ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 6, June 2015, pp 1412–1415 DOI 10.1002/art.39096 C 2015, American College of Rheumatology V
EDITORIAL
Treat to Target in Rheumatoid Arthritis: Good for the Joints as Well as the Heart? Michael T. Nurmohamed There is no doubt that cardiovascular disease (CVD) is a major source of mortality and morbidity in rheumatoid arthritis (RA), and equals the CVD burden in (contemporary) diabetes mellitus, a wellestablished CV risk factor (1–4). There is accumulating evidence that this increased CV risk is due not only to increased prevalences of the “traditional” CV risk factors, but also to the chronic underlying inflammatory process. It is well known that inflammation plays an important role at all stages of atherosclerotic disease, and in an inflammatory environment, atherosclerotic plaques are more susceptible to rupture (“vulnerable”), with subsequent thrombosis (5). Atherosclerotic plaque constitution was studied by Karpouzas et al (6), who used 64-slice computed tomography–angiography in a controlled study of 150 RA patients and 150 healthy controls and demonstrated that in RA patients, all types of coronary plaques, including vulnerable plaques, were more frequent than in healthy controls. In addition, inflammation has effects on CV risk factors, leading to, for example, insulin resistance or dyslipidemia. As a consequence, several guidelines for CV risk management have been published, mostly stating that targeting this increased CV risk should be aimed at screening for (and, if necessary, treatment of) cardiovascular risk factors as well as adequately suppressing the underlying inflammatory process. The first recommendations were developed in 2009 and were formulated by the European League Against Rheumatism (7) and advocated yearly CV risk screening for patients with RA
who were receiving treatment with statins and/or antihypertensive agents, depending on the calculated 10-year CV risk. For RA, it was recommended that existing risk functions, such as the Systematic Coronary Risk Evaluation (SCORE), be adapted by a multiplier of 1.5 to achieve a more appropriate estimate of the 10-year CV risk. Importantly, it was also stated that effective suppression of the inflammatory process is necessary to further decrease the CV risk, with the best evidence being for methotrexate and tumor necrosis factor (TNF) blockers. However, these recommendations were, to a large extent, empirical, as evidence from large-scale studies was lacking. One of the first studies suggesting that the CV (mortality) risk in RA could be reduced by methotrexate therapy was conducted by Choi et al (8). That cohort was established from January 1, 1981 onward, and followup ended on December 31, 1999. A total of 1,240 RA patients were followed up for a mean of 6 years, during which time a total of 191 patients died, 44% of which were CV deaths. The mean methotrexate dose was 13 mg/week, and methotrexate use was associated with a 70% reduction in CV mortality as compared to no methotrexate use. This effect was not observed for other disease-modifying antirheumatic drugs (DMARDs). If and to what extent cumulative disease activity was related to CV risk was not addressed in that study, but could be inferred when methotrexate use is considered a proxy for a reduction in disease activity. The first investigation that studied the effect of TNF blockers on (CV) mortality was conducted by Jacobsson et al (9). That group of investigators combined a Swedish database containing 1,430 patients, 921 of whom were being treated with TNF-blocking drugs, with a national mortality registry. There were a total of 188 deaths in 7,077 person-years in the group receiving TNF blockade, and the adjusted death hazard ratio (HR) for TNF blockade versus no TNF blockade was 0.65. Another, more recent, Swedish study determined
Michael T. Nurmohamed, MD, PhD: Amsterdam Rheumatology immunology Center, VU University Medical Center, and Reade, Amsterdam, The Netherlands. Address correspondence to Michael T. Nurmohamed, MD, PhD, Department of Rheumatology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: [email protected]. Submitted for publication February 13, 2015; accepted in revised form February 26, 2015. 1412
EDITORIAL
the risk of an acute coronary syndrome in RA in relation to the use versus no use of TNF blockers as compared to a matched general population extracted from the Swedish population registry (10). A total of 221 acute coronary syndromes occurred in 7,704 patients encompassing 32,621 patient-years. The fully adjusted models revealed an HR of 2.0 for biologic-naive RA patients and a HR of 1.6 for patients taking TNF blockers as compared to the general population. Hence, TNF blockade resulted in an important risk reduction of acute coronary syndromes; nevertheless, it was still markedly increased in comparison to the general population. This effect seems largely mediated through suppression of inflammation, as from a British cohort study, it appeared that the risk of a myocardial infarction was markedly reduced when comparing antiTNF responders versus nonresponders (incidence ratio 0.36) (11). A recent meta-analysis of 28 studies encompassing 236,525 patients investigated the reduction of CV events (defined as myocardial infarction, heart failure, stroke, and/or major adverse cardiac events) associated with treatment with methotrexate and TNF blockers as compared to no use of these drugs (12). There were 5,410 CV events, and the relative risk was 0.72 for treatment with methotrexate and 0.70 for TNF blockers. Another claims database study suggested that the reduction in CV risk might continue during the use of TNFblocking therapy over at least 3 years, with a cumulative risk reduction of 24%, 42%, and 56%, respectively, after 1, 2, or 3 years of anti-TNF treatment (13). Taken together, there is accumulating evidence that treatment with methotrexate and TNF blockers is associated with a reduced risk of CV events, but whether this is mediated through a reduction in disease activity per se or through drug-specific effects is not known. Hence, there is an obvious need for prospective studies investigating the cumulative inflammatory burden in relation to CVD. In a study reported in this issue of Arthritis & Rheumatology, Solomon and colleagues are the first to address this topic in a large-scale prospective study from the Consortium of Rheumatology Researchers of North America (CORRONA) investigators (14). About 3 times each year, 268 rheumatologists from 103 sites in 35 US states contribute data to this registry, which comprises data on disease activity, as determined with the Clinical Disease Activity Index (CDAI), as well as data on comorbidities. The CDAI includes the number of swollen joints (of 28 assessed), the number of tender joints (of 28 assessed), and the patient’s and physician’s global assessments of disease activity (range of 0–10 on
1413
each); thus, overall scores range from 0 to 76 (15). The CDAI was assessed at almost all visits, and the area under the curve for the CDAI was calculated every 6 months, enabling the calculation of a time-averaged CDAI (used as a proxy for cumulative disease activity). CV outcomes were adjudicated by 2 cardiologists and 1 neurologist according to the recommendations of the Food and Drug Administration. The primary outcome consisted of confirmed cases of myocardial infarction, stroke, or CV death. A total of 24,989 patients, with a median followup of 2.7 years, were analyzed. During this period, there were 422 rheumatologist-confirmed CV events, of which 147 (35%) had information available for adjudication. The majority of events (93%) were adjudicated as definite or probable, 3% as possible, and only 4% as no CV event. The incidence rate for the primary outcome was 7.8 per 1,000 patient years (95% CI 6.7–8.9%). The risk for the composite CV outcome was reduced by 21% (95% CI 13–29%) for every 10-point reduction in the average CDAI. When comparing high levels of disease activity (CDAI .22.0) to remission (CDAI #2.8), there was a 53% reduction in CV risk. This risk reduction was observed in all subgroups (with or without previous CVD, and use or nonuse of steroids or coxibs). Importantly, the risk reduction was, in essence, the same when the analysis was adjusted for all clinical characteristics, CV risk factors, as well as antirheumatic drugs, including DMARDs and biologic agents. More stringent analyses (i.e., including only definite or probable cases) revealed a similar pattern as the primary analysis, with a 35%, 58%, and 60% reduction, respectively, when comparing moderate disease activity, low disease activity, and remission to high levels of disease activity. Collectively, the data from this study suggest that aiming for low levels of disease activity or remission also has favorable effects on the CV risk of our patients, and this appears to be independent of the type of antirheumatic drugs used. Novel aspects in comparison to previously conducted studies included the availability of some “traditional” CV risk factors (such as the body mass index, smoking history, and family history of CVD). While data about glucose levels and blood pressure were lacking, the presence of hypertension, dyslipidemia, and diabetes mellitus was assumed in those taking antihypertensive agents, cholesterollowering agents, or antidiabetic drugs. Obviously, this large database study has some other methodologic shortcomings inherent to these types of studies, but due to the size of the cohort, it is not likely these would affect the main conclusions.
1414
What are the clinical implications of this study? First, from a cardiovascular point of view, controlling disease activity/inflammation counts more than the drug used to achieve the low disease state or remission. Second, as inflammation plays a pivotal role in atherosclerotic disease, it is not surprising that antirheumatic drugs such as methotrexate, the interleukin-1 (IL-1) inhibitor canakinumab, and the IL-6 inhibitor tocilizumab are presently investigated in several trials as secondary prevention for recurrent CV events in “general population” patients. Finally, treat-to-target for CVD prevention also implies that we should aim at preventing disease flares. This was recently demonstrated by Myasoedova et al (16), who investigated the time spent in flare and the CVD risk in a controlled study of 525 RA patients and 524 and non-RA controls followed up for 10.1 years and 7.7 years, respectively. RA flare was defined as worsening of disease leading to alteration of therapy, and data were collected retrospectively from the medical charts. Flares were noted at 18% of the visits, and the median duration of the flares was 2.4 months. The CV event rate was 2.4 per 100 person-years in RA and 1.7 per 100 person-years in controls. The CV risk in patients whose RA was in remission did not differ significantly from that in the controls. However, during flares, the HR increased to 2.4, indicating the need for stringent disease control. Obviously, tight control of disease (preferably aiming at remission) might also decrease the CV risk of our patients. Several trials have indicated that such strategies are feasible in clinical practice, provided that (personnel) resources are readily available. In a more constrained situation, the use of simplified disease activity scores such as the CDAI could be considered. In addition, the use of imaging techniques, such as hand scans or biomarker analyses, could simplify the more intense monitoring that is required for tight disease control. Potential underlying mechanisms for the CV risk reduction gained from tight disease control might include stabilization of unstable plaques, but direct evidence is presently lacking, although prospective studies using imaging techniques, such as 18F-labeled fluorodeoxyglucose– positron emission tomography, are currently under way. Another pathway might be the restoration of the antiatherogenic properties of high-density lipoprotein (HDL) cholesterol, which are lost in an inflammatory situation. One of these properties, the HDL cholesterol efflux capacity, is associated with CV risk and is impaired in an inflammatory situation. In a recent 1-year prospective study of 90 RA patients, it was demonstrated that improvement in disease activity paralleled improvement in the HDL cholesterol efflux capacity (17).
NURMOHAMED
Overall, the current state-of-the-art treatment goals for patients with RA also improve the CV risk in these patients. Nevertheless, none of the published studies has shown normalization of the CV risk against the general population. This is not surprising, as targeting the inflammatory process is only one side of the CV coin; the other side should be targeting “traditional” CV risk factors. The contribution of traditional CV risk factors beyond inflammation was nicely demonstrated by another prospective study based on the CORRONA registry (18). It was demonstrated that in CV risk prediction models, both markers of RA disease severity and CV risk contributed independently. Increasing numbers of both risk factors were also associated with a higher CV risk (18). During the last two decades, the treatment of RA has changed enormously, and with the currently available, very effective (and mostly safe) antirheumatic (biologic) drugs, continuous remission should indeed be the (cardiovascular) mission for our patients. There is currently little doubt that this will also have favorable effects on the CV risk of our patients, and this might ultimately lead to decreased (CV) mortality rates. For example, van de Hoek et al (19) conducted a 15-year followup study, from 1997 to 2012, of 1,222 randomly selected RA patients and found an overall 50% increased standardized mortality ratio, implying a .1 year loss of life. However, during these 15 years, there was a gradual decrease in the yearly standardized mortality ratios, and it is conceivable that was the result of the currently applied more-intense antirheumatic treatment. Nevertheless, despite the fact that rheumatologists (should) know that traditional CV risk factors are also important in RA, CV risk management is still poorly done in daily clinical practice (20). Another challenge for the next years is thus to fulfill this unmet need for effective CV risk management implementation strategies. AUTHOR CONTRIBUTIONS Dr. Nurmohamed drafted the article, revised it critically for important intellectual content, and approved the final version to be published.
REFERENCES 1. Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008;59:1690–7. 2. Van Doornum S, McColl G, Wicks IP. Accelerated atherosclerosis: an extraarticular feature of rheumatoid arthritis? [review]. Arthritis Rheum 2002;46:862–73. 3. Peters MJ, van Halm VP, Voskuyl AE, Smulders YM, Boers M, Lems WF, et al. Does rheumatoid arthritis equal diabetes
EDITORIAL
4.
5. 6.
7.
8. 9.
10.
11.
12.
mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis Rheum 2009;61:1571–9. Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen JB, Torp-Pedersen C, et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann Rheum Dis 2011;70:929–34. Libby P. Role of inflammation in atherosclerosis associated with rheumatoid arthritis. Am J Med 2008;121 Suppl 1:S21–31. Karpouzas GA, Malpeso J, Choi TY, Li D, Munoz S, Budoff MJ. Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease. Ann Rheum Dis 2014;73:1797–804. Peters MJ, Symmons DP, McCarey D, Dijkmans BA, Nicola P, Kvien TK, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010;69:325–31. 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. Jacobsson LT, Turesson C, Nilsson JA, Petersson IF, Lindqvist E, Saxne T, et al. Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66:670–5. Ljung L, Askling J, Rantapaa-Dahlqvist S, Jacobsson L, for the ARTIS Study Group. The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population: a national cohort study. Arthritis Res Ther 2014;16:R127. Dixon WG, Watson KD, Lunt M, Hyrich KL, British Society for Rheumatology Biologics Register Control Centre Consortium, 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 a therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2007;56:2905–12. Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, et al. The effects of tumour necrosis factor inhibitors,
1415
13.
14.
15.
16.
17.
18.
19.
20.
methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and metaanalysis. Ann Rheum Dis 2015;74:480–9. Nurmohamed MT, Bao Y, Signorovitch J, Mulani PM, Furst DE. Use of anti-TNF therapy is associated with reduced cardiovascular event risk in rheumatoid arthritis. Ann Rheum Dis 2012;71 Suppl 3:52. Solomon DH, Reed GW, Kremer JM, Curtis JR, Farkouh ME, Harrold LR, et al. Disease activity in rheumatoid arthritis and the risk of cardiovascular events. Arthritis Rheumatol 2015;67: 1449–55. Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 2005;23 Suppl 39:S100–8. Myasoedova E, Chandran A, Ilhan B, Major BT, Michet CJ, Matteson EL, et al. The role of rheumatoid arthritis (RA) flare and cumulative burden of RA severity in the risk of cardiovascular disease. Ann Rheum Dis 2015. E-pub ahead of print. Liao KP, Playford MP, Frits M, Coblyn JS, Iannaccone C, Weinblatt ME, et al. The association between reduction in inflammation and changes in lipoprotein levels and HDL cholesterol efflux capacity in rheumatoid arthritis. J Am Heart Assoc 2015;4:e001588. Solomon DH, Kremer J, Curtis JR, Hochberg MC, Reed G, Tsao P, et al. Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity. Ann Rheum Dis 2010;69:1920–5. Van den Hoek J, Boshuizen HC, Roorda LD, Tijhuis GJ, Nurmohamed MT, van den Bos T, et al. Mortality decreases in patients with rheumatoid arthritis: a 15-year prospective cohort study. Arthritis Rheumatol 2014;66 Suppl:S903. Solomon DH, Peters MJ, Nurmohamed MT, Dixon W. Motion for debate: the data support evidence-based management recommendations for cardiovascular disease in rheumatoid arthritis. Arthritis Rheum 2013;65:1675–83.
Copyright of Arthritis & Rheumatology is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
EDITORIAL
Treat to Target in Rheumatoid Arthritis: Good for the Joints as Well as the Heart? Michael T. Nurmohamed There is no doubt that cardiovascular disease (CVD) is a major source of mortality and morbidity in rheumatoid arthritis (RA), and equals the CVD burden in (contemporary) diabetes mellitus, a wellestablished CV risk factor (1–4). There is accumulating evidence that this increased CV risk is due not only to increased prevalences of the “traditional” CV risk factors, but also to the chronic underlying inflammatory process. It is well known that inflammation plays an important role at all stages of atherosclerotic disease, and in an inflammatory environment, atherosclerotic plaques are more susceptible to rupture (“vulnerable”), with subsequent thrombosis (5). Atherosclerotic plaque constitution was studied by Karpouzas et al (6), who used 64-slice computed tomography–angiography in a controlled study of 150 RA patients and 150 healthy controls and demonstrated that in RA patients, all types of coronary plaques, including vulnerable plaques, were more frequent than in healthy controls. In addition, inflammation has effects on CV risk factors, leading to, for example, insulin resistance or dyslipidemia. As a consequence, several guidelines for CV risk management have been published, mostly stating that targeting this increased CV risk should be aimed at screening for (and, if necessary, treatment of) cardiovascular risk factors as well as adequately suppressing the underlying inflammatory process. The first recommendations were developed in 2009 and were formulated by the European League Against Rheumatism (7) and advocated yearly CV risk screening for patients with RA
who were receiving treatment with statins and/or antihypertensive agents, depending on the calculated 10-year CV risk. For RA, it was recommended that existing risk functions, such as the Systematic Coronary Risk Evaluation (SCORE), be adapted by a multiplier of 1.5 to achieve a more appropriate estimate of the 10-year CV risk. Importantly, it was also stated that effective suppression of the inflammatory process is necessary to further decrease the CV risk, with the best evidence being for methotrexate and tumor necrosis factor (TNF) blockers. However, these recommendations were, to a large extent, empirical, as evidence from large-scale studies was lacking. One of the first studies suggesting that the CV (mortality) risk in RA could be reduced by methotrexate therapy was conducted by Choi et al (8). That cohort was established from January 1, 1981 onward, and followup ended on December 31, 1999. A total of 1,240 RA patients were followed up for a mean of 6 years, during which time a total of 191 patients died, 44% of which were CV deaths. The mean methotrexate dose was 13 mg/week, and methotrexate use was associated with a 70% reduction in CV mortality as compared to no methotrexate use. This effect was not observed for other disease-modifying antirheumatic drugs (DMARDs). If and to what extent cumulative disease activity was related to CV risk was not addressed in that study, but could be inferred when methotrexate use is considered a proxy for a reduction in disease activity. The first investigation that studied the effect of TNF blockers on (CV) mortality was conducted by Jacobsson et al (9). That group of investigators combined a Swedish database containing 1,430 patients, 921 of whom were being treated with TNF-blocking drugs, with a national mortality registry. There were a total of 188 deaths in 7,077 person-years in the group receiving TNF blockade, and the adjusted death hazard ratio (HR) for TNF blockade versus no TNF blockade was 0.65. Another, more recent, Swedish study determined
Michael T. Nurmohamed, MD, PhD: Amsterdam Rheumatology immunology Center, VU University Medical Center, and Reade, Amsterdam, The Netherlands. Address correspondence to Michael T. Nurmohamed, MD, PhD, Department of Rheumatology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: [email protected]. Submitted for publication February 13, 2015; accepted in revised form February 26, 2015. 1412
EDITORIAL
the risk of an acute coronary syndrome in RA in relation to the use versus no use of TNF blockers as compared to a matched general population extracted from the Swedish population registry (10). A total of 221 acute coronary syndromes occurred in 7,704 patients encompassing 32,621 patient-years. The fully adjusted models revealed an HR of 2.0 for biologic-naive RA patients and a HR of 1.6 for patients taking TNF blockers as compared to the general population. Hence, TNF blockade resulted in an important risk reduction of acute coronary syndromes; nevertheless, it was still markedly increased in comparison to the general population. This effect seems largely mediated through suppression of inflammation, as from a British cohort study, it appeared that the risk of a myocardial infarction was markedly reduced when comparing antiTNF responders versus nonresponders (incidence ratio 0.36) (11). A recent meta-analysis of 28 studies encompassing 236,525 patients investigated the reduction of CV events (defined as myocardial infarction, heart failure, stroke, and/or major adverse cardiac events) associated with treatment with methotrexate and TNF blockers as compared to no use of these drugs (12). There were 5,410 CV events, and the relative risk was 0.72 for treatment with methotrexate and 0.70 for TNF blockers. Another claims database study suggested that the reduction in CV risk might continue during the use of TNFblocking therapy over at least 3 years, with a cumulative risk reduction of 24%, 42%, and 56%, respectively, after 1, 2, or 3 years of anti-TNF treatment (13). Taken together, there is accumulating evidence that treatment with methotrexate and TNF blockers is associated with a reduced risk of CV events, but whether this is mediated through a reduction in disease activity per se or through drug-specific effects is not known. Hence, there is an obvious need for prospective studies investigating the cumulative inflammatory burden in relation to CVD. In a study reported in this issue of Arthritis & Rheumatology, Solomon and colleagues are the first to address this topic in a large-scale prospective study from the Consortium of Rheumatology Researchers of North America (CORRONA) investigators (14). About 3 times each year, 268 rheumatologists from 103 sites in 35 US states contribute data to this registry, which comprises data on disease activity, as determined with the Clinical Disease Activity Index (CDAI), as well as data on comorbidities. The CDAI includes the number of swollen joints (of 28 assessed), the number of tender joints (of 28 assessed), and the patient’s and physician’s global assessments of disease activity (range of 0–10 on
1413
each); thus, overall scores range from 0 to 76 (15). The CDAI was assessed at almost all visits, and the area under the curve for the CDAI was calculated every 6 months, enabling the calculation of a time-averaged CDAI (used as a proxy for cumulative disease activity). CV outcomes were adjudicated by 2 cardiologists and 1 neurologist according to the recommendations of the Food and Drug Administration. The primary outcome consisted of confirmed cases of myocardial infarction, stroke, or CV death. A total of 24,989 patients, with a median followup of 2.7 years, were analyzed. During this period, there were 422 rheumatologist-confirmed CV events, of which 147 (35%) had information available for adjudication. The majority of events (93%) were adjudicated as definite or probable, 3% as possible, and only 4% as no CV event. The incidence rate for the primary outcome was 7.8 per 1,000 patient years (95% CI 6.7–8.9%). The risk for the composite CV outcome was reduced by 21% (95% CI 13–29%) for every 10-point reduction in the average CDAI. When comparing high levels of disease activity (CDAI .22.0) to remission (CDAI #2.8), there was a 53% reduction in CV risk. This risk reduction was observed in all subgroups (with or without previous CVD, and use or nonuse of steroids or coxibs). Importantly, the risk reduction was, in essence, the same when the analysis was adjusted for all clinical characteristics, CV risk factors, as well as antirheumatic drugs, including DMARDs and biologic agents. More stringent analyses (i.e., including only definite or probable cases) revealed a similar pattern as the primary analysis, with a 35%, 58%, and 60% reduction, respectively, when comparing moderate disease activity, low disease activity, and remission to high levels of disease activity. Collectively, the data from this study suggest that aiming for low levels of disease activity or remission also has favorable effects on the CV risk of our patients, and this appears to be independent of the type of antirheumatic drugs used. Novel aspects in comparison to previously conducted studies included the availability of some “traditional” CV risk factors (such as the body mass index, smoking history, and family history of CVD). While data about glucose levels and blood pressure were lacking, the presence of hypertension, dyslipidemia, and diabetes mellitus was assumed in those taking antihypertensive agents, cholesterollowering agents, or antidiabetic drugs. Obviously, this large database study has some other methodologic shortcomings inherent to these types of studies, but due to the size of the cohort, it is not likely these would affect the main conclusions.
1414
What are the clinical implications of this study? First, from a cardiovascular point of view, controlling disease activity/inflammation counts more than the drug used to achieve the low disease state or remission. Second, as inflammation plays a pivotal role in atherosclerotic disease, it is not surprising that antirheumatic drugs such as methotrexate, the interleukin-1 (IL-1) inhibitor canakinumab, and the IL-6 inhibitor tocilizumab are presently investigated in several trials as secondary prevention for recurrent CV events in “general population” patients. Finally, treat-to-target for CVD prevention also implies that we should aim at preventing disease flares. This was recently demonstrated by Myasoedova et al (16), who investigated the time spent in flare and the CVD risk in a controlled study of 525 RA patients and 524 and non-RA controls followed up for 10.1 years and 7.7 years, respectively. RA flare was defined as worsening of disease leading to alteration of therapy, and data were collected retrospectively from the medical charts. Flares were noted at 18% of the visits, and the median duration of the flares was 2.4 months. The CV event rate was 2.4 per 100 person-years in RA and 1.7 per 100 person-years in controls. The CV risk in patients whose RA was in remission did not differ significantly from that in the controls. However, during flares, the HR increased to 2.4, indicating the need for stringent disease control. Obviously, tight control of disease (preferably aiming at remission) might also decrease the CV risk of our patients. Several trials have indicated that such strategies are feasible in clinical practice, provided that (personnel) resources are readily available. In a more constrained situation, the use of simplified disease activity scores such as the CDAI could be considered. In addition, the use of imaging techniques, such as hand scans or biomarker analyses, could simplify the more intense monitoring that is required for tight disease control. Potential underlying mechanisms for the CV risk reduction gained from tight disease control might include stabilization of unstable plaques, but direct evidence is presently lacking, although prospective studies using imaging techniques, such as 18F-labeled fluorodeoxyglucose– positron emission tomography, are currently under way. Another pathway might be the restoration of the antiatherogenic properties of high-density lipoprotein (HDL) cholesterol, which are lost in an inflammatory situation. One of these properties, the HDL cholesterol efflux capacity, is associated with CV risk and is impaired in an inflammatory situation. In a recent 1-year prospective study of 90 RA patients, it was demonstrated that improvement in disease activity paralleled improvement in the HDL cholesterol efflux capacity (17).
NURMOHAMED
Overall, the current state-of-the-art treatment goals for patients with RA also improve the CV risk in these patients. Nevertheless, none of the published studies has shown normalization of the CV risk against the general population. This is not surprising, as targeting the inflammatory process is only one side of the CV coin; the other side should be targeting “traditional” CV risk factors. The contribution of traditional CV risk factors beyond inflammation was nicely demonstrated by another prospective study based on the CORRONA registry (18). It was demonstrated that in CV risk prediction models, both markers of RA disease severity and CV risk contributed independently. Increasing numbers of both risk factors were also associated with a higher CV risk (18). During the last two decades, the treatment of RA has changed enormously, and with the currently available, very effective (and mostly safe) antirheumatic (biologic) drugs, continuous remission should indeed be the (cardiovascular) mission for our patients. There is currently little doubt that this will also have favorable effects on the CV risk of our patients, and this might ultimately lead to decreased (CV) mortality rates. For example, van de Hoek et al (19) conducted a 15-year followup study, from 1997 to 2012, of 1,222 randomly selected RA patients and found an overall 50% increased standardized mortality ratio, implying a .1 year loss of life. However, during these 15 years, there was a gradual decrease in the yearly standardized mortality ratios, and it is conceivable that was the result of the currently applied more-intense antirheumatic treatment. Nevertheless, despite the fact that rheumatologists (should) know that traditional CV risk factors are also important in RA, CV risk management is still poorly done in daily clinical practice (20). Another challenge for the next years is thus to fulfill this unmet need for effective CV risk management implementation strategies. AUTHOR CONTRIBUTIONS Dr. Nurmohamed drafted the article, revised it critically for important intellectual content, and approved the final version to be published.
REFERENCES 1. Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008;59:1690–7. 2. Van Doornum S, McColl G, Wicks IP. Accelerated atherosclerosis: an extraarticular feature of rheumatoid arthritis? [review]. Arthritis Rheum 2002;46:862–73. 3. Peters MJ, van Halm VP, Voskuyl AE, Smulders YM, Boers M, Lems WF, et al. Does rheumatoid arthritis equal diabetes
EDITORIAL
4.
5. 6.
7.
8. 9.
10.
11.
12.
mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis Rheum 2009;61:1571–9. Lindhardsen J, Ahlehoff O, Gislason GH, Madsen OR, Olesen JB, Torp-Pedersen C, et al. The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study. Ann Rheum Dis 2011;70:929–34. Libby P. Role of inflammation in atherosclerosis associated with rheumatoid arthritis. Am J Med 2008;121 Suppl 1:S21–31. Karpouzas GA, Malpeso J, Choi TY, Li D, Munoz S, Budoff MJ. Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease. Ann Rheum Dis 2014;73:1797–804. Peters MJ, Symmons DP, McCarey D, Dijkmans BA, Nicola P, Kvien TK, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010;69:325–31. 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. Jacobsson LT, Turesson C, Nilsson JA, Petersson IF, Lindqvist E, Saxne T, et al. Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66:670–5. Ljung L, Askling J, Rantapaa-Dahlqvist S, Jacobsson L, for the ARTIS Study Group. The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population: a national cohort study. Arthritis Res Ther 2014;16:R127. Dixon WG, Watson KD, Lunt M, Hyrich KL, British Society for Rheumatology Biologics Register Control Centre Consortium, 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 a therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2007;56:2905–12. Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, et al. The effects of tumour necrosis factor inhibitors,
1415
13.
14.
15.
16.
17.
18.
19.
20.
methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and metaanalysis. Ann Rheum Dis 2015;74:480–9. Nurmohamed MT, Bao Y, Signorovitch J, Mulani PM, Furst DE. Use of anti-TNF therapy is associated with reduced cardiovascular event risk in rheumatoid arthritis. Ann Rheum Dis 2012;71 Suppl 3:52. Solomon DH, Reed GW, Kremer JM, Curtis JR, Farkouh ME, Harrold LR, et al. Disease activity in rheumatoid arthritis and the risk of cardiovascular events. Arthritis Rheumatol 2015;67: 1449–55. Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 2005;23 Suppl 39:S100–8. Myasoedova E, Chandran A, Ilhan B, Major BT, Michet CJ, Matteson EL, et al. The role of rheumatoid arthritis (RA) flare and cumulative burden of RA severity in the risk of cardiovascular disease. Ann Rheum Dis 2015. E-pub ahead of print. Liao KP, Playford MP, Frits M, Coblyn JS, Iannaccone C, Weinblatt ME, et al. The association between reduction in inflammation and changes in lipoprotein levels and HDL cholesterol efflux capacity in rheumatoid arthritis. J Am Heart Assoc 2015;4:e001588. Solomon DH, Kremer J, Curtis JR, Hochberg MC, Reed G, Tsao P, et al. Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity. Ann Rheum Dis 2010;69:1920–5. Van den Hoek J, Boshuizen HC, Roorda LD, Tijhuis GJ, Nurmohamed MT, van den Bos T, et al. Mortality decreases in patients with rheumatoid arthritis: a 15-year prospective cohort study. Arthritis Rheumatol 2014;66 Suppl:S903. Solomon DH, Peters MJ, Nurmohamed MT, Dixon W. Motion for debate: the data support evidence-based management recommendations for cardiovascular disease in rheumatoid arthritis. Arthritis Rheum 2013;65:1675–83.
Copyright of Arthritis & Rheumatology is the property of John Wiley & Sons, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
