Antirheumatic drugs, particularly glucocorticoids, are suspected of promoting atherosclerosis, despite scant evidence to support this notion (1, 2). There have been only a few studies of the arteries of patients with rheumatoid arthritis (RA), and none that have linked arterial anatomy and function to cumulative glucocorticoid exposure. Although these drugs are helpful in RA and are widely prescribed (3), they are associated with substantial side effects, and their use remains controversial (4, 5). It is important to determine whether glucocorticoids do indeed contribute to the risk of atherosclerosis, so that physicians and patients can factor this information into their clinical decision-making (6, 7).
One potential source of error in estimating the atherogenic properties of glucocorticoids is confounding by indication: physicians prescribe glucocorticoids to patients with the most active inflammatory disease. Systemic inflammation may itself promote atherosclerosis. Therefore, efforts to measure the atherogenic effects of glucocorticoids should aim to determine the extent to which such effects are independent of the activity of inflammatory rheumatoid disease. We therefore studied the carotid and lower-limb arteries in a sample of RA patients, and related the findings to the extent of glucocorticoid exposure, before and after adjustment for indicators of RA disease activity and joint damage and cardiovascular (CV) risk factors.
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- PATIENTS AND METHODS
The sample included 779 RA patients. We began the arterial assessments in February 2000. Sixty-six patients died and 32 moved away from the San Antonio area before we could schedule an appointment. This left 681 patients still eligible to participate in the arterial assessments. Of these, we could not establish contact with 17, and 17 declined to participate. We obtained either the ABI measurements or a carotid ultrasound on 647 patients, which was 95% of those eligible. The ABI was obtained from 644 patients (95%), carotid ultrasound from 632 (93%), and both measurements from 629 (92%). Three patients who consented to undergo carotid ultrasonography did not consent to receive the ABI measurements. We obtained the ABI, without carotid ultrasonography, at the homes of 10 patients, and at nursing homes from an additional 2 patients. The visit at which we obtained the ABI measurements during the study on the disablement process in RA was the fifth visit for 3 patients, the fourth for 44 patients, the third for 215 patients, the second for 378 patients, and the first for 4 patients. The median amount of time since the patients had been enrolled in the longitudinal study of the disablement process in RA was 3 years and 3 months, ranging from <1 year to 7 years and 1 month.
The RA treatment had included glucocorticoids in 427 patients (66% of those studied). Among those who reported use of glucocorticoids, the mean cumulative dose was 16.3 gm (range 5 mg to 121 gm), over a mean of 7.5 years (range 4 months to 52 years), for a mean daily dose of 6.4 mg (median 5 mg, range 1–26 mg). The duration of glucocorticoid exposure among those who were exposed ranged from 5 days to 12,927 days, with a median of 2,137 days and a mean ± SD of 2,639 ± 2,323 days. As a comparison drug, we chose methotrexate. Among the 552 patients (71%) who were exposed to this DMARD, exposure duration ranged from 1 day to 6,966 days, with a median of 1,488 days and a mean ± SD of 1,940 ± 1,412 days. The dose of methotrexate used was not available to us.
There was a modest, but positive, correlation between the cumulative glucocorticoid dose and other variables related to time. Thus, the Pearson values for correlations with the cumulative glucocorticoid dose were 0.07 for age, 0.19 for disease duration, and 0.12 for length of time of methotrexate use. As expected, the cumulative glucocorticoid dose correlated strongly with length of time of glucocorticoid exposure (r = 0.80). Duration of glucocorticoid exposure correlated modestly with duration of methotrexate use (r = 0.15) (P ≤ 0.04 for all correlations listed).
Table 1 provides the characteristics of the patients, according to cumulative glucocorticoid dose. As expected, patients with a high cumulative dose of glucocorticoid exposure had a longer disease duration since the diagnosis of RA, had higher joint counts, and were more likely to have subcutaneous nodules and rheumatoid factor seropositivity, as compared with the unexposed patients (Table 1).
Table 1. Characteristics of the rheumatoid arthritis patients in the sample, according to cumulative glucocorticoid dose
|Patient characteristics||Cumulative glucocorticoid exposure level*|
|Unexposed||5–6,030 mg||6,072–16,240 mg||16,338–121,980 mg|
|Number of patients||220||146||141||140|
|Demographic characteristic|| || || || |
| Age, median (range) years||60 (22–84)||57 (21–87)||60 (25–90)||62 (29–84)|
| Women, no. (%)||160 (73)||114 (78)||101 (72)||90 (64)|
| Ethnicity/race, no. (%)|| || || || |
| White||80 (36)||49 (34)||43 (31)||49 (35)|
| Black||17 (8)||7 (5)||15 (11)||6 (4)|
| Hispanic||117 (53)||88 (60)||81 (57)||78 (56)|
| Asian||4 (2)||1 (1)||2 (1)||4 (3)|
| Other||2 (1)||1 (1)||0||3 (2)|
|Clinical characteristic|| || || || |
| Disease duration, median (range) years||11 (1–51)||8 (0–56)||12 (1–56)||16 (3–55)†|
| Tender joint count, mean ± SD||12.1 ± 12||14.6 ± 13||14.9 ± 13‡||16.7 ± 13†|
| Swollen joint count, mean ± SD||3.3 ± 4.5||4.9 ± 5.2‡||4.0 ± 4.7||5.1 ± 5.5†|
| Deformed joint count, mean ± SD||13.7 ± 11.2||13.8 ± 12.0||17.0 ± 12.4‡||19.9 ± 13.0†|
| Subcutaneous nodules, no. (%)||92 (42)||64 (44)||64 (49)||77 (55)‡|
| Erythrocyte sedimentation rate, mean ± SD mm/hour||38 ± 25||42 ± 25||44 ± 27||42 ± 26|
| C-reactive protein, mean ± SD mg/dl||15 ± 27||15 ± 20||17 ± 20||17 ± 22|
| Rheumatoid factor, no. (%)||164 (75)||120 (83)||125 (89)†||124 (89)§|
| HLA–DRB1 shared epitope–positive, no. (%)||157 (72)||108 (74)||92 (65)||110 (79)|
| Diabetes mellitus, no. (%)||46 (21)||29 (20)||27 (19)||22 (16)|
| Hypercholesterolemia, no. (%)||112 (51)||77 (53)||77 (55)||76 (54)|
| Former smoker, no. (%)||86 (39)||54 (37)||61 (43)||64 (46)|
| Current smoker, no. (%)||40 (18)||32 (23)||22 (16)||24 (17)|
| Systolic blood pressure, mean ± SD mm Hg||140 ± 21||139 ± 20||140 ± 21||138 ± 23|
| Diastolic blood pressure, mean ± SD mm Hg||76 ± 12||75 ± 12||76 ± 11||75 ± 12|
| Body mass index, mean ± SD kg/m2||29.4 ± 6.3||28.8 ± 6.3||28.3 ± 5.7||29.2 ± 6.7|
For 1 of the 632 patients who had received carotid ultrasound, the image of the carotid artery could not be read due to the patient's impaired mobility which prevented proper positioning of the ultrasound probe. Thus, we had 1,262 carotid artery images, of which 485 (38%) displayed plaque. Plaque frequency increased with increasing exposure to glucocorticoids, from 144 of 430 unexposed arteries (33%), to 126 of 278 exposed arteries (45%) among patients in the highest tertile of lifetime glucocorticoid exposure (P for trend = 0.005) (Table 2). This trend remained significant after adjustment for age at onset, disease duration, and sex (P = 0.03) but not after adding CV risk factors (P = 0.06) and RA joint findings as well as subcutaneous nodules, rheumatoid factor seropositivity, and ESR (P = 0.09). However, the person-based plaque analysis revealed a significant association, independent of all covariates, between glucocorticoid exposure and frequency of plaque (Table 3).
Table 2. Arterial characteristics according to cumulative glucocorticoid dose
|Artery type, characteristic||Total number||Cumulative glucocorticoid exposure level||P for trend|
|Unexposed||5–6,030 mg||6,072–16,240 mg||16,338–121,980 mg||Unadjusted||Adjusted*|
|Model 1||Model 2||Model 3|
|Carotid arteries|| || || || || || || || || |
| Intima-media thickness, mean ± SD mm||631 persons||1.084 ± 0.501||1.060 ± 0.496||1.116 ± 0.460||1.160 ± 0.544||0.1||0.5||0.4||0.6|
| Plaque, no./total no. (%)||1,262 arteries||144/430 (33)||102/278 (37)||113/276 (41)||126/278 (45)†||0.005||0.03||0.06||0.09|
|Lower-limb arteries, no./total no. (%)||2,569 arteries|| || || || || || || || |
| Normal||2,191 arteries||755/873 (86)||518/584 (89)||473/556 (85)||445/556 (80)†||0.057||0.1||0.1||0.6|
| Obstructed||208 arteries||83/873 (10)||43/584 (7)||42/556 (8)||40/556 (7)†||0.5||0.4||0.4||0.1|
| Incompressible||170 arteries||35/873 (4)||23/584 (4)||41/556 (7)||71/556 (13)‡||≤0.001||0.004||0.002||0.01|
Table 3. Frequency distribution of arterial plaque, obstruction, or incompressibility, according to cumulative glucocorticoid dose
|Glucocorticoid exposure level||No. of patients with abnormality/total in category (%)||OR (95% CI)*||P vs. unexposed||P for trend over exposure categories|
|Plaque|| || || || |
| Unexposed||100/215 (47)||1.0 (referent)||–||–|
| 5–6,030 mg||66/142 (46)||0.99 (0.65–1.52)||0.9||–|
| 6,072–16,240 mg||77/136 (57)||1.50 (0.94–2.31)||0.07||–|
| 16,338–121,980 mg||85/138 (62)||1.84 (1.19–2.85)||0.006†||0.005†|
|Incompressibility|| || || || |
| Unexposed||17/219 (8)||1.0 (referent)||–||–|
| 5–6,030 mg||14/146 (10)||1.26 (0.60–2.64)||0.5||–|
| 6,072–16,240 mg||20/139 (14)||1.99 (1.01–3.96)||0.05||–|
| 16,338–121,980 mg||24/140 (17)||2.46 (1.27–4.77)||0.008†||0.004†|
|Obstruction|| || || || |
| Unexposed||34/219 (16)||1.0 (referent)||–||–|
| 5–6,030 mg||16/146 (11)||0.67 (0.35–1.26)||0.2||–|
| 6,072–16,240 mg||16/139 (12)||0.71 (0.37–1.34)||0.3||–|
| 16,338–121,980 mg||17/140 (12)||0.75 (0.40–1.40)||0.4||0.3|
Analyses using estimates of plaque severity, defined as the degree of carotid lumen narrowing, showed a significant pattern of association with glucocorticoid exposure, similar to that observed in the plaque analyses (shown in Tables 2 and 3). However, the significance of the association was lost after adjustment for CV risk factors and RA clinical manifestations, which perhaps reflects a loss of precision when severity estimates were added.
Because the CaIMT is a person-level variable, we had 631 values for this analysis. The CaIMT determined in the 631 patients was a mean ± SD 1.102 ± 0.501 mm. As was observed in the analyses with plaque, the CaIMT tended to be greater among patients with increasing exposure to glucocorticoids, but this association did not reach statistical significance (Table 2). Similarly, patients in the highest tertile of lifetime glucocorticoid exposure had a mean ± SD CaIMT that exceeded that of patients who had never received glucocorticoids, by 0.076 mm ± 0.05 mm, but the difference did not reach the traditional criterion for statistical significance (P = 0.16).
We measured the ABI in 644 patients. For 1 of these patients, we had only 3 ABI values because we could not perform the measurement on a posterior tibial artery due to an overlying skin wound. An additional 3 patients had undergone amputation of a lower limb and therefore had only 2 arteries for measurement. Thus, the ABI was available on 2,569 arteries. Of these, the ABI was normal in 2,191 arteries (85%), obstructed in 208 (8.1%), and incompressible in 170 (6.6%). The cumulative glucocorticoid dose was significantly associated with arterial incompressibility (Table 2). This association displayed a gradient in which the proportion of incompressible arteries increased with higher glucocorticoid exposure (P for trend ≤ 0.001). This pattern was independent of age at RA onset, sex, disease duration, CV risk factors, and manifestations of RA (Table 2).
The person-based analyses recapitulated these results (Table 3). Carotid plaque was present in 328 patients (52%). Obstruction of ≥1 lower-limb artery was present in 83 patients (13%). Arterial incompressibility was present in 75 (12%) of these patients, and obstruction and incompressibility occurred in 155 (24%) of the patients. Both carotid plaque and arterial incompressibility were present in increasing frequency as the glucocorticoid exposure increased. This association was independent of all covariates, including age, sex, disease duration, CV risk factors, RA clinical manifestations, and measures of inflammation (Table 3).
Table 4 shows the arterial findings with respect to the length of time of glucocorticoid exposure, and as a referent, the methotrexate exposure time was used. In the unadjusted comparison, both of the carotid artery outcomes and lower-limb arterial incompressibility were significantly associated with the length of time of glucocorticoid exposure. In contrast, there was minimal variation in the arterial outcomes over the methotrexate exposure categories. This supports the hypothesis of a specific glucocorticoid effect, rather than just an effect of time. However, it should be noted that the association between arterial findings and duration of glucocorticoid exposure was lost after adjustment for RA manifestations. Thus, the additional dimension of dose level seems to be important to fully account for the intensity of glucocorticoid exposure.
Table 4. Arterial characteristics according to the duration of glucocorticoid or methotrexate exposure
|Drug, artery type, characteristic||Duration of exposure||P for trend*|
|Unexposed||5–1,369 days||1,387–3,038 days||3,106–12,927 days|
|Glucocorticoids|| || || || || |
| Carotid arteries|| || || || || |
| Intima-media thickness, mean ± SD mm||1.077 ± 0.492||1.049 ± 0.528||1.146 ± 0.467||1.203 ± 0.538||0.03†|
| Plaque, no. (%)||251 (36)||59 (32)||85 (46)||89 (48)||0.003†|
| Lower-limb arteries, no. (%)|| || || || || |
| Normal||1,243 (86)||335 (88)||313 (82)||296 (81)||0.09|
| Obstructed||137 (10)||11 (3)||34 (9)||26 (7)||0.5|
| Incompressible||59 (4)||34 (9)||33 (9)||44 (12)||0.001‡|
|Methotrexate|| || || || || |
| Carotid arteries|| || || || || |
| Intima-media thickness, mean ± SD mm||1.104 ± 0.496||1.059 ± 0.464||1.087 ± 0.482||1.156 ± 0.660||0.4|
| Plaque, no. (%)||152 (40)||101 (35)||110 (37)||122 (42)||0.8|
| Lower-limb arteries, no. (%)|| || || || || |
| Normal||671 (86)||508 (86)||512 (85)||500 (84)||0.9|
| Obstructed||56 (7)||45 (8)||53 (9)||54 (9)||0.4|
| Incompressible||50 (6)||41 (7)||37 (6)||42 (7)||0.8|
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- PATIENTS AND METHODS
Studies suggest that RA increases the risk of CV disease independent of traditional risk factors (17, 18) and may predispose individuals to atherosclerosis (19–22). The glucocorticoids commonly used to treat RA are a suspected cause. This suspicion is supported, in part, by the association between glucocorticoid use and carotid plaque observed in patients with systemic lupus erythematosus (SLE) (23). However, the findings in SLE may not translate well to RA. The mechanisms and intensity of vascular inflammation in SLE are likely to be substantially different from those in RA, and the glucocorticoid dose prescribed for RA is usually not as high as is commonly used in SLE. With their antiinflammatory properties, glucocorticoids in the low doses that are normally prescribed to RA patients could even have an antiatherogenic effect, given the inflammatory nature of atherosclerosis (24).
We used noninvasive methods to assess the extent of atherosclerosis. High-resolution carotid ultrasound is used widely for this purpose. Its utility is supported by 3 lines of evidence. First, histologic studies demonstrate a close correlation between carotid and coronary atherosclerosis, validating the findings in the carotid arteries as indicative of what is happening in the coronary arteries (25). Second, ultrasonographic measurements correlate highly with histologic measurements of the CaIMT (26). Third, the CaIMT is associated with CV risk factors, prevalent CV disease, and atherosclerosis in other vascular beds (27), and is a strong predictor of incident myocardial infarction and stroke (28). When performed by a single sonographer in accordance with an established protocol, with interpretation by a single expert reader, as carried out in this study, the technique is reliable.
We used the ABI to gauge the condition of peripheral arteries. This index is a simple, yet reliable way for physicians to estimate peripheral arterial function (13). Its validity as a marker of peripheral atherosclerosis is supported by studies showing that the ABI is strongly associated with claudication and CV events in other vascular beds (29–31).
We found a significant effect of glucocorticoids on arteries. Our vascular studies gave us a window into both the central (27, 32) and the peripheral arterial beds (13). In the carotid arteries, plaque frequency increased in conjunction with the glucocorticoid exposure category, with the highest frequency of plaque associated with the highest exposure category. This pattern of worsening arterial pathology with rising glucocorticoid dose was echoed by the CaIMT. However, differences in the CaIMT between exposure categories did not reach statistical significance, most likely because of the wide range over which the CaIMT was distributed in this RA sample. It should be noted, however, that the difference of 0.076 mm in CaIMT between patients who never received glucocorticoids and those in the highest lifetime exposure tertile could be clinically important. In the Cardiovascular Health Study, a population-based study that used carotid imaging methods similar to ours (12), the CaIMT difference between smokers and nonsmokers was 0.050 mm (27), a difference that was associated with an increased risk of myocardial infarction or stroke among the smokers (28). The pattern of association that we observed between carotid morphologic features and glucocorticoid exposure thus suggests a consistent deleterious influence of these agents on the central arteries.
We also noted significant effects of glucocorticoids on the lower-limb arteries, in that there was an association with arterial incompressibility. Previous research conducted more than 2 decades ago by other investigators demonstrated that arterial incompressibility is usually a manifestation of medial arterial calcification (33–35). The latter is also known as Mönckeberg's sclerosis (36). It causes stiffening of the vascular wall and occurs frequently in aging, in chronic renal failure (37), and in people with diabetes mellitus (38). Although medial arterial calcification is a predictor of CV complications and mortality (39), its risk factors differ from those of coronary heart disease and obstructive peripheral artery disease (39), suggesting that arterial medial calcification may represent a distinct process. Arterial incompressibility has not been described previously in RA or in association with glucocorticoid exposure. However, in a report published more than 30 years ago, Kalbak described medial arterial calcification in association with glucocorticoid use in RA (40). To our knowledge, no further research has been conducted on the subject. The lower-limb arterial incompressibility encountered among our glucocorticoid-treated patients is, in all likelihood, the functional consequence of calcification as characterized by Kalbak.
Glucocorticoid exposure accumulates over time in subjects who are prescribed these agents. Atherosclerosis is a process that also accrues over time. The effect of cumulative glucocorticoid exposure could thus be confounded by time-related variables such as age and disease duration. Moreover, glucocorticoid use may identify patients with more severe systemic inflammation, which itself could be associated with atherosclerosis. Because of these concerns, it was important to have a control exposure, to test the specificity of the glucocorticoid effects. We chose methotrexate for reference, because patients receiving methotrexate are likely to have more severe disease. However, the dose of methotrexate being received by our patients was not available in this study. We therefore compared the association between the exposure time for each drug and the arterial outcomes. Of the 2 agents, only exposure time for glucocorticoids was significantly associated with the CaIMT and presence of plaque as well as lower-limb arterial incompressibility, providing evidence that the glucocorticoid effect is specific. This association was lost, however, upon adjustment for covariates, suggesting the importance of the dimension of dose level, as opposed to just the exposure time variable only, in the atherogenic effect of glucocorticoids.
We did not find an association between glucocorticoids and lower-limb arterial obstruction. As is observed in the general population, the prevalence of obstructed peripheral arteries in our sample was lower than that of carotid plaque (41). Carotid ultrasound may detect early abnormalities when they are still at a purely anatomic stage, before they affect function and can be detected by functional tests such as the ABI. Alternatively, the atherogenic properties of glucocorticoids may vary between the central and peripheral circulations.
Glucocorticoid use was related to arterial abnormalities despite the low dose received by our patients. It has been suggested that the effect of glucocorticoids on blood pressure and plasma lipids could lead to atherosclerosis (42, 43). However, these mechanisms are unlikely to have operated to a significant extent in this RA sample, given the lack of association observed between blood pressure, cholesterol level, and glucocorticoid exposure. In addition, independent mechanisms may be operating, because adjustment for CV risk factors did not efface the association. One intriguing hypothesis is that glucocorticoid-induced osteoporosis and arterial calcification might share pathogenic mechanisms (44).
High exposure to glucocorticoids characterized patients with more severe RA. Compared with the patients who had never received glucocorticoids, patients in the highest tertile of glucocorticoid exposure had significantly more tender, swollen, and deformed joints and more frequently had subcutaneous nodules and rheumatoid factor. This may be because clinicians, over time, selected their sickest patients for glucocorticoid therapy. We used multivariate modeling to control for the possibility that the RA severity, which is associated with chronic systemic inflammation, may be the primary atherogenic agent, with glucocorticoids being merely a marker for RA severity. In all of the multivariate models for carotid plaque and peripheral arterial incompressibility, the glucocorticoid effect was independent of joint inflammation and damage, subcutaneous nodules, rheumatoid factor seropositivity, and ESR.
Some limitations of our study merit mention. Our sample was drawn from subspecialty referral centers, making our findings most generalizable to the type of RA patient seen by rheumatologists. There is no reason to believe, however, that with similar glucocorticoid exposure levels, the association with arterial abnormalities would be different in other settings. The variation in glucocorticoid dose, carotid morphologic features, and ABI displayed by our sample allowed us to test hypotheses about the relationship between glucocorticoid exposure and arterial abnormalities (45). Our findings should not be used to infer the prevalence of these abnormalities among people with RA in the general population.
An additional caution stems from possible inaccuracies in our measurement of glucocorticoid exposure. This is most likely to have occurred among the unexposed patients, some of whom may have received glucocorticoids that we did not record. It should be noted, however, that this potential inaccuracy would induce a bias toward the null, i.e., it would tend to attenuate differences between the exposed and unexposed groups.
In conclusion, use of glucocorticoids was associated with pathologic evidence of arterial abnormalities, independent of the effect of CV risk factors and RA clinical manifestations. This suggests that treatment with glucocorticoids may play a role in the increased risk of CV complications observed in patients with RA. Physicians who prescribe glucocorticoids should be aware of the potentially atherogenic properties of these agents.