.8 painful and 12.8±6.0 swollen joints. As shown in the Table, during the second year of treatment, patients randomized to S arms had clinical responses that were not statistically different than those who received I combination therapy, regardless of treatment arm (p-values: I vs S: 0.95, E vs T: 0.23). There were significant differences in the outcome of ACR response at 6 months between treatment arms: patients initially receiving IE or IT were significantly more likely to achieve an ACR 20/50/70 response at 6 months than those randomized to step-up arms (all p < 0.0001), regardless of treatment (E vs T).   Conclusions:      A 2-year double-blinded trial of early RA patients found no differences in the mean levels of DAS28 during weeks 48-102 among patients randomized to etanercept or triple DMARD, regardless of whether they received immediate combination treatment or MTX monotherapy with a step-up. At 6 months immediate combination treatment with either strategy was more effective than MTX monotherapy; however, there were no significant differences in groups at 2 years. Initial use of MTX monotherapy with the addition of SSZ/HCQ or etanercept, if necessary after 6 months, is a reasonable therapeutic strategy for early RA.  
  • Forest plots showing the ORs for American College of Rheumatology 50% improvement (ACR50) response rates at week 24 in patients with active rheumatoid arthritis (RA) despite methotrexate receiving abatacept7 19 20 or rituximab 16–18 or anti-tumour necrosis factor agents (TNFs) (infliximab, etanercept, adalimumab, certolizumab and golimumab)7–15 versus placebo, using the Mantel–Haenszel method (random effect model).
  • Pm 4.50 hochberg

    1. 1. Evidence-Based Care of Women with Rheumatoid Arthritis Marc C. Hochberg, MD, MPHProfessor of Medicine and Epidemiology and Public Health Head, Division of Rheumatology & Clinical Immunology University of Maryland School of Medicine Baltimore, MD
    2. 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. 3. “So much to do; so little time.” The White Rabbit, “Alice in Wonderland”Slide provided by Daniel E. Furst, M.D.
    4. 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 deformityHochberg MC, et al: Rheumatoid arthritis. Mosby/Elsevier, Philadelphia, 2009.
    5. 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%21. Silman AJ and Hochberg MC. In: Rheumatoid Arthritis; 2010, 1st ed. 2. Crowson CS, et al. ArthritisRheum. 2011;63:633-639.
    6. 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 sparedDIP, distal interphalangeal; MCP, metacarpophalangeal;MTP, metatarsophalangeal; PIP, proximal interphalangeal.
    7. 7. Characteristic Deformities• Ulnar deviation• Swan-neck deformity• Boutonniere deformity
    8. 8. 8
    9. 9. 9
    10. 10. 10
    11. 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. 12
    13. 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 response2DMARD, 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. 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. 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 diagnosisAletaha D, et al. Arthritis Rheum. 2010;62:2569-2581.
    16. 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 synovitisAletaha D,D et al: Arthritis Rheum 2010;62:2569-81.*Aletaha et al. Arthritis Rheum. 2010;62:2569-2581.
    17. 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 pastAletaha D, et al. Arthritis Rheum. 2010;62:2569-2581.
    18. 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 APRAletaha D,D et al: Arthritis Rheum 2010;62:2569-81.*Aletaha et al. Arthritis Rheum. 2010;62:2569-2581.
    19. 19. Classification Criteria in PracticeAletaha D,D et al: Arthritis Rheum 2010;62:2569-81.*Aletaha et al. Arthritis Rheum. 2010;62:2569-2581.
    20. 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 diseaseSaag KG, et al. Arthritis Rheum. 2008;59:762-784.
    21. 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. 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. 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 synovitisAletaha D, et al. Arthritis Rheum. 2010;62:2569-2581.
    24. 24. Grayscale and Power Doppler Ultrasound Images of Synovial Hypertrophy in RABrown AK, et al. Nat Rev Rheumatol. 2009;5:698-706.
    25. 25. Grayscale and Ultrasonography Images of Joint Erosion in RABrown AK, et al. Nat Rev Rheumatol. 2009;5:698-706.
    26. 26. MRI in Early RAMak W, et al. J Musculoskel Med. 2009;26:478-486.
    27. 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 years2DMARD, 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. 28. Triple DMARD Therapy in RA: ACR Responses at 2 YearsACR, American College of Rheumatology; HCQ, hydroxychloroquine; MTX, methotrexate; SSZ, sulfasalazine.O’Dell J, et al. Arthritis Rheum. 2002;46:1164-1170.
    29. 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 activitySmolen JS, et al. Ann Rheum Dis. 2010;69:631-637.
    30. 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 RemissionCDAI, Clinical Disease Activity Index; DAS-28, Disease Activity Score-28; SDAI, Simplified Disease ActivityIndex. JS, et al. Ann Rheum Dis. 2010;69:631-637.Smolen
    31. 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 ≤ 3.3ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; SDAI, SimplifiedDisease Activity Index.Felson DT, et al. Ann Rheum Dis. 2011;70:404-413.
    32. 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 RADMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor.Saag KG, et al. Arthritis Rheum. 2008;59:762-784.
    33. 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/ tocilizumabADA, 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. 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 MTXHCQ, 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. 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. 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 groupsACR, 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. 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 yrsDMARD, disease-modifying antirheumatic drug; ETN, etanercept; MTX, methotrexate; RF, rheumatoid factor.Moreland L, et al. ACR 2009; Abstract 1895.
    38. 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 regimenMoreland L, et al. ACR 2009; Abstract 1895.
    39. 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 antibodiesDMARD, 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. 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 neededto treat.Nam JL, et al. Ann Rheum Dis. 2010;69:976-986.
    41. 41. Efficacy of Biologic DMARDs in Patients with Inadequate Responses to Methotrexate Conclusion: consistent trend toward improved response with addition of biologic DMARDSalliot C, et al. Ann Rheum Dis.
    42. 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. 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 DMARDsDMARD, 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. 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 neededto treat.Kristensen LE, et al. Scand J Rheumatol. 2010;iFirst:1-7.
    45. 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 flareGorter SL, et al. Ann Rheum Dis. 2010;69:1010-1014.
    46. 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 gynecologistMcNaughton S, et al. J Nurse Pract. 2008;4:370-376.
    47. 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 pregnancyDMARD, disease-modifying antirheumatic drug; HCQ, hydroxychloroquine; TNF, tumor necrosis factor.Hazes JMW, et al. Rheumatology. 2011;50:1955-1968.
    48. 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 approachDMARD, disease-modifying antirheumatic drug; MTX, methotrexate.
    49. 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 actionDMARD, disease-modifying antirheumatic drug; MTX, methotrexate; TNF, tumor necrosis factor.
    50. 50. Thank you

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