1. Rheumatoid Arthritis Joan M. Bathon, MD Professor of Medicine Director, Arthritis Center Johns Hopkins Medical Institutions

2. 2 Disclosures Research Support  Biogen-IDEC  Amgen  Bristol Myers Squibb

3. 3 Objectives: Update in RA Diagnosis Treatment Mortality/Survival

4. 4

5. 5 Premature Mortality in Patients with RA Non RA Women Non RA Men RA Women RA Men 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 0 5 5 10 15 20 25 Years After Entry Into Study Survival Probability N = 886 SMR = 3.08 SMR = standardized mortality ratio for patients with RA compared with non-RA controls. Wolfe F, et al. Arthritis Rheum. 1994;37:481-494. Major Cause of Excess Deaths is Cardiovascular Disease

6. 6 Objectives: Update in RA Diagnosis Treatment Mortality/Survival

7. 7 Antibodies to Cyclic Citrullinated Peptides (anti-CCP)

8. 8 RA: Criteria for Classification (4 of 7) 1. Morning stiffness > 1 hour 2. Simultaneous arthritis of > 3 joints 3. Arthritis of hand joints 4. Symmetrical arthritis 5. Rheumatoid nodules 6.Serum rheumatoid factor 7.Typical radiographic changes in hands and wrists

9. 9 Anti Cyclic Citrullinated Peptide Antibodies (Anti CCP) High Specificity for RA 1,2 High Positive Predictive Value for RA 3 Detectable earlier than Rheumatoid Factor (RF) 4 Found in up to 40% of patients who are RF negative especially early in disease 5 Predictive of erosive disease and joint damage 6 Highly associated with presence of HLA genetic polymorphisms that predispose to RA (“shared epitope”) 1. Schellekens GA et al. Arthritis Rheum 2000; 43: 155-63. 2. Lee DM Schur PH. Ann Rheum Dis 2003; 62: 870-4. 3. Jansen LMA et al. J Rheumatol 2002; 29: 2074-6. 4. Nielen MMJ et al. Arthritis Rheum 2004; 50: 380-6. 5. Vallbracht I, et al. Ann Rheum Dis 2004; 63: 1079-84. 5. van Gaalen FA et al. Ann Rheum Dis. 2005 Mar 30; [Epub ahead of print]

10. 10 Anti-CCP and RF Antibodies are Frequently Detected Before Clinical Onset of Disease Nielen MMJ et al. Arthritis Rheum 2004; 50: 380-6.

11. 11 Anti-CCP Predicts Progression to RA How well can clinical parameters predict development of RA? (1 yr f/u) ACR criteria plus CCP OR95% CIp-value Morning stiffness >1 hour2.1(0.8–5.3)0.108 Arthritis of three or more joints5.0(1.8–13.2)0.001 Arthritis of wrist, MCP, PIP1.2(0.4–3.3)0.762 Symmetric involvement of joints6.1(2.0–19.0)0.002 Rheumatoid nodules0.003(0.0–∞)0.795 Positive IgM rheumatoid factor1.7(0.5–5.6)0.406 Erosions on radiographs8.7(2.4–31.2)0.001 Positive anti-CCP2 antibody38.6(9.9–151.0)<0.001 ROC AUC0.923 van Gaalen et al, Arthritis Rheum 2004;50:709–15

12. 12 Anti-CCP as Prognostic Marker of Erosive disease in Early RA 145 patients with RA onset Followed for 5 years At baseline: 57% CCP1+/69% IgM RF+ Radiographic progression monitored with Sharp score Performance of CCP and RF in predicting joint damage CCP1 Total2.5 (1.2 to 5.0)64% Erosions3.4 (1.6 to 7.2)49% Narrowing1.8 (0.8 to 3.6)56% RF Total0.7 (0.3 to 1.5)47% Erosions1.2 (0.5 to 2.8)27% Narrowing0.5 (0.2 to 1.1)40% Meyer O et al, Ann Rheum Dis 2003;62:120–6

13. 13 Antibodies to Citrullinated Proteins are Highly Specific for RA L-arginine residue (+charged) L-citrulline residue (neutral) Peptidylarginine deiminase (PADI) Ca 2+ H N O NH NH 2 H 2 N+ H N O NH NH 2 O

14. 14 Vossenaar ER; BioEssays 25:1106–1118, 2003.

15. 15 Citrullinated Substrates Keratin Filaggrin Fibrin and fibrinogen Vimentin Others ??

16. 16 #1 Diagnosis: Summary Revision of criteria for diagnosis of RA is underway The presence of anti-CCP antibody will undoubtedly constitute a new diagnostic criterion Anti-CCP antibodies are also a prognostic factor for more severe disease

17. 17 Objectives: Update in RA Diagnosis Treatment Mortality/Survival

18. 18 Rheumatoid Arthritis: Expectations of Treatment Reduce pain, stiffness and fatigue Improve Quality of Life Prevent joint destruction Maintain full function Reduce CV events Prolong lifespan

19. 19 RA: Treatment Strategies Treat early Treat “hard” Treat with combination of agents Treat with a targeted goal

20. 20 #1 TREAT EARLY Rationale –Delay in therapy is associated with more joint damage –Active disease of long duration is less responsive to treatment than active disease of short duration Goals –Prevent damage and disability –Start DMARD within 6 wks of sx/dx

21. 21 Change in Median Sharp Score 0 0 2 2 4 4 6 6 8 8 10 12 14 0 0 6 6 12 18 24 Time (months) *Patients were treated with chloroquine or salazopyrine Lard LR, et al. Am J Med. 2001;111:446-451. Treatment: The Earlier the Better Delayed Treatment 1993-1995* (median lag time to treatment = 123 days; n=109) Early Treatment 1996-1998* (median lag time to treatment = 15 days; n=97)

22. 22 Disease Duration Predicts Response to Treatment in RA* *Primary trial data analyzed from 14 randomized, controlled trials: (11) MTX, CyA + MTX, COBRA, and Prosorba Anderson JJ, et al. Arthritis Rheum. 2000;43:22-29. N=1435 Tender joint count Swollen joint count ESR Proportion of Patients Improving 20% 0-11-22-55-10>10 0.8 0.7 0.6 0.5 0.4 0.3 Disease Duration (Years)

23. 23 #2 TREAT HARD Maximally efficacious dose of disease modifying agent (DMARD) that is tolerated by the patient Rapid dose escalation of MTX (up to 20 mg over 8 wks)

24. 24 8.3 1.3 PredictedActual Mean change 9.5 1.3 8.7 0.8 0 2 4 6 8 10 PredictedActualPredictedActual Etanercept and MTX Halt Radiographic Progression in Early RA Etanercept 10 mg Etanercept 25 mg Methotrexate Bathon et al, NEJM 2000

25. 25 #3 TREAT WITH COMBINATION OF AGENTS (when appropriate) Rationale –Combination of agents is superior to monotherapy in every study reported in RA –For signs/sx and retardation of joint damage Types of combinations –Non-biologic + non-biologic DMARD –Non-biologic + biologic DMARD

26. 26 COBRA Trial Long-term Structural Benefits Median Sharp Score Years of Follow-up 60 0 0 15 30 45 SSZ+MTX +steroids SSZ alone COBRA: Prednisolone (initially 60 mg/d, tapered in 6 weekly steps to 7.5 mg/d) plus methotrexate 7.5 mg/wk x 40 wks plus sulfasalazine 2 g/d. SSZ: Sulfasalazine 2 g/d. Landewé RB, et al. Arthritis Rheum. 2002;46:347-356. 1 1 2 2 3 3 4 4 0 0 5 5

27. 27 RA: Treatment Strategies #4 - Treat with a targeted goal* – Remission of disease activity – Or, at least low disease activity *numerical goal, as in DM and HTN

28. 28 Leflunomide SSA MTX 25 mg MTX 15 mg Group 1 Sequential monotherapy n=126 MTX + IFX Gold MTX + CsA + pred AZA + pred MTX + SSA + HCQ MTX + SSA MTX 25 mg MTX 15 mg Group 2 Step-up combination n=121 MTX + SSA + HCQ + pred MTX + IFX MTX + CsA + pred Leflunomide Gold MTX + IFX MTX + CsA + pred MTX 25 mg + SSA + pred MTX 7.5 mg/wk + SSA + pred 60→7.5 mg/day Group 3 Initial combination n=133 Leflunomide Gold AZA + pred SSA MTX + IFX 10 mg/kg MTX 25 mg + IFX 3 mg/kg Group 4 Initial IFX + MTX n=128 Leflunomide MTX + CsA + pred Gold AZA + pred BeST Trial

29. 29 Mean HAQ 0 0.4 0.8 1.2 1.6 0369121518212427303336 Time (months) * * Sequential monotherapy Step-up therapy Initial combi with prednisone Initial combi with infliximab % in remission (DAS <1.6) % with DAS <1.6 0 25 50 75 100 0369121518212427303336 Time (months) 44% Van der Kooij SM, et al EULAR 2007, Barcelona, #OP0125

30. 30 Radiographic progression 0–3 y Pts with xray progression at 3 y P=0.001, groups 1+2 vs 3+4 Median3.83.01.81.5 Mean9.56.63.93.3 % with progression of SHS 60 40 20 0 80 100 4443 29 25 Sequential mono Step-up combi Combi with prednisone Combi with infliximab Van der Kooij SM, et al EULAR 2007, Barcelona, #OP0125 BeST Study

31. 31 BeST Study: Conclusions Goal directed therapy resulted in –excellent outcomes for signs and symptoms regardless of therapeutic agent(s) used. Radiological outcomes better with –early combination than delayed combination. Goal of treatment should be remission or, at least, low disease activity

32. Specific Therapeutic Agents for RA

33. 33 Landmark Developments: Therapeutic Corticosteroids - 1940s Methotrexate - 1980s Anti-TNF therapy – 1998

34. 34 RA TREATMENT: 2008 Methotrexate - most commonly used first DMARD –High benefit to risk ratio If response to MTX monotherapy inadequate, add second agent –Oral agents: hydroxychloroquine, sulfasalazine –Anti-TNF therapy If combination of MTX + TNF inhibitor inadequate, substitute TNF inhibitor for newer biologic

35. 35 TNF Inhibitors: Excellent Efficacy and Comparable for All Three Improve signs and symptoms (joint pain and swelling) Improve laboratory parameters (ESR and CRP) Slow or prevent radiographic progression (erosions and joint space narrowing) Effective in early and late disease Do they reduce mortality?

36. 36 TNF Inhibitors: Safety Issues Infectious –opportunistic and ?common bacteria? Malignancy: non Hodgkin’s lymphoma ? Congestive heart failure Demyelinating disease

37. 37 Options for TNF Failures 50% of pts have only mild-mod response Switch TNF inhibitor (while continuing MTX) ??? –Data are muddy but worth considering New biologics: –Inhibitor of T cell costimulation: abatacept –B cell depleting mAb: rituximab On the horizon: tocilizumab (anti-IL6)

38. 38 Does Treatment of RA….. Prolong lifespan? Reduce cardiovascular events? Reduce cardiovascular risk factors?

39. 39 Objectives: Update in RA Diagnosis Treatment Mortality/Survival

40. 40 Premature Mortality in Patients with RA Non RA Women Non RA Men RA Women RA Men 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 0 5 5 10 15 20 25 Years After Entry Into Study Survival Probability N = 886 SMR = 3.08 SMR = standardized mortality ratio for patients with RA compared with non-RA controls. Wolfe F, et al. Arthritis Rheum. 1994;37:481-494. Major Cause of Excess Deaths is Cardiovascular Disease

41. 41 Top Three Causes of Death in RA Cardiovascular Pulmonary Infection

42. 42 New Mortality/Survival Data: Equivocal Results Observational Studies of RA vs nonRA –Mayo Clinic: no change in mortality rates.  In fact, gap is widening beteween RA and nonRA –European studies of early inflammatory arthritis  Some show improvement, some not Observational Studies of DMARDs within RA populations –Also equivocal Explanations ?? –Short time frame –Methodological issues

43. 43 Top Three Causes of Death in RA Cardiovascular Pulmonary Infection

44. 44 RA is associated with higher rates of: Overall mortality CV associated mortality CV associated morbidity CV risk factors Do DMARDs reduce these complications?

45. 45 Atypical CV Presentation in RA Patients Maradit-Kremers H, Arthritis Rheum 2005;52:402-422.

46. 46 Douglas, Ann Rheum Dis 2006;65:348–353. Reduced Survival in RA Patients with Acute Coronary Syndrome

47. 47 RA: Mortality Standardized Mortality Ratio (SMR) is 1.28-3.0 compared to non-RA controls 1-3 Lifespan of RA patients is decreased by 5-10 years compared to non-RA controls CV disease is the largest contributor to excess deaths 1 Wolfe, et al. Arthr Rheum. 1994;37:481; 2 Doran et al. Arthr Rheum. 2002;46:625; 3 Van Doorrnum et al. Arthr Rheum. 2002;46:862.

48. 48 RA: Clinical CV Events Adjusted incidence rate for CV events is 2-4 fold higher in RA patients compared to non-RA controls 1, 2 –Myocardial infarctions (MI) –strokes (CVA) 1 del Rincon I, et al. Arthr Rheum. 2001;44:2737; 2 Solomon D, et al. Circulation. 2003;107:1303.

49. 49 Statement of the Problem Morbidity and mortality due to cardiovascular (CV) disease are higher in RA populations than in controls. Hypothesis: Accelerated CV disease in RA populations is due to chronic inflammation. Implication: Aggressive treatment of inflammation in RA patients should lower morbidity and mortality associated with CV disease.

50. 50 Potential Mechanisms for Increased Risk of CVD in RA Increased prevalence of conventional risk factors? Increased thrombotic tendency Drug toxicity –Steroids, COX-2, MTX, anti-TNF De-conditioning Inflammation = independent, additive risk factor

51. 51 Are CV Risk Factors More Prevalent in RA Patients? Not by clinical definitions (HTN, DM, hypercholesterolemia, obesity, etc) But, yes, alternate definitions: –Increased prevalence of insulin resistance 1,2 –Pro-atherogenic lipid profiles 3,4 –Increased BMI 5 and percentage of body fat 6 –Increased prevalence of metabolic syndrome TNF-mediated? Correlate with ESR, CRP 1 Dessein PH, et al. J Rheum. 2003;30:1403; 2 Paolisso G, et al. Metabolism. 1991;40:902; 3 Lee YH, et al. Clin Rheum. 2000;19:324; 4 Heldenberg D, et al. Clin Rheum. 1983;2:387; 5 del Rincon I, et al. Arthr Rheum. 2001;44:2737; 6 Giles JT, et al. 2005 ACR annual meeting, San Diego, CA.

52. 52 Do non-biologic DMARDs --- Reduce CV risk factors? Reduce CV events? Reduce CV mortality? Sparse Data

53. 53 Cardiovascular Disease in RA Hydroxychloroquine Protects Against Incident Diabetes in RA Wasko et al. JAMA 2007; 298: 187.

54. 54 StudyNumber of Patients Mortality Rate Kraus et al 2000 271 ↓ Landewe 2000623 ↑ Choi et al 20021240 ↓ Methotrexate: Effect on Mortality Rates is Inconsistent

55. 55 Do biologic inhibitors --- Reduce CV risk factors? Reduce subclinical CV disease? Reduce CV events? Reduce CV mortality?

56. 56 Do biologic (anti-TNF) inhibitors --- Reduce CV risk factors? Reduce subclinical CV disease? Reduce CV events? Reduce CV mortality?

57. 57 Cardiovascular Disease in RA Results Conflicting… 2 studies with improvement in HOMA with infliximab 1,2 1 study with no change in hyperinsulinemic euglycemic clamp with adalimumab 3 Non-RA– little effect of TNF inhibition on insulin sensitivity 4 TNF inhibition and Insulin Resistance in RA 1 Kiortsis et al. Ann Rheum Dis 2005; 64: 765. 2 Tam et al. Clin Rheumatol 2007; 26: 1495. 3 Rosenvinge et al. Scand J Rheumatol 2007; 36: 91. 4 Bernstein et al. Arch Intern Med 2006; 166: 902.

58. 58 Cardiovascular Disease in RA Results also conflicting General themes: –HDL-C increases 1,2,3 –LDL-C increases 1,2,3 –Atherogenic index decreases or stays the same 1,2,3 –Triglycerides go up in some studies 3 May represent patient’s pre-disease lipid profile Similar effects seen with effective non-biologic DMARDs 4,5 TNF Inhibition and Lipids in RA 1 Popa et al. Ann Rheum Dis 2005; 64: 303. 4 Park et al. Am J Med 2002; 113: 188. 2 Vis et al. J Rheumatol 2005; 32: 252. 5 Boers et al. Ann Rheum Dis 2003; 62: 842 3 Tam et al. Clin Rheumatol 2006; 26: 1495.

59. 59 Do biologic (anti-TNF) inhibitors --- Reduce CV risk factors? Reduce subclinical CV disease? Reduce CV events? Reduce CV mortality?

60. 60 Does Anti-TNF Therapy Reduce Subclinical CV Disease? Endothelial dysfunction* –Transient improvement, not sustained Coronary artery calcium –No prospective data Carotid intima-medial thickness (IMT) or plaque –No prospective data *Gonzalez-Juanatey et al, Arthritis Rheum 2004; Cardillo et al Clin Pahrmacol Ther 2006; Bilsborough et al, Rheumatol Int 2006

61. 61 Do biologic (anti-TNF) inhibitors --- Reduce CV risk factors? Reduce subclinical CV disease? Reduce CV events? Reduce CV mortality?

62. 62 Does Anti-TNF Therapy Reduce Clinical CV Events Best Design: Intervention Trial –CV events are relatively infrequent. Therefore,  Large number of patients must be studied  Long period of treatment required –What comparator group?  Placebo unethical  Non-biologic DMARD ??

63. 63 Anti-TNF Therapy and Clinical CV Events Observational Studies –Types:  Prospective cohort study  Nested case-control studies –Data Bases  RA registries »Frequently lack information on CV risk factors  Administrative (claims) data bases »Usually lack information on RA characteristics (severity) –These unmeasured factors may confound the results → → overestimate or underestimate the effect of treatment

64. 64 Jacobbson et al - 2005 Methods –Prospective cohort study –Subjects (RA pts < 80 y.o.):  National register of RA pts on TNF inhibitors, n= 531  Community based RA pts on non-biol DMARDs, n = 543 –Exposure period to drugs: 5-8 yrs? –Primary outcome: First CV event –Statistical adjustments: disease severity, COPD, DM, prednisone, smoking. Other CV risk data unknown. Jacobbson L et al, J Rheum 2005;32:1213

65. 65 Jacobbson – Reduction of events with TNF inhibitor but not statistically significant TreatmentNo. of eventsIncidence rate per 1000 patient- years* Relative Risk (95% CI) No TNF inhibitor 8535.4 1.0 (referent) TNF inhibitor 13140.62 (0.34-1.12) p=0.111 *age and sex adjusted rates

66. 66 Solomon et al - 2006 Methods –Nested case-control (1:10) –Subjects: 3,501 Medicare RA patients on DMARDs (mean age 80 yo) –Primary Outcome: MI or CVA  Prior CV events not excluded –Exposure period: 90 days prior to event –Comparison to MTX –Statistical adjustments: prior CV events, comorbidity, CV meds. Not available: RA disease activity/severity, important CV risk factors (smoking, BMI, ASA use, Framingham risk score). Solomon DH et al, Arthritis Rheum 2006; 54:3790 *cyclosporine, azathioprine, leflunomide

67. 67 Noncytotoxic 892 Cytotoxic 208 Steroids Only 1266 Biologic Other 228 Biologic MTX 117 Biologic 149 MTX 1180 4 2 1 0.5 0.3 84128201482669 Solomon et al. Adjusted RR – MI/CVA

68. 68 Suissa et al - 2006 Methods –Nested case control study (1:10 match)  107, 908 RA patients in PharMetrics database –Primary Outcome: Acute MIs (first) –Exposure to drug(s): 12 mos prior to event –Comparison to no DMARD –Statistical adjustments: prior non-MI CV disease, comorbidity (HTN, DM, hypercholesteremia), CV drugs. Not available: RA activity/severity, smoking, BMI Suissa S et al, Arthritis Rheum 2006; 55:531

69. 69 Other DMARDs 513 Biologics 366 LEF 200 MTX 757 No DMARD 4361 2 1 0.5 0.3 416 60642 34 Suissa et al. Adjusted RR – Acute MI

70. 70 Singh et al (abstract), 2007 Methods –Nested case control study (1:4 match)  California Medicaid Population (MediCal) –Population: 19, 233 RA patients taking  MTX = 13,383; other nonbiologic DMARDs = 14,95; TNF inhibitors = 4,943 –Primary Outcome: Acute MI –Comparison to MTX monotherapy –Exposure to drug: filling of a prescription 60 days prior to event –Statistical adjustments: 38 potentially confounding factors (including smoking, lipids). ??No data on RA disease activity/severity?? Singh G et al, EULAR and ACR 2007

71. 71 Singh – 80% reduction in risk with MTX + TNF inhibitor. Increased risk with steroids. TreatmentAdjusted RR (95% CIs) MTX mono1.0 (referent) TNF inhib + MTX0.20 (0.05-0.88) TNF inhib mono1.17 (0.50-2.75) TNF inhib + other DMARD1.78 (0.60-5.27) Other DMARDs without MTX0.88 (0.60-1.31) Combination of DMARDs + MTX 0.93 (0.54-1.62) Corticosteroids1.37 (1.07-1.75)

72. 72 Dixon et al - 2007 Methods –Prospective national cohort study –Population  National register  No. on anti-TNF=8659; nonbiologic DMARDs=2170 –Primary outcome: first MI –Exposure: ever exposed –Comparison to nonbiologic DMARDs –Statistical adjustments: RA disease activity/severity, BMI, smoking, co-morbidity, CV drugs. Data on other CV risk factors not available. Dixon et al, Arthritis Rheum 2007

73. 73 BSRBR 1.0 2 Incidence Rate Ratio* (95% CI) 0.1 0.4 0.2 DMARD 0.6 10 6 4 Anti-TNF * Adjusted for age, gender, disease severity, BMI, smoking, co-morbidity and baseline drug use 1.44 Dixon et al. Arth Rheum 2007 1763

74. 74 BSRBR 1.0 2 0.1 0.4 0.2 0.6 10 6 4 Responders Non-responders (Referent) 0.36 Anti-TNF Treated Only Incidence Rate Ratio* (95% CI) * Adjusted for age, gender, disease severity, BMI, smoking, co-morbidity and baseline drug use Dixon et al. Arth Rheum 2007

75. 75 Risk of CV Events 8 4 2 1 0.5 0.25 0.06 Bio v MTX Bio/MTX v MTX Bio/Oth v MTX TNF v DMARDs TNF v No Dmards Solomon 2006 MI/CVA Jacobssen 2005 All CVD Dixon 2007 MI Singh 2007 MI Suissa 2006 MI

76. 76 Limitations Different outcomes (predominantly MI) Different lengths of exposure to drugs Inadequate information on many confounding CV risk factors Inadequate information on RA characteristics in most studies –Confounding by indication (channelling bias) Different populations Different comparator groups (no DMARD, MTX, all nonbiol) Variable exclusion of prior CV events

77. 77 Heart Failure (HF) in RA Prevalence of symptomatic HF increased in RA vs nonRA –Adjusted RR 1.43 (Wolfe et al) 1 –Hazard ratio 1.87 (Rochester Minn) 2  Even after adjusting for ischemic CHD In animal studies, overexpression of TNF in the heart leads spontaneously to inflammatory myocarditis, CHF and death –Anti-inflammatory agents may reduce risk for CHF 1 Wolfe et al. J Rheum 2003; 30:36; 2 Nicola 2005; A&R 52:412

78. 78 Anti-TNF Therapy in Non-RA Patients with CHF Non RA patients with moderate to severe CHF –Etanercept, no effect –Infliximab, increased hospitalizations/mortality

79. 79 Anti-TNF Therapy in Non-RA Patients with CHF Non RA patients with moderate to severe CHF –Etanercept, no effect –Infliximab, increased hospitalizations/mortality

80. 80 Wolfe 2004 – Decrease in prevalent but not incident CHF in patients treated with TNF inhibitors No anti-TNF N=7,339 Anti-TNF N=5,832 Prevalent3.8%3.1% Adjusted difference* Referent-1.2 (-1.2, -0.5) % Incident0.4% (n=12) Adjusted difference* Referent-0.1 (-0.1, 0.0) % Wolfe F et al, Am J Med 2004 *Adjusted for propensity score

81. 81 Bernatsky - 2006 Methods –Nested case control study (1:10 match)  41,885 RA patients in administrative database –Primary Outcome: hospitalization for CHF  Prior CHF excluded –Exposure to drug(s): ??ever exposed?? –Comparison to no DMARD –Statistical adjustments: comorbidity, prior CV disease, HTN, DM, hypercholesterolemia. Not available: RA disease activity/severity, smoking, BMI. Bernatsky S et al, Rheumatology 2005; 44:677

82. 82 Anti-TNFOther DMARDSMTXNo DMARD 2.00 1.00 0.50 0.25 Adjusted RR Hosp. CHF Bernatsky et al Bernatsky et al. Rheumatology 2005

83. 83 SUMMARY: ANTI-TNF THERAPY AND CV MORBIDITY IN RA Treatment of RA is associated with….. Transient improvement in some CV risk factors –Insulin resistance, endothelial dysfunction –Effect on lipids is more complex Effect on CV events (MIs, CVAs) inconclusive –Limitations of study designs and available data Effect on CHF inconclusive –Possible reduction but need to reconcile with data in non-RA pts with CHF Can an intervention study be done with clinical CV events as outcome?

84. 84 Conclusions Great advances in the treatment of RA –Specific agents –Treatment strategies (especially tight control) Although not definitively proven yet, seems likely that these agents and strategies will result in –Less CV morbidity and mortality –Reduced overall mortality

85. 85 center arthritis JOHNS HOPKINS http:www.hopkins-arthritis.org

86. 86 RA: Unanswered Questions What is the cause? Who will get it? How to cure it? How to prevent it?

87. 87 center arthritis JOHNS HOPKINS http:www.hopkins-arthritis.org

88. 88 When to use combination of MTX + TNF inhibitor as initial therapy? Consider if patient has high number of risk factors for poor outcome: –Very high titer RF and/or anti-CCP –Strong family history, suggesting SE –Radiographic erosions at baseline –Very high inflammatory markers

89. 89 Inhibitors of TNF-  Soluble TNF Receptor –Etanercept Anti-TNF Monoclonal Antibodies –Infliximab –Adalimumab In de velopment –Golimumab (monoclonal antibody) –Certolizumab (pegylated-TNF receptor) –Dominant negative TNF

90. 90 Expressed as standardized mortality ratios, hazard ratios, IRR Effect of TNF Inhibitors on Mortality Risk Jacobsson L, et al EULAR 2007, Barcelona, #SP0045

91. 91 Treatment of RA patients with a TNF inhibitor (temporarily, partially) improves CV risk factors Insulin resistance 1,2 Dyslipidemia 3,4 Endothelial dysfunction 5,6 1 Dessein PH, et al. Arthritis Res. 2002;4:R12; 2 Dessein PH, et al. J Rheum. 2004;31:867; 3 Vis M, et al. J Rheum. 2005;32:252; 4 Park Y-B, et al. Am J Med. 2002;113:188; 5 Gonzalez-Juanatey C, et al. Arthritis Care Res. 2004;51:447; 6 Hurlimann D, et al. Circulation. 2002;106:2184