The Influence of Rheumatoid Arthritis Disease Characteristics on Heart Failure

Study setting and design

This study was conducted using the population-based resources of the Rochester Epidemiology Project (REP) medical records linkage system¹⁴. This system facilitates access to the complete inpatient and outpatient medical records of residents of Olmsted County, Minnesota, from all community medical providers including the Mayo Clinic, its affiliated hospitals, and the Olmsted Medical Center. REP resources ensure virtually complete ascertainment of all clinically recognized cases of RA and associated complications among the residents of Olmsted County^14,15.

The study included a retrospectively identified incidence cohort of RA patients who were Olmsted County residents ≥ 18 years of age and first met the 1987 American College of Rheumatology (ACR) criteria¹⁶ between January 1, 1980, and January 1, 2008. RA incidence date was defined as the earliest date at which each patient fulfilled ≥ 4 ACR criteria for RA. The original and complete medical records of all RA patients were screened longitudinally until HF incidence, death, migration, or last date of followup (January 1, 2008) by trained nurse abstractors blinded to the study hypothesis. HF was defined based on the Framingham criteria^17,18. HF diagnosis requires ≥ 2 of the major criteria [i.e., paroxysmal nocturnal dyspnea or orthopnea, neck vein distention, rales, radiographic cardiomegaly (i.e., increasing heart size on chest radiograph), acute pulmonary edema, S3 gallop, increased central venous pressure ≥ 16 cm of water at the right atrium, circulation time ≥ 25 seconds, hepatojugular reflux, weight loss > 4.5 kg in 5 days in response to treatment of congestive HF)], or the presence of 1 major criterion and ≥ 2 minor criteria (i.e., bilateral ankle edema, nocturnal cough, dyspnea on ordinary exertion, hepatomegaly, pleural effusion, decrease in vital capacity by 33% from maximal value recorded, and tachycardia rate ≥ 120 beats/min). Minor criteria were counted only if they could not be attributed to another medical condition. Ejection fraction (EF) was determined by echocardiography and classified as preserved EF (≥ 50%) or reduced EF (< 50%).

CV risk factors

The following CV risk factors were abstracted from the medical records at baseline and longitudinally throughout the followup as described⁵, and were defined according to standardized diagnostic criteria as follows. Hypertension was defined according to the criteria of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure as ≥ 2 ambulatory blood pressure readings ≥ 140 mm Hg systolic and/or ≥ 90 mm Hg diastolic obtained during a 1-year period, physician diagnosis, or documented use of antihypertensive medications¹⁹. Dyslipidemia was defined in accord with Adult Treatment Panel III guidelines²⁰ as elevated lipid values of total cholesterol ≥ 240 mg/dl (≥ 6.2 mmol/l), low-density cholesterol ≥ 160 mg/dl (≥ 4.1 mmol/l), triglycerides ≥ 200 mg/dl (≥ 2.3 mmol/l) or high-density cholesterol < 40 mg/dl (< 1.0 mmol/l), physician diagnosis or documented use of lipid-lowering medications. Obesity was present if body mass index (BMI) was ≥ 30 kg/m² based on the guidelines on the Identification, Evaluation and Treatment of Overweight and Obesity in Adults²¹. Diabetes mellitus was defined as fasting plasma glucose ≥ 126 mg/dl (≥ 7.0 mmol/l), physician diagnosis or documented use of insulin and/or oral hypoglycemic agents in accord with the diagnostic criteria adopted by the American Diabetes Association^22,23. Personal history of coronary heart disease (CHD) was defined at baseline and throughout the followup as the presence of one of the following: angina pectoris, coronary artery disease, myocardial infarction (MI; including silent events), and coronary revascularization procedures (i.e., coronary artery bypass graft, percutaneous angioplasty, insertion of stents, and atherectomy). MI was defined using standardized epidemiologic criteria²⁴, and Minnesota coding²⁵ of the electrocardiogram (ECG). Silent MI was considered as present at the date of the first documentation of a characteristic ECG or a recorded physician’s diagnosis in a patient with no documented history of MI. The definition of alcohol abuse was based on physician diagnosis of chronic alcoholism documented in the medical records. Smoking status (categorized as never, current, or former) and family history of premature CHD (defined as presence of CHD in first-degree relatives at age < 65 yrs females and < 55 yrs males) were collected only at baseline.

RA characteristics and medications

The information on RA characteristics included RF status, erythrocyte sedimentation rate (ESR) at RA incidence and repeatedly high ESR (i.e., ≥ 3 ESR measures ≥ 60 mm/h with a minimum interval of 30 days between 2 measurements), large-joint swelling, joint erosions/destructive changes on radiographs, joint surgeries (i.e., arthroplasty and synovectomy) and extraarticular manifestations of RA (ExRA). ExRA were classified according to criteria used in our previous studies²⁶. Severe ExRA were defined according to Malmö criteria²⁷ and included pericarditis, pleuritis, Felty’s syndrome, glomerulonephritis, vasculitis, peripheral neuropathy, scleritis, and episcleritis. Data regarding start and stop dates for use of systemic corticosteroids (e.g., oral/parental/intraarticular forms of prednisone, prednisolone, methylprednisolone, hydrocortisone, dexamethasone), disease-modifying anthirheumatic drugs (DMARD: MTX, hydroxychloroquine, other DMARD), and biologic response modifiers [anti-tumor necrosis factor-α (anti-TNF-α) agents, anakinra, abatacept, rituximab] were collected for all patients. Data on the use of nonsteroidal antiinflammatory drugs (NSAID) and coxibs were also recorded. Data on the use of acetylsalicylic acid (ASA) for arthritis were collected, i.e., the use of > 6 tablets of ASA per day (> 1950 mg/day) for at least 3 months. The history of rheumatic fever was documented.

The study protocol was approved by Review Boards from the Mayo Clinic and Olmsted Medical Center.

Statistical methods

Descriptive statistics were used to characterize the demographics, traditional CV risk factors, and RA disease characteristics. Cox proportional hazard models were used to examine the association of HF with RA characteristics. Adjustment for age and sex was performed using age as the time scale and stratifying by sex. The models were additionally adjusted for calendar year of RA incidence. Time-dependent covariates were used to represent factors that developed during followup. Each RA disease characteristic was examined individually in models adjusted for age, sex, and calendar year. In addition, models adjusted for age, sex, calendar year, CV risk factors, and CHD were examined. Medications were modeled 2 ways: (1) as use at any time where the time-dependent covariates reflected medication start dates only; and (2) as current use where the time-dependent covariates represented the time each patient was taking each medication, beginning at start date and ending at stop date for each medication. For each analysis of medications, all medications were assessed simultaneously in a multivariable model.

Patients’ characteristics

Among 815 incident RA cases identified during the 1980–2007 period, 20 fulfilled the Framingham criteria for HF before RA incidence, and were excluded from the study. The remaining 795 patients comprised the study cohort. Baseline characteristics are reported in Table 1. Mean age at RA incidence was 55.3 years; 69% were women. Patients were followed for a mean 9.7 years (total of 7692 patient-years). Hypertension, dyslipidemia, and obesity were the most common CV risk factors at baseline (65%, 57%, and 41% of patients, respectively), and their prevalence increased during followup. At the time of RA incidence, 22% of patients were current smokers and 33% were former smokers. Family history of premature CHD was noted in 22% of patients. At baseline, 10% of patients had a personal history of CHD, and 23% had CHD at any time during followup. The proportion of patients with diabetes mellitus increased from 11% at baseline to 20% at any time during followup. Alcohol abuse was documented in 7% of patients at baseline and in 8% of patients at any time during followup.

During the followup, 92 patients developed HF. Of these, 31 patients had HF with reduced EF and 36 patients had HF with preserved EF. For the remaining 25 patients data on EF were not available. Of the above CV risk factors and CV comorbidities, family history of CHD (HR 1.6, 95% CI 1.03, 2.6), personal history of CHD (HR 3.1, 95% CI 1.96, 4.9), particularly angina (HR 2.3, 95% CI 1.4, 3.6) and revascularization procedures (HR 2.3, 95% CI 1.3, 3.97), and alcohol abuse (2.4, 95% CI 1.2, 4.8) were significantly associated with the risk of HF. No time trends in the risk of HF were found (p = 0.5).

RA characteristics and medications and their effects on HF

Data on RA characteristics are summarized in Table 2. RF positivity was present in 66% of patients. Mean ESR at RA incidence was 24.2 mm/h and 12% of RA patients had ≥ 3 ESR measures of ≥ 60 mm/h. Most patients (78%) experienced large-joint swelling at some time during followup. The great majority of patients (95%) had at least one radiograph. Joint erosions/destructive changes were found in 53% of patients. Joint surgery, i.e., arthroplasty or synovectomy, was performed in 17% and 11% of patients, respectively. Severe ExRA developed in 11% of patients. The most common other ExRA were rheumatoid nodules (in 33% of patients). History of rheumatic fever was noted in 3% of patients.

RF positivity (HR 1.6, 95% CI 1.0, 2.5; p = 0.049), increased ESR at RA incidence (HR 1.6 per 30 mm/h increase, 95% CI 1.2, 2.0), repeatedly high ESR (HR 2.1, 95% CI 1.2, 3.5), and severe ExRA (HR 3.1, 95% CI 1.9, 5.1) were significantly associated with HF (Table 2). Patients with RA disease duration < 1 year were twice as likely to develop HF compared to patients with RA duration ≥ 1 year (HR 2.0, 95% CI 1.1, 3.8). The results remained essentially unchanged after adjustment for CV risk factors and CHD (data not shown).

Table 3 shows the data on antirheumatic medications. During followup, 58% of patients were treated with MTX, 60% were treated with hydroxychloroquine, 32% were treated with other DMARD, and 17% were treated with biologic response modifiers, of which the majority (95%) received anti-TNF-α therapy. Most patients received corticosteroids at some time during followup (77%). The majority of patients (91%) used NSAID at some time during followup. About half the patients were treated with coxibs (49%). Analysis of medications used at any time revealed no significant associations with HF. Additional analyses of current use of medications were also performed (Table 3). Patients currently using MTX were half as likely to develop HF as nonusers (HR 0.5, 95% CI 0.3, 0.9). The association changed only minimally (HR 0.4, 95% CI 0.2, 0.8) following additional adjustment for RA characteristics including RF positivity, RA duration, ESR at RA incidence, and severe ExRA. Patients currently using biologic response modifiers or other DMARD were also somewhat less likely to develop HF than those who did not currently use these agents; however, these associations were not statistically significant. The association of anti-TNF-α treatment with HF was identical to the effect of biologic response modifiers overall. Use of hydroxychloroquine did not appear to be associated with HF. Current use of corticosteroids was associated with 2-fold increased risk of HF (HR 2.0, 95% CI 1.3, 3.2). These associations remained unchanged after adjustment for CV risk factors and CHD (data not shown).

Additional analyses were performed to elucidate the influence of concurrent MTX and corticosteroid use. Among MTX users, 76% were using corticosteroids concurrently, and no increased risk of HF was found among these concurrent users compared to patients using neither MTX nor corticosteroids (HR 0.8, 95% CI 0.3, 2.0; p = 0.67). An increased risk of HF persisted among patients taking corticosteroids without MTX (HR 2.2, 95% CI 1.3, 3.6; p = 0.002). However, no significant difference in risk of HF was noted among patients taking MTX without corticosteroids (HR 0.6, 95% CI 0.3, 1.4; p = 0.27).

We also investigated whether risk factors differ for HF with preserved EF and HF with reduced EF. We found that males were more likely to have HF with reduced EF than females (HR 3.7, 95% CI 1.8, 7.7). This association remained significant after adjustment for CV risk factors and CHD. No gender difference was found for HF with preserved EF (HR 0.9, 95% CI 0.5, 1.9 in males vs females). No other statistically significant differences were found between risk factors for HF with reduced EF and HF with preserved EF (data not shown).