Abstract
Background Cardiovascular complications are one of the most common and the most serious extraskeletal manifestations of ankylosing spondylitis (AS). Infliximab, a monoclonal antibody against tumor necrosis factor, is widely used in the treatment of AS. QT dispersion (QTd), which relates to left ventricular function and is used as an index of cardiac dysrhythmia, may be useful as a prognostic guide. Early detection of possible cardiac involvement may not be clinically evident, whereas it may be detected by electrocardiography.
Objectives The aim of this prospective study was to assess the effect of infliximab treatment on QT intervals in patients with AS.
Methods Twenty-one patients (17 females and 4 males) with AS who were in the active phase of disease (Bath Ankylosing Spondylitis Disease Activity Index score >4) were enrolled in the study. Infliximab was administered intravenously at a dosage of 5 mg/kg at weeks 0, 2, and 6 and every 6 weeks thereafter. QT intervals were recorded before and after 6 months of treatment.
Results QT corrected (QTc) for heart rate was significantly reduced in the patients with AS after 6 months of infliximab therapy (406 ± 5.5 vs 388 ± 6.6 milliseconds; P = 0.029). There was no difference in the QTc dispersion (34.3 ± 11.1 vs 34.1 ± 8.6; P = 0.171). Body mass index and lipid profile were slightly increased after the treatment, but the difference was statistically insignificant.
Conclusion Inflammation can affect the ventricles with an unknown mechanism, and QTc may be slightly prolonged as a result in the active phase of AS. In our study, QTc was shortened under infliximab therapy by suppressing inflammation. Therefore, this effect may protect patients with AS from fatal arrhythmias and sudden cardiac death.
Ankylosing spondylitis (AS) is a chronic systemic inflammatory rheumatic disease. Cardiovascular complications are one of the most common and the most serious extraskeletal manifestations of AS.1Patients with AS have to be at higher risk of myocardial infarction in a systematic review and meta-analysis.2Management of cardiovascular risk factors and control of systemic inflammation should be taken into account in AS.
Spondylitic cardiovascular disease is a well-recognized complication of AS.3This generally consists of ascending aortitis and fibrosis, which can lead to complete heart block in severe cases. Various studies indicate a higher rate of aortitis, conduction abnormalities, valvular heart diseases, and cardiomyopathies in patients with AS.3–5Cardiac dysfunction is usually a finding of advanced-stage AS and the frequency is 5% to 10%.3–5
Infliximab, a genetically produced murine fragment antigen-binding fragment dissolved to a human immunoglobulin-1 (IgG1): fragment crystallizable portion, has been approved for use in patients with AS. The fragment antigen-binding fragment binds human TNF and has an anti-TNF effect.6Infliximab is used for the treatment of active patients with active AS who are resistant to nonsteroidal anti-inflammatory drugs and sulphasalazine.2,6There are limited data on infliximab therapy and its effect on cardiac ventricular repolarization.
The QT is a measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle. The electrocardiographic QT interval explores which repolarization that occurs during the left ventricular diastolic phase; furthermore, the QT corrected for heart rate (QTc) has been correlated with both atherosclerotic disease and cardiovascular mortality. QT dispersion (QTd) is used as a benefit marker to determine myocardial electrical instability and possible cardiovascular mortality.7,8Previous studies showed that QT intervals were associated with an increased risk of cardiovascular morbidity.9,10In addition, it is known that there is an association between the QT interval duration and subclinical atherosclerotic disease.11
The aim of this prospective study was to assess the effect of infliximab treatment on QT intervals in patients with AS.
MATERIALS AND METHODS
Patient Selection and Evaluation
The patients in this study consisted of volunteers whose condition was diagnosed as AS according to the Modified New York Criteria.12The individuals, in the active phase of AS whose Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score was higher than 4 were consecutively selected from among those attending the university-affiliated outpatient internal medicine clinic and who wanted to participate in the study. The study was approved by the local ethical committee, and consent forms were received from all the volunteers after they had been informed about the study.
Patients who were younger than 17 years, older than 65 years, had a BASDAI score of less than 4, or vascular and cardiac disease (hypertension, diabetes mellitus, peripheral vascular disease, coronary artery disease, congestive heart failure, arrhythmias, renal failure, thyroid function disorders, etc) were excluded. Patients taking drugs that prolonged the QT interval, as well as those with an electrolyte imbalance, were also excluded.
Twenty-one patients (17 females and 4 males) were enrolled in the study between September 2007 and September 2008. The median age was 35 years (range, 17–65). Fasting blood samples were collected for the determination of lipid profiles (cholesterol, low-density lipid [LDL], triglyceride, and high-density lipid [HDL]), thyroid functions, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complete blood counting; the biochemical parameters included serum electrolyte, liver, and renal function tests.
The complaint level due to the disease was measured with the visual analog scale in millimeters by the patient drawing a vertical line on a straight horizontal line of 100 mm. Disease activity was measured by the BASDAI, and assessment of the functional capacities of the patients was performed by using the Bath Ankylosing Spondylitis Functional Index (BASFI) in its validated Turkish version.13,14The BASDAI and BASFI scores were calculated by a rheumatologist. All measurements and tests were performed before therapy and at the sixth month after therapy.
Treatment Regimen
Infliximab was administered intravenously at a dosage of 5 mg/kg at weeks 0, 2, and 6 and every 6 weeks thereafter. The treatment was continued in all patients with an improvement being observed in the BASDAI scores of at least 20 mm after 3 months. Patients were allowed to take nonsteroidal anti-inflammatory drugs.
Electrocardiographic Data
A computed standard 12-lead electrocardiogram was performed with commercially available software (Norav System, Delray Beach, FL). The electrocardiogram’s wave interval and amplitude were digitally measured using dedicated Norav software, and they were reviewed by 2 observers who were blind to the clinical data.
The QT intervals were measured from the onset of the QRS complex to the end of the T-wave. All R-R intervals containing premature beats were excluded. The preceding R-R interval to the measured QT was used to calculate the heart rate and the corrected QT interval (QTc) using the Bazett formula.15QT dispersion was calculated as the difference between the maximum and the minimum QT interval obtained in any of the 12 leads. QTc dispersion was calculated as the difference between the maximum and the minimum QTc interval.
Echocardiographic Data
Echocardiograms were performed by a Vivid 3 Pro (GE Medical Systems, Milwaukee, WI) echocardiograph with an M-mode, 2-dimensional, pulsed, continuous wave using standardized procedures. Before the treatment regimen, individuals were screened by measuring left ventricular and right ventricular functions to exclude or include patients in the study. The echocardiographic evaluation was performed by the same cardiologist during the study.
Statistical Analysis
All statistical analyses were conducted using the statistical program SPSS 14.0 for Windows (SPSS, Chicago, IL). P < 0.05 was considered statistically significant. The association of factors was evaluated by using the Wilcoxon signed rank test.
RESULTS
A total of 21 patients with a BASDAI score of 4 or higher and a diagnosis of AS were enrolled to the study. The female-to-male ratio was 17:4. The median age was 35 years (range, 17–65). Body mass index and AS duration were detected in all individuals. The BASDAI and BASFI scores were significantly reduced after the treatment (71.7 ± 3.8 to 27.3 ± 4.8; P = 0.001 and 53.2 ± 6.4 to 22.6 ± 5.4; P = 0.002, respectively). From the serological markers, only the ESR (37.2 ± 5.2 to 17.4 ± 3.7; P = 0.009) and CRP (3.06 ± 0.66 to 0.30 ± 0.10; P = 0.0001) levels were significantly decreased. Blood parameters such as CRP, ESR, cholesterol, LDL, triglyceride, and HDL, before and after therapy, are illustrated in Table 1. Although, QTc was significantly reduced after infliximab therapy (406 ± 5.5 to 388 ± 6.6; P = 0,029), the change rates in QTd were not statistically significant (34.1 ± 8.6 to 33.5 ± 2.2; P = 0.171).
The echocardiographic evaluation of left ventricular (ejection fraction, P > 0.05) parameter did not differ significantly after treatment in the patients with AS (66.5 ± 5.2 to 67.3 ± 5.5; P = 0.489; (Table 1).
DISCUSSION
Ankylosing spondylitis is an inflammatory disorder that can affect the cardiac system. Cardiac involvement is usually a late finding of AS inflammation, which is blamed for the cardiac manifestations. Cardiovascular causes probably increase mortality rates.5,16
Previous studies showed that QT intervals were associated with an increased risk of cardiovascular morbidity.9–11In the ARIC study, the prognostic significance of QTc interval for incident coronary heart disease (CHD) with 13 years of follow-up was tested and, after adjusting for age, hypertensive status, diabetes, race, systolic blood pressure, smoking, HDL and LDL cholesterol, R-R interval, and menopausal status in women, showed that QTc was predictive of future coronary events in women with logistic regression analysis.9The women’s dominance in our study seems to be concordant with these findings. Dekker et al.10also investigated the value QTc for incident CHD and cardiovascular disease (CVD) mortality. They found in higher quintiles of QTc that cardiovascular risk profile deteriorated and risk of CHD and CVD mortality increased with longer QTc. Finally, they concluded that long QTc is associated with increased risk of CHD and CVD in healthy men and women. In addition, the relationship between QT interval duration and carotid intima media thickness (IMT) was examined in a prospective study, and an association and correlation with subclinical atherosclerotic disease was shown by Strohmer et al.11
It is known that prolonged QT intervals increase the risk of cardiac events and arrhythmia, therefore shortening in QT intervals may cause to decrease this risk. In patients with AS, especially in the asymptomatic phase of cardiac disease, QT alterations have not been studied so far. There are very limited data on this subject. In our prospective study, after 6 months of infliximab therapy, QTc was significantly reduced in the absence of clinical history or symptoms of cardiovascular disease. It is possible that suppression of inflammatory status may cause the QTc to be shortened.
There are only 2 studies on infliximab-related cardiac problems.17,18The first one was a prospective, single-blind, placebo-controlled, crossover study in which Lazzerini et al.17reported that infliximab infusion caused new-onset ventricular tachyarrhythmias in patients with spondyloarthritis (n = 55) or rheumatoid arthritis (n = 20). In this study, they reported that arrhythmia incidence did not achieve statistical significance. The second study examined QT intervals in 20 patients who were affected by inflammatory bowel disease (IBD). The authors argued that the QTc and QTc dispersion measurements of the patients with IBD were longer than those of the healthy controls and concluded that it might be due to the systemic inflammation.18We have known that AS is one of the well-known systemic inflammatory diseases, which can also affect the cardiovascular system just as IBD. Consequently, if we suppress or control the inflammation, QT intervals may be shortened.
Mann et al.6showed that anti-TNF drugs should be carefully used in patients with heart failure. It is known that TNF-α can also trigger coronary vasodilatation by inducing nitric oxide and that anti–TNF-α agents can inhibit protective mechanisms and cause thromboembolic events.19In another study, Sote et al.20published the case of a patient who developed complete heart block after infliximab therapy. In addition, some authors reported that infliximab might cause acute coronary syndrome in a patient with Crohn disease.21In this current study, any cardiac or noncardiac infusion reactions were seen in any of the patients during the 6-month treatment period.
Conversely, we tested that infliximab therapy may have favorable effects on cardiac functions so that it suppresses systemic inflammation by long-term usage but not short term. In addition, in a porcine cardiac arrest model, Niemann et al.22suggested that the drug may have a beneficial effect on myocardial dysfunction. Our study was designed to monitor myocardial electrophysiological changes by QT intervals in patients with AS who were treated with infliximab. We found that QTc was significantly shortened in the patients with AS on the sixth month after infliximab therapy.
In conclusion, inflammation can affect the ventricles with an unknown mechanism, and QTc may be slightly prolonged as a result in the active phase of AS. In our study, QTc was shortened under infliximab therapy by suppressing inflammation. Therefore, this effect may protect patients with AS from fatal arrhythmias and sudden cardiac death.