Hindawi Publishing Corporation

International Journal of Rheumatology

Volume 2011, Article ID 728471, 6 pages
doi:10.1155/2011/728471

Review Article
Cardiopulmonary Manifestations of Ankylosing Spondylitis

Mahnaz Momeni,1 Nora Taylor,1 and Mahsa Tehrani2

1 Rheumatology Division, The George Washington University Medical Center, 2150 Pennsylvania Avenue, 3-416 NW,
Washington, DC 20037, USA
2 Internal Medicine Division, The George Washington University Medical Center, Washington, DC 20052, USA

Correspondence should be addressed to Mahnaz Momeni, mmomeni@mfa.gwu.edu

Received 20 November 2010; Revised 21 January 2011; Accepted 9 February 2011

Academic Editor: Kenneth C. Kalunian

Copyright © 2011 Mahnaz Momeni et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Ankylosing spondylitis is a chronic inflammatory condition that usually affects young men. Cardiac dysfunction and pulmonary
disease are well-known and commonly reported extra-articular manifestation, associated with ankylosing spondylitis (AS). AS has
also been reported to be specifically associated with aortitis, aortic valve diseases, conduction disturbances, cardiomyopathy and
ischemic heart disease. The pulmonary manifestations of the disease include fibrosis of the upper lobes, interstitial lung disease,
ventilatory impairment due to chest wall restriction, sleep apnea, and spontaneous pneumothorax. They are many reports detailing
pathophysiology, hypothesized mechanisms leading to these derangements, and estimated prevalence of such findings in the AS
populations. At this time, there are no clear guidelines regarding a stepwise approach to screen these patients for cardiovascular
and pulmonary complications.

1. Cardiac Manifestations of tion may, however, predate the onset of any joint symptoms,
Ankylosing Spondylitis and the presence of ankylosing spondylitis as an underlying
cause may not be initially appreciated [1].
Introduction. Ankylosing spondylitis is a chronic and inflam- One of the first pathophysiologic descriptions of valvular
matory condition, affecting the spine, sacroiliac, and periph- disease in AS was put forward by Bulkley and Roberts, who
eral joints. This entity most often affects young men and studied autopsy findings in eight patients with AS. They
may lead to spinal vertebral fusion. Human leukocyte antigen noted aortic root dilatation along with fibrous proliferation
(HLA)-B27 is present in the majority of patients with AS along the intima [4]. Further examination demonstrated a
and is reported to contribute to the pathophysiologic mani- cellular inflammatory process coupled with platelet aggre-
festations of this condition [1]. gation leading to endarteritis around the aortic root and
It has been estimated that cardiac manifestations in valve. This in turn stimulates fibroblast hyperactivity leading
patients with AS are found in 2–10% of patients. It was to tissue thickening involving aortic annulus, cusps, aorto-
initially in the 1930s when aortitis found in a group of mitral junction along with the conduction system [5]. The
patients with spondylitis. It is widely accepted today that not thickening of the valvular cusps, dilatation of the aortic root,
only is aortic pathology linked to AS, but there is also risk for and abnormal cusp displacement via the thickened subaortic
conduction defects, valvular regurgitation, and cardiomy- tissue all lead to aortic regurgitation as seen in many patients
opathy, associated with this entity [1]. This is especially with AS [1].
important, given that in many patients, cardiac changes may Roldan et al. studied the root and valves in AS patients
begin prior to the onset of clinical symptoms [2, 3]. (n = 44) using transthoracic echocardiography (TEE) and
found aortic root and valve disease in (82%) as compared
1.1. Valvular Disease. The presence of aortic root and valve with control (27%). Other irregularities were aortic root
disease in ankylosing spondylitis is related to the duration of thickening, increased root stiffness and dilatation. Except for
the underlying disease. Aortic disease and aortic regurgita- the duration of AKS, aortic root disease and valve disease
2 International Journal of Rheumatology

were unrelated to the activity, severity or therapy of AKS. Since most of the studies points towards early detection
During followup of 25 patients over 39 months in this and treatment of rheumatologic cardiac manifestations,
study, in up to 24% new aortic root or valve abnormalities then early testing of these patients becomes important [8].
developed, in 12% existing valve regurgitation worsened There are multiple modalities listed in the literature to aid
significantly and in 20% abnormalities resolved. Twenty in the evaluation of cardiac manifestations of rheumatic
percent of patients developed heart failure, underwent valve disease, such as utilization of 24-hour holter monitoring
replacement [5]. Aortic regurgitation is most commonly seen and echocardiography [8]. In a study by Yildirir et al. they
in patients with AS; however, mitral regurgitation is also demonstrate that a simple way to evaluate for the presence
known to occur, although less common [1]. The proposed of or propensity for developing arrhythmias is via measuring
mechanism is basically a continuation of the fibrosis of the QT dispersion. Yildirir et al. demonstrated that calculation
subaortic tissues which can progress to reach the mitral of the QT dispersion on a standard EKG is cheap, quick and
valve leaflet. Thereby, a stiffening and hence reduction reveals valuable information regarding patient susceptibility
of the mitral valvular mobility occurs, eventually leading to arrhythmias. This approach is way more cost effective than
to mitral regurgitation. Another potential mechanism for sending all patients off for holter monitoring amongst other
mitral regurgitation may be as a result of severe aortic tests, and can easily be instituted in-office, whereby only
regurgitation, leading to a hypertrophied left ventricle and patients with increased arrhythmia risk can be referred for
hence a distortion of the mitral valve apparatus [1]. further workup [8].

1.2. Conduction and Rhythm Abnormalities. Conduction 1.3. Myocardial Disease. It is widely demonstrated that the
abnormalities are amongst the most commonly observed myocardial dysfunction evident in patients with AS is that
cardiac manifestations of patients with AS that usually of the diastolic variety, as opposed to systolic. For example,
predate other cardiac manifestations such as valvular insuf- in a study by Yildirir et al. they found significant diastolic
ficiency [6]. In a study by Dik et al. they found a statistically dysfunction in AS patients, particularly an abnormal relax-
significant higher prevalence of AS patients with first-degree ation pattern [2]. This was demonstrated via echocardiog-
AV block as well as an association of these blocks with the raphy, by the statistically significant lower E-wave velocity
duration of disease activity [7]. There have been two preva- (early diastolic filling), higher A-wave velocity (late diastolic
lent theories about the etiology of conduction disturbances filling), and overall low E/A ratio, which becomes evident in
in patients with AS: inflammation in the intraventricular patients with diastolic dysfunction [2]. Similarly, Gould et
septum leading to damage versus anomalies in the AV nodal al. evaluated the peak filling throughout exercise, along with
artery leading to AV node dysfunction [7]. Certainly, the the time to achieve peak filling during strenuous activity via
above processes may play hand in hand, given that both AV radionucleotide angiography. Both of these measures were
blocks along with atrial and ventricular extra-systoles have considerably decreased in the patients with AS versus the
been reported [7, 8]. Interestingly, in the observational study normal volunteers [11]. Hence, these findings also support
by Dik et al. they also report an increased finding of conduc- an overall decrease in compliance, and thus a reduction in
tion disturbances in patients who are HLA-B27 positive, even diastolic function.
in patients without rheumatologic manifestations of AS [7]. Coronary flow reserve (CFR) is a measurement, which
Toussirot et al. found factors which highlight autonomic evaluates the function of the coronaries in terms of their
nervous system derangements, in patients with AS [9]. For microvascular circulation. This measure has been touted
example, there was a finding of a small but statistically sig- by some experts as an important tool, holding prognostic
nificant elevation in heart rates. This correlated with disease significance in the evolution of atherosclerosis in patients
severity, as measured by ESR and CRP levels [9]. Further- [3]. Caliskan et al. recently used transthoracic Doppler
more, an inability to maintain steady arterial blood pressures echocardiography (TTDE) to determine the CFR in AS
with changes in position (i.e., supine to erect), was found. patients. Their findings were consistent with a significant
Based on their findings, the group postulated that these decrease in CFR in AS patients. Interestingly, the levels of
autonomic derangements may lead to conduction defects CRP and TNF-alpha correlated with the decline in CFR in
and arrhythmias, thereby negatively impacting prognosis. these patients [3].
They further extrapolated that these subtle autonomic find- Another study looked at an actual outcome, being
ings may be evident prior to more concrete EKG findings, myocardial infarction, in patients with AS. They found a 2-3
hence a clinical practice implication [10]. Contradictory fold increase in the rate of infarctions in the AS population
to this report is a paper two years later, by Yildirir et which they studied. Of note, amongst AS patients with and
al. refuting autonomic dysfunction in the AS population without a myocardial infarct history, there was no difference
[10]. This group utilized heart rate variability as a measure in the use and type of antirheumatic therapy [12]. This is
of autonomic control and found no statistically significant a significant observation; however, difficult to interpret as
difference between the AS versus the control group. An the sample size is very limited (17 patients). A study with
acknowledged limitation was the young population in this multiple antirheumatic treatment arms would be ideal for
latter study, along with the fact that all patients were this type of analysis.
under significant treatment with antiinflammatory agents, There has been research demonstrating that markers of
hence hypothetically halting the advancement of autonomic inflammation (i.e., CRP, IL-6) can reach a high enough level
dysfunction [10]. to start disturbing lipid metabolism and diminishing insulin
International Journal of Rheumatology 3

activity, hence causing insulin resistance and dyslipidemia, by HRCT compared with 8% by traditional chest X-ray
leading to increased overall trend for atherogenecity [13]. In [20]. A similar finding was seen in a study by Turetschek et
a study by Divecha et al. they found a significant elevation in al. in which 25 nonsmoking ankylosing spondylitis patients
IL-6 and CRP levels in patients with AS, over that of healthy underwent pulmonary function testing, chest X-ray, and thin
subjects. This is significant, as it has been reported that section CT with 15/21 (71%) of patients found to have
even a subclinical but chronic elevation in the levels of these abnormalities on thin-section CT [21].
markers accelerate risk of coronary heart disease, in patients
without autoimmune illnesses [13]. Furthermore given that 2.2. Apical Fibrosis and Interstitial Lung Disease. Upper lobe
the clinical use of statins in a rheumatoid arthritis trial not fibrosis is a long recognized lung abnormality associated with
only helped with lipids but also led to reduced IL-6 levels, ankylosing spondylitis. The incidence of apical fibrosis in
so it is important to assess the role of these pharmacologic ankylosing spondylitis is low with estimates ranging from
agents in patients with AS and other spondyloarthritides 1.3–30% and has an association with longer disease duration
[13–15]. [22]. Apical fibrosis often appears greater than five years
after the start of the arthritic symptoms associated with
the disease [23]. The fibrosis can be unilateral or bilateral
2. Pulmonary Manifestations of in nature and is can be followed by cystic changes to
Ankylosing Spondylitis the lung [24]. The cause of the fibrosis is unknown but
recurrent aspiration leading to aspiration pneumonitis from
Introduction. Pulmonary involvement in ankylosing spon-
defective ventilation, alterations in apical mechanical stress
dylitis is an extra-articular manifestation of the disease that
from a rigid thoracic spine, and recurrent impaired cough
was first described in 1941 in an article reviewing twenty
secondary to alterations in respiratory mechanics have been
cases of ankylosing spondylitis [16] when two cases were
proposed [25, 26]. The abnormal lung parenchyma is a
noted to have “healed apical tuberculosis”. The pulmonary
fertile bed for superinfection with a variety of organisms
manifestations of the disease include fibrosis of the upper
including atypical Mycobacterium, Mycobacterium tuberculo-
lobes, interstitial lung disease, and ventilatory impairment
sis, Aspergillus, and Metschnikowia pulcherima [27–29]. The
due to chest wall restriction, sleep apnea, and spontaneous
distribution and appearance of the upper lobe abnormalities
pneumothorax. The incidence of lung involvement in anky-
in ankylosing spondylitis patients led many physicians
losing spondylitis has changed with the development of
in the past to incorrectly diagnose these patients with
high-resolution computed tomography (HRCT). Although
Mycobacterium tuberculosis. However, Ho et al. in a study
improved techniques in visualization of the lung have
in Taiwan illustrated how differentiation between the two
allowed identification of more abnormalities of the lung
often requires further diagnostic evaluation and a high index
parenchyma associated with ankylosing spondylitis there is
of suspicion for infection when review of medical records
little known about the natural history of such abnormalities
of 2136 ankylosing spondylitis patients in Taiwan revealed
and the potential for therapies used in treatment of ankylos-
63/2136 (2.9%) with apical fibrosis and chronic infection
ing spondylitis to halt the progression of the lung disease.
from Mycobacterium Tuberculosis found in 41/63 (65%) of
those patients [30].
2.1. High-Resolution Computed Tomography. The introduc- Interstitial lung disease (ILD), beyond apical fibrosis, is
tion of HRCT in pulmonary evaluation of ankylosing now a recognized feature of pulmonary involvement in anky-
spondylitis patients has shown that lung parenchymal losing spondylitis as a result of improved visualization of the
changes occur earlier and are more extensive than once lung parenchyma with HRCT [19]. Pathologic diagnosis of
believed. In an evaluation of 26 patients with ankylosing ILD in the setting of ankylosing spondyltitis has rarely been
spondylitis for less than 5 years by Baser et al. HRCT described due to a relative paucity of autopsy studies and the
changes were seen in 13/25 (50%) of patients [17]. Upper cause of the ILD in this setting is still unclear. Case reports
lobe fibrosis was identified in 1.3% of 2080 cases in a and small series to date have shown evidence of chronic
retrospective review in 1977 but recent studies using HRCT inflammatory cell infiltrates and prominent interstitial fibro-
have shown a more extensive involvement of the lung [18]. sis with elastic degeneration of collagen and hyaline by needle
The use of HRCT for evaluation of whole lung involvement biopsy and lobectomy examinations [31]. One case study
was first utilized by Casserly et al. in 1997 revealing lung in 1971 described a patient with longstanding ankylosing
involvement in 19/26 (70%) ankylosing spondylitis patients spondylitis admitted to the hospital with pancytopenia and
meeting the New York criteria for ankylosing spondylitis. diffuse bilateral interstitial and alveolar infiltrates involving
This uncontrolled study using HRCT to examining the lung the middle and upper lung fields [32]. Percutaneous lung
parenchyma saw a far larger number of abnormalities on biopsy was performed and revealed interstitial pneumonitis
HRCT as compared with only 4/26 (15.3%) abnormal plain and fibrinous alveolitis.
X-rays in the same patients. Lung parenchymal abnormalities Multiple studies have shown the association between ILD
observed included interstitial lung disease, emphysema, and ankylosing spondylitis [17, 19, 33]. Baser et al. was
apical fibrosis, mycetoma, and nonsepcific intestinal lung the first to show that these parenchymal changes can occur
disease [19]. Sampaio-Barros et al. evaluated pulmonary early in the course of the disease, less than 5 years after the
involvement of ankylosing spondylitis in 52 patients with start of ankylosing spondylitis symptoms, with parenchymal
no lung complaints and found that 40% had abnormalities abnormalities in 13/26 (50%) of all patients, 8/21 (38.1%) of
4 International Journal of Rheumatology

asymptomatic patients, and in 5/5 (100%) of symptomatic 2.5. Sleep Apnea. An increased incidence of sleep apnea in
patients. The parenchymal abnormalities were broad includ- patients with ankylosing spondylitis has been described
ing emphysema, bronchiectasis, ground glass opacities, sep- in several studies [38]. Fatigue is a common symptom
tal thickening, parenchymal micronodules, pleural thicken- in ankylosing spondylitis and is a question on the Bath
ing, parenchymal bands, and apical fibrosis with emphysema Ankylosing Spondylitis Disease Activity Index (BASDAI)
being the most common abnormality seen in 9/21 (34.6%) of used to determine the severity of an individual patients’
patients. Similar findings were seen by Souza et al. with 11/17 disease [39]. Obstructive sleep apnea was found in 12% of
(65%) of patients having evidence of ILD on HRCT [33]. In patients in a small study by Erb et al. of 17 patients with
an observational study of HRCT in ankylosing spondylitis, ankylosing spondylitis. This percentage was significantly
Casserly et al. [19] found interstitial lung disease in 4/26 higher than the 1–4% seen in the general population.
(16%) of ankylosing spondylitis patients. Simultaneous Possible mechanisms for the cause of obstructive sleep apnea
evaluation with chest X-ray did not reveal any abnormalities in ankylosing spondylitis put forward by Erb et al. include
in any of the 4 patients found to have ILD on HRCT, however, restriction of the oropharyngeal airway by compression from
all 4 patients had abnormal pulmonary function testing. cervical spine involvement or temporomandibular involve-
ment, restrictive pulmonary disease, or cervical spine disease
causing compression of the respiratory centers found in the
2.3. Chest Wall Restriction and Ventilatory Abnormalities.
medulla [40]. In an attempt to further assess the prevalence
Restricted chest wall motion can lead to restricted pul-
of obstructive sleep apnea in ankylosing spondylits, Solak et
monary function. Dorsal kyphosis from involvement of the
al. [38] followed with a study of 31 ankylosing spondylitis
thoracic spine, costoverterbral, sternoclavicular, and ster-
patient and subjected all patients to a polysomnography
nomanubrial joints leads to impairment of chest wall expan-
evaluation and pulmonary function testing. Results revealed
sion with breathing. Disease activity was not associated with
7/31 (22.6%) found to have obstructive sleep apnea with
PFT abnormalities in one study evaluating 36 ankylosing
the mean age of those suffering from sleep apnea (43.4 ±
spondylitis patients compared to 34 controls who underwent
5.7) being statistically higher than those without sleep apnea
pulmonary function testing, smoking and quality of life
(33.2 ± 10.6). Pulmonary function testing of the same group
questionnaires [34]. The opposite was seen in an alternate
revealed a restrictive pattern in 12 (53.3%) of patients with
study by Maghraoui et al. of 55 ankylosing spondylitis
no increased incidence of pulmonary function abnormalities
patients with a statistically significant correlation between
in the group with obstructive sleep apnea as compared
disease activity and PFT abnormalities [35]. The predomi-
to those without sleep apnea. An obstructive pattern on
nant abnormality on pulmonary function testing is a restric-
pulmonary function testing was not observed in any patients.
tive pattern and has been seen in numerous studies [31].
Given the increased incidence of obstructive sleep apnea
in ankylosing spondylitis, formal sleep evaluation should be
2.4. Spontaneous Pneumothorax. Spontaneous pneumotho- considered in patients complaining of severe fatigue. Treat-
rax is a very rare complication of ankylosing spondylitis, ment of obstructive sleep apnea in ankylosing spondylitis
with one retrospective review in Taiwan revealing a total is the same as for patients without ankylosing spondylitis
of 3/1028 cases for an incidence of 0.29% [36]. The and includes CPAP (continuous positive airway pressure),
three cases were all seen in the setting of patients with smoking cessation, and, if needed, weight loss to achieve a
apical lung fibrotic changes confirmed by X-ray. Apical normal body mass index.
lung abnormalities were seen in 22 patients total (22/1028, Recent studies on sleep disturbance in ankylosing spon-
2.1%), with spontaneous pneumothorax in 3 (3/22, 13.6%) dylitis look at the effect of golimumab and adalimumab in
leading the authors to propose the primary risk factor the reduction of sleep disturbance in patients suffering from
for spontaneous pneumothorax in ankylosing spondylitis ankylosing spondylitis [41, 42]. Neither study addressed
patients to be apical fibrosis. All three of the individuals who the issue of sleep apnea specifically but instead looked at
had a spontaneous pneumothorax related to their disease validated measures of sleep disturbance and improvement of
happened to be smokers. The contribution of smoking these measures with the use of golimumab and adalimumab.
to the risk of spontaneous pneumothorax in ankylosing Deodhar et al. looked at sleep disturbance in patients treated
spondylitis patients is unclear given the small numbers with golimumab 50 or 100 mg as compared with placebo
of spontaneous pneumothorax overall. Mean duration of using the Jenkins Sleep Evaluation Questionnaire (JSEQ).
time from diagnosis of ankylosing spondylitis to timing of Patients on both doses of golimumab had a significant
spontaneous pneumothorax was 13.0 ± 6.2 years. Recurrence greater improvement of their JSEQ compared to placebo
of spontaneous pneumothorax occurred in 2 out of 3 cases from baseline to week 12 and week 24 [41]. Rudwaleit
with the third case undergoing talc pleurodesis at the first et al. performed a similar subanalysis of the RHAPSODY
occurrence leading the authors to conclude in their paper (Review of Safety and Effectiveness with Adalimumab in
with a recommendation that a prophylactic procedure to Patients with Active Ankylosing Spondylitis) to assess the
prevent recurrence be considered at the first event. This was effect of adalimumab on sleep after 12 weeks of treatment
echoed in a case report published by Kaneda et al. discussing using the Medical Outcomes Sleep Study Scale (MOS-
a case of recurrent bilateral repeat pneumothorax in a 53- SS) and showed that at week 12, adalimumab improved
year-old male with ankylosing spondylitis who ultimately sleep in all of the MOS-SS domains. Improvement was
required bilateral chemical pleurodesis [37]. similar in both patients with and without radiographically
International Journal of Rheumatology 5

advanced ankylosing spondylitis [42]. While both of these [6] J. Kaźmierczak, M. Peregud-Pogorzelska, J. Biernawska et al.,
studies indicate ankylosing spondylitis improves patients’ “Cardiac arrhythmias and conduction disturbances in patients
assessment of sleep disturbance, interesting future studies with ankylosing spondylitis,” Angiology, vol. 58, no. 6, pp. 751–
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