1. Top of page
  2. Abstract
  6. Acknowledgements


Glucocorticoids are suspected to cause atherosclerosis. Because of the possibility that their antiinflammatory effect may be antiatherogenic, this study investigated the effect of glucocorticoids on the arteries of patients with rheumatoid arthritis (RA).


We assessed the arteries of 647 patients with RA. Central atherosclerosis was measured using high-resolution carotid ultrasound for the presence of plaque and for the extent of carotid artery intima-media thickness (CaIMT). Peripheral atherosclerosis was assessed using the systolic pressures of the dorsal pedal, posterior tibial, and brachial arteries to obtain the ankle-brachial index (ABI). Cumulative glucocorticoid dose was determined using pharmacy records, supplemented by self-report. Cardiovascular (CV) risk factors and RA clinical manifestations were ascertained using clinical and laboratory methods.


Among the RA patients studied, 427 (66%) had received glucocorticoids. Of those who had never received glucocorticoids, 100 (47%) of 215 had carotid plaque and 17 (8%) of 219 had ≥1 incompressible lower-limb artery (ABI >1.3). Among patients in the highest tertile of lifetime glucocorticoid exposure (>16.24 gm prednisone), the frequency of carotid plaque increased to 85 (62%) of 138 (P = 0.006) and that of lower-limb arterial incompressibility increased to 24 (17%) of 140 (P = 0.008), with differences remaining significant after adjustment for age at onset, disease duration, sex, CV risk factors, and RA clinical manifestations (tender, swollen, and deformed joint counts, subcutaneous nodules, rheumatoid factor seropositivity, and erythrocyte sedimentation rate). The CaIMT also displayed an increase with higher glucocorticoid exposure, but the differences did not reach significance. Lower-limb artery obstruction (ABI ≤0.9) was not associated with glucocorticoid exposure.


In this RA sample, glucocorticoid exposure was associated with carotid plaque and arterial incompressibility, independent of CV risk factors and RA clinical manifestations. This supports a role for glucocorticoids in the CV complications that occur in RA.

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.


  1. Top of page
  2. Abstract
  6. Acknowledgements


Between January 1996 and April 2000, we recruited consecutive patients who satisfied the classification criteria for RA (8) from 6 local rheumatology clinics, and included them in a study of the disablement process in RA (9). We have described our sample previously (10). After the initial recruitment, we conducted annual followup assessments. Between February 2000 and February 2003, we invited all patients for an additional visit to undergo a carotid ultrasound and receive measurements to determine the ankle-brachial index (ABI).

Data collection procedures.

Our study was approved by the Institutional Review Board. All subjects gave written, informed consent. A physician and a trained research associate evaluated the subjects.

Demographic information.

We ascertained each patient's age at the time of the vascular studies as well as age at the time of RA diagnosis. We also collected information on each patient's sex and race/ethnicity. This information was gathered by self-report, as defined previously (10).

Carotid ultrasonography.

One certified technician performed a duplex scan of the carotid arteries in all patients, following a standardized vascular protocol developed for the Multi-Ethnic Study of Atherosclerosis (11). We used an ATL HDI-3000 High Resolution Imaging machine with an L7-4 Transducer (Philips Medical Systems North America, Bothell, WA). The technician acquired 4 standardized B-mode images and a Doppler flow measurement from both sides of the neck. The first image was of the distal common carotid artery, and the 3 other images were centered on the site of maximum near- and far-wall thickening in the proximal internal carotid artery or carotid bulb. Results were recorded on Super VHS tape and mailed to a central facility (Ultrasound Reading Center, New England Medical Center, Boston, MA) for grading of the carotid artery intima-media thickness (CaIMT) and carotid plaque. At the reading center, the images were digitized at 30 frames per second, and arterial diameter fluctuations with the cardiac cycle were observed. Images were selected and read by a single, certified reader who was blinded to each subject's characteristics (12).

Carotid plaque was identified as a discrete projection from the wall into the vessel lumen, with a thickness at least twice that of the adjacent IMT. Plaque severity was estimated based on stenosis of the lumen, using the following categories: absence of obstruction, presence of obstruction from 1% to 24% of the lumen, from 25% to 49% of the lumen, from 50% to 74% of the lumen, from 75% to 99% of the lumen, and 100% of the lumen, or complete obstruction of the lumen. In the case of multiple plaques, the largest plaque was selected for measurement. If plaque was continuous, we identified the highest peak for measurement.

Carotid arteries could differ within a person as to the presence of plaque. A given individual could have none, 1, or 2 carotid arteries with plaque. Therefore, in one set of plaque analyses, we considered the presence or absence of plaque within each carotid artery individually. In a second set of analyses, we considered the number of affected carotid arteries within a person. For the CaIMT, we measured in the diastole at each of the near and far walls of the right and left common carotid arteries, and on the anterior oblique, lateral, and posterior oblique views of the internal carotid artery, for a total of 16 IMT measurements per person. The maximum IMT of the common and internal carotid arteries was obtained by averaging the maximal measurement from the near and far walls at each projection, from the right and left sides. The composite maximum CaIMT was then calculated by averaging the common and internal carotid artery maximal IMT values. The result is a single CaIMT value per person, with results expressed in millimeters and calculated to 3 digits after the decimal point.

Our study involved a single ultrasonographer and a single reader. Nevertheless, to assess the technique's reliability, our reader reevaluated 50 images, and a different reader reevaluated a separate set of 50 images. The intrareader intraclass correlation coefficient for CaIMT was 0.99, and the interreader coefficient was 0.94. For plaque, the intrareader kappa statistic was 1.0, while the interreader kappa value was 0.94.

Assessment of peripheral arteries.

With the patient placed in a supine position for 15 minutes, we used a Parks 8.1-MHz Pocket Doppler probe (model 841-A; Parks Medical Electronics, Aloha, OR) and 4 size-appropriate blood-pressure cuffs, to measure the systolic pressure in the dorsal pedal, posterior tibial, and brachial arteries in both sides of the body. We calculated the ABI for each lower extremity artery by dividing its pressure by the mean of the right and left brachial pressures (13). Each subject could have up to 4 ABI values, one each for the right and left dorsal pedal and posterior tibial arteries. We used the Hiatt's cutoff values to classify ABI values (13). Arteries with an ABI ≤0.9 were considered obstructed, since these values occur often in claudication (13). Arteries with an ABI >1.3 were considered incompressible, because these values occur in stiff, calcified arteries (13). We considered an ABI >0.9 and ≤1.3 as normal (13). Assessment of the interrater reliability of the ABI, measured independently by 2 study physicians in 20 consecutive study patients, revealed a Spearman-Brown reliability coefficient of 0.96.

Ascertainment of glucocorticoid use.

At the baseline and each of the followup visits, we asked patients to provide a list of their medications, and we reviewed pharmacy and medical records. We asked patients whether they were receiving glucocorticoids, and if so, we asked for the date at which these medications were first prescribed as well as the dose currently in use. We estimated the cumulative oral glucocorticoid dose by multiplying the current daily dose by the number of days since glucocorticoids were initiated. For the few patients who received glucocorticoids on alternate days or on other nondaily schedules, we averaged the dose over the number of days to obtain the daily amount. We considered patients who had received glucocorticoids less often than monthly, either orally or by injection, as not having received glucocorticoids. At each followup visit, we calculated the cumulative dose since the previous visit. The total cumulative glucocorticoid dose is presented as the summed dose over each interval, expressed in prednisone equivalents. During the baseline and followup visits, we also asked patients whether they were receiving disease-modifying antirheumatic drugs (DMARDs) alone or in combination, and we obtained the date at which each DMARD was first prescribed.

Assessment of CV risk factors.

We ascertained CV risk factors at multiple times since patients were recruited into the study of the disablement process in RA, up until the arterial measurements were performed. For hypertension, we averaged blood pressure measurements obtained at each study visit. For obesity, we measured height and weight at the time of the arterial assessments, to calculate the current body mass index. Diabetes mellitus and hypercholesterolemia were ascertained from a medical record and medication review, supplemented by self-report. We considered these conditions present if a physician recorded them in the medical record, or if a patient had taken antidiabetic or lipid-lowering medications during the course of the study. In addition, we considered patients to have hypercholesterolemia if their plasma cholesterol level, measured while fasting, was ever 200 mg/dl or higher during a study visit, or if they received lipid-lowering drugs. We considered an alternative definition of hypercholesterolemia by adding to the above definition persons whose low-density lipoprotein (LDL) cholesterol level was ≥160 mg/dl, or persons with ≥2 CV risk factors and an LDL level ≥130 mg/dl. Persons who had ever smoked cigarettes were classified as current smokers if they continued to smoke, and former smokers if they had quit in the past.

Musculoskeletal examination.

As described in detail elsewhere (14), we assessed 48 joints in each patient for the presence or absence of tenderness or pain on motion, swelling, or deformity, and for the presence of subcutaneous nodules. In the case of the tender and swollen joint counts, we averaged the counts obtained during the current and earlier study visits, aiming to capture the effect of these variables over time. In the case of the deformed joint count, which reflects the extent of damage accrued over time (14), we used the count obtained at the time of the arterial assessments.

Laboratory studies.

For determination of the erythrocyte sedimentation rate (ESR), we used the Westergren technique, and nephelometry for measurement of the C-reactive protein level (Quest Diagnostics, San Juan Capistrano, CA). Serum rheumatoid factor was measured by the latex agglutination technique. Patients were considered seropositive if any determination during the study was positive. Total plasma, LDL, high-density lipoprotein, and very low density lipoprotein cholesterol levels were measured using a Synchron LX automated system (Beckman Coulter, Fullerton, CA). We asked patients to fast overnight for the laboratory tests. We averaged values obtained on the same day of the arterial measurements with values obtained during earlier study visits, aiming to capture the effect of these variables on the arteries over time.

Statistical analysis.

To test the hypothesis that glucocorticoid exposure is associated with an increased frequency of arterial abnormalities, we classified the cumulative prednisone dose levels into 4 categories, the first of which included only patients who had never received glucocorticoids. The second, third, and fourth categories were defined by tertiles of the cumulative glucocorticoid dose. The boundaries were 5–6,030 mg for the second category, 6,072–16,240 mg for the third category, and 16,338–121,980 mg for the fourth category. We used several approaches to adjust the comparisons between glucocorticoid exposure categories and the measured covariates, depending on the type of artery and outcome in question.

For analysis of the CaIMT, an interval variable that provides a single value per person (12), we used ordinary least squares regression. The carotid arteries with plaque in a given person can number none, 1, or 2. Likewise, the number of lower-limb arteries that are normal, obstructed, or incompressible on the ABI can each range from none to 4 in a single person. Moreover, the number of arteries available for study can vary from person to person, and in the case of the ABI, obstruction and incompressibility can coexist in a single person. To account for the possibility of a quantitative effect of glucocorticoids and CV risk factors on the number of affected arteries, we performed artery-level analyses, using robust standard errors to account for within-person correlation (15).

We also conducted parallel analyses on a person-by-person basis, considering patients to either have or be free of each of the arterial abnormalities. For analyses of the carotid plaque and person-level ABI, we used logistic regression. For the artery-level ABI, we used polytomous logistic regression, with normal ABI as the referent category (16). We tested each outcome for trend in relation to the ordered glucocorticoid exposure levels, and for differences between each steroid exposure level, with the unexposed category as the referent category. We present both unadjusted and adjusted 2-sided P values. Analyses were conducted using Stata, version 8 (Stata Corporation, College Station, TX).


  1. Top of page
  2. Abstract
  6. Acknowledgements

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 characteristicsCumulative glucocorticoid exposure level*
Unexposed5–6,030 mg6,072–16,240 mg16,338–121,980 mg
  • *

    Tertiles were defined on the basis of the glucocorticoid dose distribution among patients who received them, with a separate category for patients who did not (unexposed).

  • P ≤ 0.001 versus unexposed.

  • P ≤ 0.05 versus unexposed.

  • §

    P ≤ 0.01 versus unexposed.

Number of patients220146141140
Demographic characteristic    
 Age, median (range) years60 (22–84)57 (21–87)60 (25–90)62 (29–84)
 Women, no. (%)160 (73)114 (78)101 (72)90 (64)
 Ethnicity/race, no. (%)    
  White80 (36)49 (34)43 (31)49 (35)
  Black17 (8)7 (5)15 (11)6 (4)
  Hispanic117 (53)88 (60)81 (57)78 (56)
  Asian4 (2)1 (1)2 (1)4 (3)
  Other2 (1)1 (1)03 (2)
Clinical characteristic    
 Disease duration, median (range) years11 (1–51)8 (0–56)12 (1–56)16 (3–55)
 Tender joint count, mean ± SD12.1 ± 1214.6 ± 1314.9 ± 1316.7 ± 13
 Swollen joint count, mean ± SD3.3 ± 4.54.9 ± 5.24.0 ± 4.75.1 ± 5.5
 Deformed joint count, mean ± SD13.7 ± 11.213.8 ± 12.017.0 ± 12.419.9 ± 13.0
 Subcutaneous nodules, no. (%)92 (42)64 (44)64 (49)77 (55)
 Erythrocyte sedimentation rate, mean ± SD mm/hour38 ± 2542 ± 2544 ± 2742 ± 26
 C-reactive protein, mean ± SD mg/dl15 ± 2715 ± 2017 ± 2017 ± 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 Hg140 ± 21139 ± 20140 ± 21138 ± 23
 Diastolic blood pressure, mean ± SD mm Hg76 ± 1275 ± 1276 ± 1175 ± 12
 Body mass index, mean ± SD kg/m229.4 ± 6.328.8 ± 6.328.3 ± 5.729.2 ± 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, characteristicTotal numberCumulative glucocorticoid exposure levelP for trend
Unexposed5–6,030 mg6,072–16,240 mg16,338–121,980 mgUnadjustedAdjusted*
Model 1Model 2Model 3
  • *

    Adjustment covariates were as follows: model 1 = age at onset, sex, disease duration; model 2 = age at onset, sex, disease duration, diabetes mellitus, hypercholesterolemia, systolic blood pressure, past or current smoking, body mass index; model 3 = age at onset, sex, disease duration, diabetes mellitus, hypercholesterolemia, systolic blood pressure, past or current smoking, body mass index, tender, swollen, and deformed joint counts, presence of rheumatoid nodules, rheumatoid factor seropositivity, and erythrocyte sedimentation rate.

  • P = 0.007 versus unexposed, unadjusted; P = 0.025 versus unexposed, adjusted for model 1 covariates; P = 0.059 versus unexposed, adjusted for model 2 covariates; P = 0.08 versus unexposed, adjusted for model 3 covariates.

  • P = 0.001 versus unexposed, unadjusted; P = 0.004 versus unexposed, adjusted for model 1 covariates; P = 0.002 versus unexposed, adjusted for model 2 covariates; P = 0.01 versus unexposed; adjusted for model 3 covariates.

Carotid arteries         
 Intima-media thickness, mean ± SD mm631 persons1.084 ± 0.5011.060 ± 0.4961.116 ± 0.4601.160 ± 0.5440.
 Plaque, no./total no. (%)1,262 arteries144/430 (33)102/278 (37)113/276 (41)126/278 (45)0.0050.030.060.09
Lower-limb arteries, no./total no. (%)2,569 arteries        
 Normal2,191 arteries755/873 (86)518/584 (89)473/556 (85)445/556 (80)0.0570.10.10.6
 Obstructed208 arteries83/873 (10)43/584 (7)42/556 (8)40/556 (7)
 Incompressible170 arteries35/873 (4)23/584 (4)41/556 (7)71/556 (13)≤0.0010.0040.0020.01
Table 3. Frequency distribution of arterial plaque, obstruction, or incompressibility, according to cumulative glucocorticoid dose
Glucocorticoid exposure levelNo. of patients with abnormality/total in category (%)OR (95% CI)*P vs. unexposedP for trend over exposure categories
  • *

    OR = odds ratio; 95% CI = 95% confidence interval.

  • P ≤ 0.05 after adjustment for age, sex, disease duration, diabetes mellitus, hypercholesterolemia, systolic blood pressure, past or current smoking, body mass index, tender, swollen, and deformed joint counts, presence of rheumatoid nodules, rheumatoid factor seropositivity, and erythrocyte sedimentation rate.

 Unexposed100/215 (47)1.0 (referent)
 5–6,030 mg66/142 (46)0.99 (0.65–1.52)0.9
 6,072–16,240 mg77/136 (57)1.50 (0.94–2.31)0.07
 16,338–121,980 mg85/138 (62)1.84 (1.19–2.85)0.0060.005
 Unexposed17/219 (8)1.0 (referent)
 5–6,030 mg14/146 (10)1.26 (0.60–2.64)0.5
 6,072–16,240 mg20/139 (14)1.99 (1.01–3.96)0.05
 16,338–121,980 mg24/140 (17)2.46 (1.27–4.77)0.0080.004
 Unexposed34/219 (16)1.0 (referent)
 5–6,030 mg16/146 (11)0.67 (0.35–1.26)0.2
 6,072–16,240 mg16/139 (12)0.71 (0.37–1.34)0.3
 16,338–121,980 mg17/140 (12)0.75 (0.40–1.40)0.40.3

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, characteristicDuration of exposureP for trend*
Unexposed5–1,369 days1,387–3,038 days3,106–12,927 days
  • *

    Unadjusted P value for trend across the ordered durations of exposure. For intima-media thickness, model was ordinary least squares regression; for plaque, model was logistic regression; for lower-limb arteries, model was a multinomial logistic regression with normal arteries as the referent category.

  • Adjustment for the model 1–3 covariates (listed in Table 2) led to loss of significance of the association.

  • The association between duration of glucocorticoid exposure and incompressible lower-limb arteries was independent of age at onset, sex, disease duration (P = 0.03 in model 1 from Table 2), and cardiovascular risk factors (P = 0.03 in model 2 from Table 2). The association lost significance upon adjustment for the disease manifestations listed in model 3 from Table 2 (P = 0.1).

 Carotid arteries     
  Intima-media thickness, mean ± SD mm1.077 ± 0.4921.049 ± 0.5281.146 ± 0.4671.203 ± 0.5380.03
  Plaque, no. (%)251 (36)59 (32)85 (46)89 (48)0.003
 Lower-limb arteries, no. (%)     
  Normal1,243 (86)335 (88)313 (82)296 (81)0.09
  Obstructed137 (10)11 (3)34 (9)26 (7)0.5
  Incompressible59 (4)34 (9)33 (9)44 (12)0.001
 Carotid arteries     
  Intima-media thickness, mean ± SD mm1.104 ± 0.4961.059 ± 0.4641.087 ± 0.4821.156 ± 0.6600.4
  Plaque, no. (%)152 (40)101 (35)110 (37)122 (42)0.8
 Lower-limb arteries, no. (%)     
  Normal671 (86)508 (86)512 (85)500 (84)0.9
  Obstructed56 (7)45 (8)53 (9)54 (9)0.4
  Incompressible50 (6)41 (7)37 (6)42 (7)0.8


  1. Top of page
  2. Abstract
  6. Acknowledgements

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.


  1. Top of page
  2. Abstract
  6. Acknowledgements

The authors thank Dr. M. P. Stern for his mentoring, Drs. S. Pogosian and G. Navarro-Cano for their help conducting the study of the disablement process in RA (known as the ÓRALE study), and Drs. R. Arroyo, D. Battafarano, R. Cuevas, M. Fischbach, J. Huff, A. de Jesus, R. Molina, M. Mosbacker, F. Murphy, C. Orces, C. Parker, T. Rennie, J. Russell, J. Rutstein, and J. Wild for giving us permission to study their patients.


  1. Top of page
  2. Abstract
  6. Acknowledgements
  • 1
    Raynauld JP. Cardiovascular mortality in rheumatoid arthritis: how harmful are corticosteroids? J Rheumatol 1997; 24: 4156.
  • 2
    Moreland LW, O'Dell JR. Glucocorticoids and rheumatoid arthritis: back to the future? Arthritis Rheum 2002; 46: 255363.
  • 3
    Van Everdigen AA, Jacobs JW, Siewertsz van Reesema DR, Bijlsma JW. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease modifying properties, and side effects. Ann Intern Med 2002; 136: 112.
  • 4
    Conn DL. Resolved: low-dose prednisone is indicated as a standard treatment in patients with rheumatoid arthritis. Arthritis Rheum 2001; 45: 4627.
  • 5
    Saag KG. Resolved: low-dose glucocorticoids are neither safe nor effective for the long-term treatment of rheumatoid arthritis. Arthritis Rheum 2001; 45: 46871.
  • 6
    Pincus T, Sokka T, Stein CM. Are long-term very low doses of prednisone for patients with rheumatoid arthritis as helpful as high doses are harmful? Ann Intern Med 2002; 136: 768.
  • 7
    Saag KG. Glucocorticoid use in rheumatoid arthritis. Curr Rheumatol Rep 2002; 4: 21825.
  • 8
    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: 31524.
  • 9
    Escalante A, del Rincon I. How much disability in rheumatoid arthritis is explained by rheumatoid arthritis? Arthritis Rheum 1999; 42: 171221.
  • 10
    Del Rincon I, Battafarano DF, Arroyo RA, Murphy FT, Escalante A. Heterogeneity between men and women in the influence of the HLA–DRB1 shared epitope on the clinical expression of rheumatoid arthritis. Arthritis Rheum 2002; 46: 14808.
  • 11
    Bild DE, Bluemke DA, Burke GL, Detrano R, Diez Roux AV, Folsom AR, et al. Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol 2002; 156: 87181.
  • 12
    O'Leary DH, Polak JF, Wolfson SK Jr, Bond MG, Bommer W, Sheth S, et al. Use of sonography to evaluate carotid atherosclerosis in the elderly: the Cardiovascular Health Study. Stroke 1991; 22: 115563.
  • 13
    Hiatt WR. Drug therapy: medical treatment of peripheral arterial disease and claudication. N Engl J Med 2001; 344: 160821.
  • 14
    Orces CH, del Rincon I, Abel MP, Escalante A. The number of deformed joints as a surrogate measure of damage in rheumatoid arthritis. Arthritis Rheum 2002; 47: 6772.
  • 15
    Rogers WH. Sg17: regression standard errors in clustered samples. Stata Technical Bulletin 1993; 1923.
  • 16
    Kleinbaum DG, Klein M. Logistic regression: a self-learning text. 2nd ed. New York: Springer-Verlag; 2002.
  • 17
    Del Rincon I, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001; 44: 273745.
  • 18
    Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003; 107: 13037.
  • 19
    Park YB, Ahn CW, Choi HK, Lee SH, In BH, Lee HC, et al. Atherosclerosis in rheumatoid arthritis: morphologic evidence obtained by carotid ultrasound. Arthritis Rheum 2002; 46: 17149.
  • 20
    Wallberg-Jonsson S, Backman C, Johnson O, Karp K, Lunstrom E, Sundqvist KG, et al. Increased prevalence of atherosclerosis in patients with medium term rheumatoid arthritis. J Rheumatol 2001; 28: 2597602.
  • 21
    Kumeda Y, Inaba M, Goto H, Nagata M, Henmi Y, Furumitsu Y, et al. Increased thickness of the arterial intima-media detected by ultrasonography in patients with rheumatoid arthritis. Arthritis Rheum 2002; 46: 148997.
  • 22
    Del Rincon I, Williams K, Stern MP, Freeman GL, O'Leary DH, Escalante A. Association between carotid atherosclerosis and markers of inflammation in rheumatoid arthritis patients and healthy subjects. Arthritis Rheum 2003; 48: 183340.
  • 23
    Manzi S, Selzer F, Sutton-Tyrrell K, Fitzgerald SG, Rairie JE, Tracy RP, et al. Prevalence and risk factors of carotid plaque in women with systemic lupus erythematosus. Arthritis Rheum 1999; 42: 5160.
  • 24
    Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 11526.
  • 25
    Young W, Gofman JW, Tandy R, Malamud N, Waters ES. The quantification of atherosclerosis. III. The extent of correlation of degrees of atherosclerosis within and between the coronary and cerebral vascular beds. Am J Cardiol 1960; 6: 3008.
  • 26
    Persson J, Formgren J, Israelsson B, Berglund G. Ultrasound-determined intima-media thickness and atherosclerosis: direct and indirect validation. Atheroscler Thromb 1994; 14: 2614.
  • 27
    O'Leary DH, Polak JF, Kronmal RA, Kittner SJ, Bond MG, Wolfson SK Jr, et al. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. Stroke 1992; 23: 175260.
  • 28
    O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999; 340: 1422.
  • 29
    Belch JJ, Topol EJ, Agnelli G, Bertrand M, Califf RM, Clement DL, et al. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med 2003; 163: 88492.
  • 30
    Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286: 131724.
  • 31
    Murabito JM, Evans JC, Larson MG, Nieto K, Levy D, Wilson PW, et al. The ankle-brachial index in the elderly and risk of stroke, coronary disease, and death. Arch Intern Med 2003; 163: 193942.
  • 32
    Persson J, Formgren J, Israelsson B, Berglund G. Ultrasound-determined intima-media thickness and atherosclerosis: direct and indirect validation. Atheroscler Thromb 1994; 14: 2614.
  • 33
    Emanuele MA, Buchanan BJ, Abraira C. Elevated leg systolic pressures and arterial calcification in diabetic occlusive vascular disease. Diabetes Care 1981; 4: 28992.
  • 34
    Orchard TJ, Strandness DE Jr. Assessment of peripheral artery disease in diabetics: report and recommendation of an international workshop sponsored by the American Diabetes Association and the American Heart Association. Circulation 1993; 88: 81928.
  • 35
    Zierler RE, Sumner DS. Physiologic assessment of peripheral arterial occlusive disease. In: RutherfordRB, editor. Vascular surgery. Philadelphia: Saunders; 2000. p. 14065.
  • 36
    Monckeberg JG. Über die reine mediaverkalkung der extremitätenarterien und ihr verhalten zur arteriosklerose. Virchows Arch Pathol Anat Physiol Klin Med 1903; 171: 14167.
  • 37
    Leskinen Y, Salenius JP, Lehtimaki T, Huhtala H, Saha H. The prevalence of peripheral arterial disease and medial arterial calcification in patients with chronic renal failure: requirement for diagnostics. Am J Kidney Dis 2002; 40: 4729.
  • 38
    Maser RE, Wolfson SK Jr, Ellis D, Stein EA, Drash AL, Becker DJ, et al. Cardiovascular disease and arterial calcification in insulin-dependent diabetes mellitus: interrelations and risk factor profiles. Arterioscler Thromb 1991; 11: 95865.
  • 39
    Lehto S, Niskanen L, Suhonen M, Ronnemaa T, Laasko M. Medial artery calcification: a neglected harbinger of cardiovascular complication in non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 1996; 16: 97883.
  • 40
    Kalbak K. Incidence of arteriosclerosis in patients with rheumatoid arthritis receiving long-term corticosteroid therapy. Ann Rheum Dis 1972; 3: 196200.
  • 41
    Zheng JJ, Sharrett AR, Chambless LE, Rosamong WD, Nieto FJ, Sheps DS, et al. Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis 1997; 131: 11525.
  • 42
    Stern MP, Kolterman OG, Fries JF, McDevitt HO, Reaven GM. Adrenocortical steroid treatment of rheumatic diseases: effects on lipid metabolism. Arch Intern Med 1973; 132: 97101.
  • 43
    Sholter DE, Armstrong PW. Adverse effects of corticosteroids on the cardiovascular system. Can J Cardiol 2000; 16: 50511.
  • 44
    Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 12608.
  • 45
    RothmanK, GreenlandS, editors. Generalizability. In: Precision and validity in epidemiologic studies. Philadelphia: Lippincott-Raven; 1998. p. 1334.