Special Articles
Tumor necrosis factor inhibition: A part of the solution or a part of the problem of heart failure in rheumatoid arthritis?
Sherine E. Gabriel *
Mayo Clinic, Rochester, Minnesota email: Sherine E. Gabriel ( gabriel.sherine@mayo.edu
)
* Correspondence to Sherine E. Gabriel, Department of Health Sciences Research, Mayo
Clinic, 200 1st Street SW, Rochester, MN 55905
Abstract
No abstract.
Received: 25 September 2007; Accepted: 7 December 2007
Digital Object Identifier (DOI)
10.1002/art.23280 About DOI
Article Text
The past decade has witnessed a paradigm shift in our understanding of rheumatoid arthritis (RA). Our view of this chronic disease has shifted from that of an illness characterized largely by physical impairment, disability, and reduced quality of life to one that is also characterized by excess cardiovascular mortality and morbidity ([ 1 ][ 2 ]).
While there seems to be little doubt as to the existence of excess risk for cardiovascular disease in RA, the precise determinants underlying these risks remain elusive. Thus, clinical rheumatologists are uncertain regarding how to help their RA patients reduce their cardiovascular risk. In particular, it remains unclear whether the medications used to treat RA represent a part of the problem, or a part of the solution ([ 3-15 ]).
The issues related to tumor necrosis factor (TNF) inhibition are particularly complex.
TNF , an inflammatory cytokine released by activated monocytes, macrophages, and T lymphocytes, promotes inflammatory responses that are central to the pathogenesis and progression of RA ([ 16 ]). TNF is also known to mediate cardiac injury through a variety of biologic mechanisms, thus contributing to the progression of heart failure
([ 17 ]). These observations led to several large randomized controlled trials designed to assess the efficacy of TNF inhibitor therapy in the treatment of heart failure.
Unfortunately, these efforts were unsuccessful; the trials were stopped prematurely due to lack of efficacy and a suggestion of worsening heart failure in the TNF-treated groups
([ 18 ][ 19 ]). Since then the Food and Drug Administration (FDA) has received numerous reports of cases of new and/or worsening heart failure in patients with RA and/or
Crohn's disease treated with TNF inhibitors. A recent analysis demonstrated a nearly 3fold increase in drug-related serious adverse events (including mortality) reported to the
FDA from 1999 through 2005, and it was noted that TNF inhibitors were among the
15 most frequently named offending drugs ([ 20 ]).

Taken together, these data suggest that TNF inhibitors may promote and/or worsen heart failure in patients with RA. However, high disease activity and systemic inflammation (typically associated with high levels of circulating cytokines) have been consistently shown to increase cardiovascular risk in RA ([ 21-23 ]); thus, inhibition of
TNF should reduce heart failure risk in RA patients. Therein lies the dilemma. On the one hand, it is biologically plausible that by dramatically reducing systemic inflammation, treatment with TNF inhibitors would result in an overall reduction of heart failure risk. On the other hand, it is also possible that these agents increase heart failure risk in persons with RA, as they have been suggested to do in the general population ([ 17 ]). Thus, although TNF inhibitors represent a major advance in the treatment of rheumatic disease, the direction of their impact on cardiovascular risk in
RA is unknown.
In a study reported in this issue of Arthritis & Rheumatism , Listing and colleagues tackled this important and challenging question ([ 24 ]). Unfortunately, while some useful insights are offered, the results fall short of providing clinically useful guidance and leave many questions unanswered. Key elements of the study are highlighted below.
The objective of this analysis from the German biologics register RABBIT (German acronym for Rheumatoid Arthritis - Observation of Biologic Therapy) was To determine the hazard risk of developing or worsening heart failure in RA patients treated with TNF inhibitors.
While observational studies such as this one can provide important information regarding risk, they cannot answer the fundamental clinical question, i.e., will treating my RA patient with a TNF inhibitor increase his or her risk of developing heart failure? The only scientifically credible way to definitively answer this question is by using a randomized controlled clinical trial design. This is largely because observational studies are subject to confounding by indication and confounding by contraindication. Confounding by indication occurs when differences in outcomes between treated and untreated patients are due not to the treatment effect, but to the indication for treatment (i.e., when an indication for treatment, e.g., disease severity, is also a risk factor for the outcome). Similarly, confounding by contraindication occurs when differences in outcomes between treated and untreated patients are due not to the treatment effect, but to the contraindication for treatment (i.e., when a contraindication for treatment, e.g., comorbidity, is also a risk factor for the outcome).
In the case of TNF inhibitor therapy for RA and risk of heart failure, confounding by indication would occur if RA patients with more aggressive disease were more likely to receive TNF inhibitor therapy and aggressive RA itself was an independent risk for heart failure. Alternatively, confounding by contraindication would occur if RA patients who were at higher risk for heart failure (perhaps those with a history of hypertension or diabetes mellitus) were less likely to receive TNF inhibitor therapy. Since both of these potential biases are plausible, the direction of the resulting impact is unknowable.
While Listing et al measured and adjusted for several potential confounders, in the absence of random treatment assignment, potential bias resulting from unmeasured confounders cannot be eliminated.

Eligible cases in the RABBIT study must have fulfilled the American College of
Rheumatology (ACR) criteria for RA ([ 25 ]) and must have been started on new treatment with infliximab, etanercept, adalimumab, or anakinra. Eligible controls must also have fulfilled the ACR criteria for RA and have been started on therapy with a conventional disease-modifying antirheumatic drug (DMARD) after unsuccessful treatment with at least 1 other DMARD. Thus, this study population, though large and carefully followed up, is highly selected and may therefore not be representative of persons with RA in the community. Moreover, the comparability of cases and controls is unknown, leaving substantial potential for confounding and bias.
The statistical analysis plan described by Listing and colleagues ([ 24 ]) was detailed and rigorous and, perhaps most importantly, was specified in advance, thus limiting the potential for post hoc analyses and data dredging.
While this approach is highly commendable and lends credibility to the findings, the authors conducted an ad hoc additional analysis, i.e., a simplified Cox model to estimate an overall risk of anti-TNF treatment as a combined risk comprising a possible beneficial effect (via the efficacy of these agents) and a possible harmful effect (direct risk of the agents).
By excluding the time-dependent covariates (e.g., Disease Activity Score 28-joint assessment, C-reactive protein [CRP] level, glucocorticoid treatment) from this analysis, the authors were attempting to remove the potential confounding that may have been introduced with these variables. For example, if (hypothetically) TNF inhibitor therapy decreased heart failure risk largely through its effect on lowering CRP, then adjusting for CRP levels in the model would mask the beneficial effect of TNF inhibitor therapy.
The results of this analysis were highly nonsignificant both for new heart failure cases and for new or worsening heart failure combined ( P = 0.47 and P = 0.29, respectively).
While the estimated hazard rates suggest that the overall risk may be reduced by 30-
35%, this analysis also indicates that the risk may be increased by as much as 84%.
These results do not support the conclusion (noted in the conclusion section of the abstract and the final paragraph of the text), i.e., TNF inhibitor treatment is more likely to be beneficial than harmful with regard to the risk of heart failure.
There were several other important methodologic weaknesses that limit enthusiasm for this study, including: the lack of standardized definitions for the outcome measures
(heart failure and heart failure worsening), the high dropout rate (15.5% at 48 months), the exclusion of smoking as a risk factor in the mathematical models (due to unavailability of data), and the poor statistical power of the study overall. The latter is a function not of the large number of RA cases and controls in the study population, but of the very small number of events, i.e., 25 new cases of heart failure and 12 cases of heart failure worsening.
Despite these concerns, this study represents an important contribution to the growing literature on heart disease in RA and further highlights the complexity and challenges

surrounding this critically important issue. In addition, this investigation helps us to more clearly focus on the next questions that must be answered if we are to fully understand the tenuous balance between the tremendous benefits offered by the new biologic therapies and their potential risks.
First, there is a need for larger, more rigorous observational studies to allow us to tease out the individual contribution of various treatments and their impact on cardiovascular disease in RA. It is likely impossible for one site or one registry, or a study of one cohort, to accomplish this alone. As noted by Listing and colleagues ([ 24 ]), even a registry as large as the RABBIT registry was grossly underpowered to conduct many of the needed analyses. Thus, such studies will require collaboration across many data resources, in several countries: ideally, including both academia and industry. Second, serious consideration should be given to launching large simple trials examining the risk of heart failure and other cardiovascular events in RA patients treated with TNF inhibitors. This is the only way to definitively resolve the fundamental questions about cardiovascular safety facing rheumatologists today. Third, there is a need to develop effective screening methods and approaches to identify those RA patients in our practices who are at highest cardiovascular risk and who would benefit from early intervention.
While the above proposals appear daunting, I am reminded of William J. Mayo, who once said The best interest of the patient is the only interest to be considered; and in order that the sick may have the benefit of advancing knowledge, a union of forces is necessary ([ 26 ]). I believe that if we are truly motivated to do only what's best for our patients with RA, we will assemble the necessary union of forces to accomplish these important goals.
Acknowledgements
The author gratefully acknowledges Hilal Maradit Kremers, MD, MSc, and Cynthia
Crowson, MS, for their assistance in the preparation of the manuscript.
References
1 Gabriel SE, Crowson CS, Maradit Kremers H, Doran MF, Turesson C, O'Fallon
WM, et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum 2003; 48 : 54-8. Links
2 Boers M, Dijkmans B, Gabriel S, Maradit-Kremers H, O'Dell J, Pincus T. Making an impact on mortality in rheumatoid arthritis: targeting cardiovascular comorbidity.
Arthritis Rheum 2004; 50 : 1734-9. Links
3 Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002; 359 : 1173-7.
Links
4 Landewe RB, van den Borne BE, Breedveld FC, Dijkmans BA. Methotrexate effects in patients with rheumatoid arthritis with cardiovascular comorbidity [letter]. Lancet
2000; 355 : 1616-7. Links

5 Carmona L, Descalzo MA, Perez-Pampin E, Ruiz-Montesinos D, Erra A, Cobo T, et al, on behalf of the BIOBADASER and EMECAR Groups. All-cause and causespecific mortality in rheumatoid arthritis are not greater than expected when treated with tumour necrosis factor antagonists. Ann Rheum Dis 2007; 66 : 880-5. Links
6 Jacobsson LT, Turesson C, Gulfe A, Kapetanovic MC, Petersson IF, Saxne T, et al.
Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol
2005; 32 : 1213-8. Links
7 Wolfe F, Michaud K. Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy. Am J Med 2004; 116 : 305-11. Links
8 Bernatsky S, Hudson M, Suissa S. Anti-rheumatic drug use and risk of hospitalization for congestive heart failure in rheumatoid arthritis. Rheumatology
(Oxford) 2005; 44 : 677-80. Links
9 Curtis JR, Martin C, Saag KG, Kramer J, Patkar N, Shatin D, et al. Risk of heart failure among younger adults exposed to infliximab and etanercept [abstract].
Arthritis Rheum 2006; 54 Suppl 9: S372. Links
10 Dixon WG, Watson KD, Lunt M, Hyrich KL, British Society for Rheumatology
Biologics Register Control Centre Consortium, Silman AJ, et al, on behalf of the
British Society for Rheumatology Biologics Register. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor therapy: results from the British Society for Rheumatology
Biologics Register. Arthritis Rheum 2007; 56 : 2905-12. Links
11 Solomon DH, Avorn J, Katz JN, Weinblatt ME, Setoguchi S, Levin R, et al.
Immunosuppressive medications and hospitalization for cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54 : 3790-8. Links
12 Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, Garcia-Porrua C, Llorca J,
Gonzalez-Gay MA. Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor antibody. Arthritis Rheum 2004; 51 : 447-50. Links
13 Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, et al. Antitumor necrosis factor- treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002; 106 : 2184-7. Links
14 Van Doornum S, McColl G, Wicks IP. Tumour necrosis factor antagonists improve disease activity but not arterial stiffness in rheumatoid arthritis. Rheumatology
(Oxford) 2005; 44 : 1428-32. Links
15 Van Halm VP, Nurmohamed MT, Twisk JW, Dijkmans BA, Voskuyl AE. Diseasemodifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study. Arthritis Res Ther
2006; 8 : R151. Links
16 Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001; 344 : 907-16. Links
17 Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 2002; 91 : 988-98. Links
18 Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, et al.
Targeted anticytokine therapy in patients with chronic heart failure: results of the
Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004;
109 : 1594-602. Links

19 Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT, for the ATTACH
Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor- , in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against
Congestive Heart failure (ATTACH) trial. Circulation 2003; 107 : 3133-40. Links
20 Moore TJ, Cohen MR, Furberg CD. Serious adverse drug events reported to the
Food and Drug Administration, 1998-2005. Arch Intern Med 2007; 167 : 1752-9.
Links
21
Sattar N, McCarey DW, Capell H, McInnes IB. Explaining how high-grade systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation
2003; 108 : 2957-63. Links
22 Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE.
Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis
Rheum 2005; 52 : 722-32. Links
23 Gonzalez-Gay MA, Gonzalez-Juanatey C, Pineiro A, Garcia-Porrua C, Testa A,
Llorca J. High-grade C-reactive protein elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis. J Rheumatol 2005; 32 : 1219-23.
Links
24 Listing J, Strangfeld A, Kekow J, Schneider M, Kapelle A, Wassenberg S, et al.
Does tumor necrosis factor inhibition promote or prevent heart failure in patients with rheumatoid arthritis? Arthritis Rheum 2008; 58 : 667-77. Links
25 Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The
American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31 : 315-24. Links
26 The necessity of cooperation in the practice of medicine. Collected Papers of Saint
Mary's Hospital Proceedings of the Staff Meetings of the Mayo Clinic. 1910.
Special Articles
Tumor necrosis factor inhibition: A part of the solution or a part of the problem of heart failure in rheumatoid arthritis?
Sherine E. Gabriel *
Mayo Clinic, Rochester, Minnesota email: Sherine E. Gabriel (gabriel.sherine@mayo.edu)
*Correspondence to Sherine E. Gabriel, Department of Health Sciences Research, Mayo Clinic,
200 1st Street SW, Rochester, MN 55905
Abstract
Abstract Acknowledgements References
No abstract.
Received: 25 September 2007; Accepted: 7 December 2007
Digital Object Identifier (DOI)
10.1002/art.23280 About DOI
Article Text

The past decade has witnessed a paradigm shift in our understanding of rheumatoid arthritis (RA). Our view of this chronic disease has shifted from that of an illness characterized largely by physical impairment, disability, and reduced quality of life to one that is also characterized by excess cardiovascular mortality and morbidity ([ 1 ][ 2 ]).
While there seems to be little doubt as to the existence of excess risk for cardiovascular disease in RA, the precise determinants underlying these risks remain elusive. Thus, clinical rheumatologists are uncertain regarding how to help their RA patients reduce their cardiovascular risk. In particular, it remains unclear whether the medications used to treat RA represent a part of the problem, or a part of the solution ([ 3-15 ]).
The issues related to tumor necrosis factor (TNF) inhibition are particularly complex.
TNF , an inflammatory cytokine released by activated monocytes, macrophages, and T lymphocytes, promotes inflammatory responses that are central to the pathogenesis and progression of RA ([ 16 ]). TNF is also known to mediate cardiac injury through a variety of biologic mechanisms, thus contributing to the progression of heart failure
([ 17 ]). These observations led to several large randomized controlled trials designed to assess the efficacy of TNF inhibitor therapy in the treatment of heart failure.
Unfortunately, these efforts were unsuccessful; the trials were stopped prematurely due to lack of efficacy and a suggestion of worsening heart failure in the TNF-treated groups
([ 18 ][ 19 ]). Since then the Food and Drug Administration (FDA) has received numerous reports of cases of new and/or worsening heart failure in patients with RA and/or
Crohn's disease treated with TNF inhibitors. A recent analysis demonstrated a nearly 3fold increase in drug-related serious adverse events (including mortality) reported to the
FDA from 1999 through 2005, and it was noted that TNF inhibitors were among the
15 most frequently named offending drugs ([ 20 ]).
Taken together, these data suggest that TNF inhibitors may promote and/or worsen heart failure in patients with RA. However, high disease activity and systemic inflammation (typically associated with high levels of circulating cytokines) have been consistently shown to increase cardiovascular risk in RA ([ 21-23 ]); thus, inhibition of
TNF should reduce heart failure risk in RA patients. Therein lies the dilemma. On the one hand, it is biologically plausible that by dramatically reducing systemic inflammation, treatment with TNF inhibitors would result in an overall reduction of heart failure risk. On the other hand, it is also possible that these agents increase heart failure risk in persons with RA, as they have been suggested to do in the general population ([ 17 ]). Thus, although TNF inhibitors represent a major advance in the treatment of rheumatic disease, the direction of their impact on cardiovascular risk in
RA is unknown.
In a study reported in this issue of Arthritis & Rheumatism , Listing and colleagues tackled this important and challenging question ([ 24 ]). Unfortunately, while some useful insights are offered, the results fall short of providing clinically useful guidance and leave many questions unanswered. Key elements of the study are highlighted below.
The objective of this analysis from the German biologics register RABBIT (German acronym for Rheumatoid Arthritis - Observation of Biologic Therapy) was To determine the hazard risk of developing or worsening heart failure in RA patients treated with TNF inhibitors.
While observational studies such as this one can

provide important information regarding risk, they cannot answer the fundamental clinical question, i.e., will treating my RA patient with a TNF inhibitor increase his or her risk of developing heart failure? The only scientifically credible way to definitively answer this question is by using a randomized controlled clinical trial design. This is largely because observational studies are subject to confounding by indication and confounding by contraindication. Confounding by indication occurs when differences in outcomes between treated and untreated patients are due not to the treatment effect, but to the indication for treatment (i.e., when an indication for treatment, e.g., disease severity, is also a risk factor for the outcome). Similarly, confounding by contraindication occurs when differences in outcomes between treated and untreated patients are due not to the treatment effect, but to the contraindication for treatment (i.e., when a contraindication for treatment, e.g., comorbidity, is also a risk factor for the outcome).
In the case of TNF inhibitor therapy for RA and risk of heart failure, confounding by indication would occur if RA patients with more aggressive disease were more likely to receive TNF inhibitor therapy and aggressive RA itself was an independent risk for heart failure. Alternatively, confounding by contraindication would occur if RA patients who were at higher risk for heart failure (perhaps those with a history of hypertension or diabetes mellitus) were less likely to receive TNF inhibitor therapy. Since both of these potential biases are plausible, the direction of the resulting impact is unknowable.
While Listing et al measured and adjusted for several potential confounders, in the absence of random treatment assignment, potential bias resulting from unmeasured confounders cannot be eliminated.
Eligible cases in the RABBIT study must have fulfilled the American College of
Rheumatology (ACR) criteria for RA ([ 25 ]) and must have been started on new treatment with infliximab, etanercept, adalimumab, or anakinra. Eligible controls must also have fulfilled the ACR criteria for RA and have been started on therapy with a conventional disease-modifying antirheumatic drug (DMARD) after unsuccessful treatment with at least 1 other DMARD. Thus, this study population, though large and carefully followed up, is highly selected and may therefore not be representative of persons with RA in the community. Moreover, the comparability of cases and controls is unknown, leaving substantial potential for confounding and bias.
The statistical analysis plan described by Listing and colleagues ([ 24 ]) was detailed and rigorous and, perhaps most importantly, was specified in advance, thus limiting the potential for post hoc analyses and data dredging.
While this approach is highly commendable and lends credibility to the findings, the authors conducted an ad hoc additional analysis, i.e., a simplified Cox model to estimate an overall risk of anti-TNF treatment as a combined risk comprising a possible beneficial effect (via the efficacy of these agents) and a possible harmful effect (direct risk of the agents).
By excluding the time-dependent covariates (e.g., Disease Activity Score 28-joint assessment, C-reactive protein [CRP] level, glucocorticoid treatment) from this analysis, the authors were attempting to remove the potential confounding that may have been introduced with these variables. For example, if (hypothetically) TNF

inhibitor therapy decreased heart failure risk largely through its effect on lowering CRP, then adjusting for CRP levels in the model would mask the beneficial effect of TNF inhibitor therapy.
The results of this analysis were highly nonsignificant both for new heart failure cases and for new or worsening heart failure combined ( P = 0.47 and P = 0.29, respectively).
While the estimated hazard rates suggest that the overall risk may be reduced by 30-
35%, this analysis also indicates that the risk may be increased by as much as 84%.
These results do not support the conclusion (noted in the conclusion section of the abstract and the final paragraph of the text), i.e., TNF inhibitor treatment is more likely to be beneficial than harmful with regard to the risk of heart failure.
There were several other important methodologic weaknesses that limit enthusiasm for this study, including: the lack of standardized definitions for the outcome measures
(heart failure and heart failure worsening), the high dropout rate (15.5% at 48 months), the exclusion of smoking as a risk factor in the mathematical models (due to unavailability of data), and the poor statistical power of the study overall. The latter is a function not of the large number of RA cases and controls in the study population, but of the very small number of events, i.e., 25 new cases of heart failure and 12 cases of heart failure worsening.
Despite these concerns, this study represents an important contribution to the growing literature on heart disease in RA and further highlights the complexity and challenges surrounding this critically important issue. In addition, this investigation helps us to more clearly focus on the next questions that must be answered if we are to fully understand the tenuous balance between the tremendous benefits offered by the new biologic therapies and their potential risks.
First, there is a need for larger, more rigorous observational studies to allow us to tease out the individual contribution of various treatments and their impact on cardiovascular disease in RA. It is likely impossible for one site or one registry, or a study of one cohort, to accomplish this alone. As noted by Listing and colleagues ([ 24 ]), even a registry as large as the RABBIT registry was grossly underpowered to conduct many of the needed analyses. Thus, such studies will require collaboration across many data resources, in several countries: ideally, including both academia and industry. Second, serious consideration should be given to launching large simple trials examining the risk of heart failure and other cardiovascular events in RA patients treated with TNF inhibitors. This is the only way to definitively resolve the fundamental questions about cardiovascular safety facing rheumatologists today. Third, there is a need to develop effective screening methods and approaches to identify those RA patients in our practices who are at highest cardiovascular risk and who would benefit from early intervention.
While the above proposals appear daunting, I am reminded of William J. Mayo, who once said The best interest of the patient is the only interest to be considered; and in order that the sick may have the benefit of advancing knowledge, a union of forces is necessary ([ 26 ]). I believe that if we are truly motivated to do only what's best for

our patients with RA, we will assemble the necessary union of forces to accomplish these important goals.
Acknowledgements
The author gratefully acknowledges Hilal Maradit Kremers, MD, MSc, and Cynthia
Crowson, MS, for their assistance in the preparation of the manuscript.
Acknowledgements
The author gratefully acknowledges Hilal Maradit Kremers, MD, MSc, and Cynthia
Crowson, MS, for their assistance in the preparation of the manuscript.
References
1 Gabriel SE, Crowson CS, Maradit Kremers H, Doran MF, Turesson C, O'Fallon
WM, et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum 2003; 48 : 54-8. Links
2 Boers M, Dijkmans B, Gabriel S, Maradit-Kremers H, O'Dell J, Pincus T. Making an impact on mortality in rheumatoid arthritis: targeting cardiovascular comorbidity.
Arthritis Rheum 2004; 50 : 1734-9. Links
3 Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002; 359 : 1173-7.
Links
4 Landewe RB, van den Borne BE, Breedveld FC, Dijkmans BA. Methotrexate effects in patients with rheumatoid arthritis with cardiovascular comorbidity [letter]. Lancet
2000; 355 : 1616-7. Links
5 Carmona L, Descalzo MA, Perez-Pampin E, Ruiz-Montesinos D, Erra A, Cobo T, et al, on behalf of the BIOBADASER and EMECAR Groups. All-cause and causespecific mortality in rheumatoid arthritis are not greater than expected when treated with tumour necrosis factor antagonists. Ann Rheum Dis 2007; 66 : 880-5. Links
6 Jacobsson LT, Turesson C, Gulfe A, Kapetanovic MC, Petersson IF, Saxne T, et al.
Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol
2005; 32 : 1213-8. Links
7 Wolfe F, Michaud K. Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy. Am J Med 2004; 116 : 305-11. Links
8 Bernatsky S, Hudson M, Suissa S. Anti-rheumatic drug use and risk of hospitalization for congestive heart failure in rheumatoid arthritis. Rheumatology
(Oxford) 2005; 44 : 677-80. Links
9 Curtis JR, Martin C, Saag KG, Kramer J, Patkar N, Shatin D, et al. Risk of heart failure among younger adults exposed to infliximab and etanercept [abstract].
Arthritis Rheum 2006; 54 Suppl 9: S372. Links
10 Dixon WG, Watson KD, Lunt M, Hyrich KL, British Society for Rheumatology
Biologics Register Control Centre Consortium, Silman AJ, et al, on behalf of the

British Society for Rheumatology Biologics Register. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor therapy: results from the British Society for Rheumatology
Biologics Register. Arthritis Rheum 2007; 56 : 2905-12. Links
11 Solomon DH, Avorn J, Katz JN, Weinblatt ME, Setoguchi S, Levin R, et al.
Immunosuppressive medications and hospitalization for cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54 : 3790-8. Links
12 Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, Garcia-Porrua C, Llorca J,
Gonzalez-Gay MA. Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor antibody. Arthritis Rheum 2004; 51 : 447-50. Links
13 Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, et al. Antitumor necrosis factor- treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002; 106 : 2184-7. Links
14 Van Doornum S, McColl G, Wicks IP. Tumour necrosis factor antagonists improve disease activity but not arterial stiffness in rheumatoid arthritis. Rheumatology
(Oxford) 2005; 44 : 1428-32. Links
15 Van Halm VP, Nurmohamed MT, Twisk JW, Dijkmans BA, Voskuyl AE. Diseasemodifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study. Arthritis Res Ther
2006; 8 : R151. Links
16 Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001; 344 : 907-16. Links
17 Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 2002; 91 : 988-98. Links
18 Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, et al.
Targeted anticytokine therapy in patients with chronic heart failure: results of the
Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004;
109 : 1594-602. Links
19 Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT, for the ATTACH
Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor- , in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against
Congestive Heart failure (ATTACH) trial. Circulation 2003; 107 : 3133-40. Links
20 Moore TJ, Cohen MR, Furberg CD. Serious adverse drug events reported to the
Food and Drug Administration, 1998-2005. Arch Intern Med 2007; 167 : 1752-9.
Links
21
Sattar N, McCarey DW, Capell H, McInnes IB. Explaining how high-grade systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation
2003; 108 : 2957-63. Links
22 Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE.
Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis
Rheum 2005; 52 : 722-32. Links
23 Gonzalez-Gay MA, Gonzalez-Juanatey C, Pineiro A, Garcia-Porrua C, Testa A,
Llorca J. High-grade C-reactive protein elevation correlates with accelerated atherogenesis in patients with rheumatoid arthritis. J Rheumatol 2005; 32 : 1219-23.

Links
24 Listing J, Strangfeld A, Kekow J, Schneider M, Kapelle A, Wassenberg S, et al.
Does tumor necrosis factor inhibition promote or prevent heart failure in patients with rheumatoid arthritis? Arthritis Rheum 2008; 58 : 667-77. Links
25 Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The
American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31 : 315-24. Links
26 The necessity of cooperation in the practice of medicine. Collected Papers of Saint
Mary's Hospital Proceedings of the Staff Meetings of the Mayo Clinic. 1910.