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A 73-year-old woman with rheumatoid arthritis and shortness of breath
Article first published online: 30 MAY 2008
Copyright © 2008 by the American College of Rheumatology
Arthritis Care & Research
Volume 59, Issue 6, pages 892–899, 15 June 2008
How to Cite
Pappas, D. A., Taube, J. M., Bathon, J. M. and Giles, J. T. (2008), A 73-year-old woman with rheumatoid arthritis and shortness of breath. Arthritis & Rheumatism, 59: 892–899. doi: 10.1002/art.23720
- Issue published online: 30 MAY 2008
- Article first published online: 30 MAY 2008
- Manuscript Accepted: 13 FEB 2008
- Manuscript Received: 3 DEC 2007
- Sibley Hospital Foundation
- Mackley Award
- Arthritis National Research Foundation
The patient, a 73-year-old woman with rheumatoid arthritis (RA), presented in October 2004 to the emergency department with increasing dyspnea. She had had stable dyspnea on exertion of 1 city block for ∼10 years. This had been attributed to interstitial lung disease associated with RA. Two weeks prior to admission, the patient had developed dyspnea at rest and orthopnea. In addition, for the preceding 2 months, she had experienced frequent heart palpitations. She recalled having a runny nose and feeling feverish and nauseated immediately prior to the deterioration in her breathing status. She denied chest pain and paroxysmal nocturnal dyspnea. She stated that she had lost ∼25 pounds of weight over the preceding 4 months.
Five months prior to this admission, she had undergone an echocardiogram to evaluate persistent dyspnea. Her ejection fraction was 35–40% at that time. Apart from Doppler findings suggestive of mild pulmonary hypertension (PH; right ventricular systolic pressure 42 mm Hg), no other abnormalities were noted. Subsequent cardiologic evaluation included a myocardial perfusion study showing a small area of possible stress-induced ischemia in the inferior septum, and a radionucleotide ejection fraction of 60%. The only change in her treatment regimen at that time was the addition of atorvastatin.
Past medical history
The patient had received a diagnosis of RA >10 years previously. Records obtained from her treating rheumatologist confirmed the diagnosis on the basis of hours of morning stiffness; wrist, hand, and ankle synovitis; rheumatoid factor seropositivity; an elevated erythrocyte sedimentation rate (ESR); and radiographic evidence of joint space narrowing and erosions (Figure 1).
Her RA was initially treated with sulfasalazine (SSZ; 1 gm twice daily), various nonsteroidal antiinflammatory drugs (NSAIDs), and low-dose prednisone (5 mg/day). In 1993, SSZ was changed to methotrexate (MTX; 10 mg orally each week), but the MTX was discontinued several months later when she developed dyspnea, a persistent cough, and increased interstitial lung markings on chest radiograph. The patient resumed SSZ and began hydroxychloroquine (HCQ; 200 mg daily). In 1996, SSZ was discontinued because her RA was judged to be inactive, but the patient continued HCQ monotherapy. Her ESR remained elevated, ranging over the next several years between 70 and 100 mm/hour. She continued to report morning stiffness, and was treated intermittently with a variety of NSAIDs for hand discomfort. Progressive loss of mobility in her right wrist was documented over the ensuing years.
The patient continued to have pulmonary symptoms even after the MTX was discontinued, and she was evaluated longitudinally by a pulmonologist. In both 1997 and 2002, computed tomography scans of the chest exhibited “stable fibrosing scarring or interstitial pneumonitis.” Pulmonary function tests were consistent with a moderate restrictive ventilatory defect. She was offered but declined a lung biopsy, and was then lost to pulmonary followup. The remainder of her medical history was significant for hypertension, type 2 diabetes mellitus, hyperlipidemia, and glaucoma. She suffered a cerebrovascular accident in 1992, but recovered without permanent neurologic sequelae.
Her medications at the time of admission included HCQ (200 mg daily) and prednisone (5 mg daily), as well as low-dose aspirin, metformin, atorvastatin, hydrochlorothiazide, furosemide, and timolol eye drops. It is not clear why and when the furosemide had been added to her regimen. She did not have any known medication allergies.
Social and family history
The patient had quit smoking ∼10 years prior to this admission, but had a cigarette smoking history of 80 packs per year. Her father died of an unspecified liver disease at age 37 years, and her mother died due to complications of diabetes at age 73 years.
The patient was in moderate distress from dyspnea. However, she was afebrile and had an oxygen saturation of 92% on room air and 97% on 2 liters by nasal cannula. She was slightly tachypneic with a respiratory rate of 20 breaths/minute, but her heart rate was 60 beats/minute and regular. Her initial blood pressure was 146/82 mm Hg. The peripheral pulses in the upper and lower extremities were strong and symmetric. The jugular venous pressure was estimated to be 12 cm. On cardiac examination, the patient had no murmurs, rubs, or other adventitious sounds. Lung auscultation revealed rales throughout the lung fields, most evident at the bases. There was no hepatic engorgement and no splenomegaly. The lower extremities had mild pitting edema. The musculoskeletal examination revealed synovial thickening of the metacarpophalangeal and proximal interphalangeal joints, but there was no joint tenderness. There was decreased extension of the right wrist.
Laboratory and radiologic evaluation
Results of the initial laboratory workup are shown in Table 1. The patient's total serum bilirubin and alanine aminotransferase were slightly elevated. The serum N-terminal pro–brain natriuretic peptide was 7,371 pg/ml (normal range 0–125), but her creatinine kinase and troponin levels were normal. An electrocardiogram (EKG) revealed a sinus bradycardia (58 beats/minute) with a prolonged QT interval (corrected QT [QTc] 635 msec; normal ≤440). There were no ST segment or T wave abnormalities, and no sign of left ventricular hypertrophy. A chest radiograph revealed cardiomegaly (heart to chest ratio 18:34) and Kerley B lines superimposed upon interstitial fibrotic changes (Figure 2). An echocardiogram performed in the emergency department showed an ejection fraction of 35–40%, but revealed no valvular abnormalities.
|Reference range||17:25||23:55||Time of arrest|
|White blood cell count, per mm3||4,500–11,000||7,080|
|Differential count, %|
|Erythrocyte count, per mm3||4.0–5.2 × 106||4.63 × 106|
|Mean corpuscular hemoglobin, pg/cell||26.0–34.0||30.5|
|Mean corpuscular volume, μm3||80.0–100.0||90.9|
|Platelet count, per mm3||150,000–350,000||370,000|
|Urea nitrogen, mg/dl||7–22||21|
|Total protein, gm/dl||6.0–8.2||8.1|
|Alkaline phosphatase, units/liter||30–120||96|
|Total bilirubin, mg/dl||0.1–1.2||1.4|
|Aspartate aminotransferase, units/liter||0–31||25|
|Alanine aminotransferase, units/liter||0–31||71|
|CK-MB fraction, ng/ml||0–7||<1||<1|
|Troponin 1, ng/ml||0.00–0.50||<0.06||<0.06|
|Serum N-terminal pro–brain natriuretic peptide, pg/ml||0–125||7,371|
The patient is a 73-year-old woman with longstanding RA, interstitial lung disease, and mild PH who now presents with several weeks of worsening shortness of breath and dyspnea on exertion.
The patient was diagnosed with exacerbation of congestive heart failure (CHF) and was treated with diuretics in the emergency department. She received 60 mg of furosemide intravenously and had a urine output of 2,100 ml. This led to symptomatic improvement, and she was admitted to the medicine service in stable condition. However, on the floor, her condition deteriorated over the next several hours, and cardiopulmonary arrest ensued. An EKG revealed atrial fibrillation with a left bundle branch block, which progressed to pulseless electric activity and then to asystole. Multiple doses of intravenous epinephrine and atropine were successful in restoring a cardiac rhythm, and the patient was transferred to the cardiac care unit (CCU) with sinus bradycardia and a borderline blood pressure. In the CCU, the patient became progressively more hypotensive (blood pressure 81/23 mm Hg) and suffered another asystolic event, from which she was resuscitated. A post-resuscitation EKG revealed ST segment elevation, raising the possibility of an acute coronary syndrome.
Following the placement of a transcutaneous pacemaker and the initiation of cardiac pressors, the patient underwent coronary angiography. Moderate atherosclerotic coronary artery disease was detected, but no critical arterial narrowings were present. An intraaortic balloon pump was placed and she was transferred back to the CCU. Despite pressor support, she became progressively hypotensive and died several hours later of cardiogenic shock, multiorgan failure, and disseminated intravascular coagulation. An autopsy was performed.
The proximate cause of death was CHF that progressed to cardiogenic shock and fatal dysrhythmias. A number of etiologies were considered as the cause of this syndrome.
The patient had several risk factors for ischemic coronary artery disease, including hypertension, hyperlipidemia, diabetes, a history of cigarette smoking, and a previous cerebrovascular event. In addition, RA itself is an independent risk factor for accelerated atherosclerosis (1–3). However, our patient had had a negative myocardial perfusion test before admission and a cardiac catheterization that failed to implicate a critical coronary artery stenosis as the cause of her death.
Hypertensive cardiomyopathy or structural heart disease
The patient's longstanding hypertension could have been the cause of her CHF. However, left ventricular hypertrophy was not evident on her EKGs, and her echocardiogram had documented a normal left ventricular size and wall thickness. Structural etiologies such as valvular disease were excluded by echocardiography and catheterization.
The patient reported symptoms consistent with a viral upper respiratory tract infection, such as a rhinorrhea and a possible mild fever. This, along with the rather acute decompensation, suggests the possibility of viral myocarditis, which can lead to both mechanical heart failure and/or arrhythmia. However, neither elevated cardiac enzymes nor EKG findings consistent with myopericarditis were noted.
The best-known complication of antimalarial therapy, retinopathy, is estimated to have an incidence of 0.38%, based on a recent study (4). HCQ-induced myopathy, which can cause creatinine kinase elevations and proximal muscle weakness, is also recognized (5). In addition, HCQ has been associated with myocardial toxicity in a small number of patients. HCQ cardiotoxicity can present with either conduction abnormalities or systolic and diastolic CHF (6, 7). Antimalarial-related cardiotoxicity has been associated with biventricular myocardial hypertrophy (8), a restrictive pattern on Doppler examination (9), or dilated cardiomyopathy (10). The pathologic findings in HCQ cardiotoxicity include enlarged and vacuolated cells on light microscopy and the presence of myelinoid and curvilinear bodies within the cardiac myocytes in transmission electron microscopy (7, 11). Myocardial necrosis or degeneration is also observed (6). Although in our patient the echocardiogram did not demonstrate a picture consistent with HCQ toxicity, this explanation cannot be entirely excluded.
Infiltrative diseases can lead to cardiomyopathy and CHF. In this case, the patient's underlying RA could have been associated with secondary (AA) amyloidosis (12). When amyloidosis occurs in the setting of RA, the arthritis is typically severe and longstanding. Although the incidence of AA amyloidosis is declining among patients with RA (13), RA remains a major cause of AA amyloidosis because infectious etiologies, formerly more common, are now treated more effectively than in the past (13).
When amyloidosis affects the myocardium, it usually causes a restrictive physiology in advanced disease, with a characteristic sparkling pattern noted occasionally on echocardiography (14). Such an echocardiographic pattern was not noted in our case. In addition, amyloid involvement in inflammatory diseases is usually accompanied by renal involvement, of which there was no indication in this case (15). Despite these caveats, AA amyloidosis leading to cardiomyopathy cannot be excluded with certainty in our patient.
Prolonged QT interval
Our patient had a prolonged QT interval (QTc 635 msec). Patients with prolonged QT intervals, either congenital or acquired, are susceptible to a type of arrhythmia known as torsade de pointes (polymorphic ventricular tachycardia) (16). Chronic HCQ treatment has been associated with acquired QT prolongation in 1 case report (17). In addition, anti-Ro/SSA antibodies (18) have also been associated with prolongation of the QTc interval; however, anti-Ro antibodies were not detected in our patient. Regardless of the etiology of the prolonged QTc interval in our patient, the arrhythmia identified was not torsade de pointes. Therefore, it seems unlikely that the patient's prolonged QT interval contributed to her death.
The patient's acute decompensation could have been due to a pulmonary embolism. Pulmonary embolism must always be considered when a patient experiences a rapid cardiopulmonary decline. In this case, because of the acuity of the patient's cardiac complications, she could not be evaluated for the possibility of pulmonary embolism during life.
Given the patient's mild PH demonstrated previously by echocardiography, it is possible that excessive diuresis in the emergency department may have contributed to the patient's downward spiral by decreasing the right ventricular preload. Patients with PH must undergo diuresis gently, because this may interfere with the cardiac output by decreasing the right ventricular preload, induce hypokalemia and subsequent arrhythmias, or cause metabolic alkalosis, which may suppress the ventilatory drive.
Cardiac dysfunction in RA
Cardiac complications of RA were first recognized in the 1950s (19). In recent years, it has become clear that a variety of cardiac problems related to RA contribute to the increased morbidity and mortality associated with this disease (20). The role of RA in causing heart failure, acute coronary syndromes, and cardiac arrhythmias is now the subject of intensive investigation.
RA and heart failure.
RA itself can be associated with a variety of cardiac manifestations, including myocarditis, rheumatoid nodules within the myocardium or conduction system, pericardial disease, coronary vasculitis, and valvular disease (14). RA is associated with a higher prevalence of symptomatic CHF compared with individuals without RA (21), as well as a greater risk of subclinical diastolic dysfunction (22, 23). CHF is an important contributor to the increase in morbidity and mortality associated with RA (20), and its excess is not explained by traditional risk factors or clinical ischemic disease (24), suggesting that chronic rheumatoid inflammation explains the increased susceptibility.
Targeted inhibitors of tumor necrosis factor α (TNFα), e.g., etanercept, infliximab, and adalimumab, have been implicated in some studies as a potential cause of myocardial dysfunction (25–27). These data contradict those from animal models of cytokine-induced heart failure that strongly support a mechanistic role for macrophage-derived cytokines, particularly TNFα, in the pathogenesis of CHF in RA (28–34). In any event, our patient was not receiving therapy with TNFα inhibitors, even though surrogate clinical markers of active systemic inflammatory disease such as the ESR were persistently elevated. It is likely that some elements of her rheumatic disease were unrecognized and undertreated for several years.
RA and acute coronary syndromes.
Patients with RA are also at increased risk for acute coronary syndrome. Microvascular inflammation mediated by RA is believed to be responsible for this risk. Raza et al (35) have inferred from one illustrative case that myocardial microvascular abnormalities can result in clinical ischemia without angiographic evidence of coronary disease, and that these abnormalities can be reversed with immunosuppressive therapy.
Coronary arteritis causing myocardial infarction is rare in patients with RA. This complication usually occurs in patients with flagrant systemic vasculitis (e.g., skin ulcers, vasculitic neuropathy, scleritis) and longstanding, joint-destructive RA (36). In contrast to atherosclerosis, rheumatoid vasculitis frequently involves intramyocardial arteries that are smaller than the epicardial vessels (37–39). It is conceivable that microvascular disease of this nature could have been present in our patient, but was overlooked by the conventional approach (coronary catheterization) to excluding ischemic disease.
RA and cardiac arrhythmias.
Patients with RA have accentuated sympathetic activity, which may predispose to ventricular arrhythmias (40). In a recent study of cardiovascular autonomic dysfunction, a significant proportion of patients with RA had abnormalities of either sympathetic or vagal tone (41). Furthermore, decreased heart rate variability encountered in active RA has been associated with sudden cardiac death (42, 43).
Patients with RA have increased QT dispersion, which becomes more evident as the disease progresses (44, 45). QT dispersion is defined as the difference between the minimum and maximum QT interval in a 12-lead EKG. Large QT dispersion, an indication of heterogeneity in ventricular repolarization, is a marker of cardiovascular morbidity and mortality related to complex ventricular arrhythmias (44). However, Holter monitoring in 2 studies did not reveal increased difference in arrhythmias between RA patients and matched controls (46, 47).
Complete heart block has been described in case series of patients with RA. Granulomata in or near the atrioventricular node and infiltration of the conducting system by lymphocytes, plasma cells, and histiocytes have been reported in the autopsies of patients with RA (48). Other mechanisms responsible for complete heart block in patients with RA are amyloidosis or hemorrhage into a rheumatoid nodule.
Although the mechanisms described above are potential explanations for cardiac decompensation among patients with RA in general, in our patient, CHF preceded her evolution of cardiac arrhythmias.
A complete autopsy was conducted. Examination of the thoracic cavity revealed small bilateral pleural effusions, multiple pleural adhesions to the thoracic cavity, and adhesions between pulmonary lobes. These findings are consistent with previous fibrinous pleuritis, a typical complication of rheumatoid lung disease.
The lower lobes of each lung showed honeycombing fibrosis. The bronchial mucosa was normal. No pulmonary emboli were identified. Microscopic examination of the lungs revealed other findings commonly seen in rheumatoid lung disease, including foci of pulmonary vasculitis and interstitial fibrosis with a mixed inflammatory infiltrate, consistent with usual interstitial pneumonitis.
Examination of the heart also showed evidence of rheumatic disease. On gross examination, the heart weighed 530 gm (normal weight 306 gm for our patient's age and weight; 95% confidence interval 209–448) (49) and was grossly remarkable for mild to moderate coronary artery disease. A small serosanguineous pericardial effusion was also present. The pericardial, epicardial, and endocardial surfaces were all smooth. The myocardium was grossly unremarkable. The aortic and mitral valves showed minor thickening. This patient had nonocclusive atherosclerosis in the left anterior descending artery, with no evidence of resultant ischemia or infarction in the myocardium. Of note, a diffuse myocarditis was present microscopically. More specifically, a mixed inflammatory infiltrate was present and localized to the interstitium of the heart (Figure 3). There was no myocardial necrosis or degeneration, thus excluding the possibility of infectious or HCQ-related myocardial toxicity. Amyloid was not identified.
Although coronary disease was present, there were no ischemic changes in the myocardium, and the patchy involvement of small intramyocardial arteries typically seen in coronary vasculitis was not observed (39). The liver showed evidence of chronic passive congestion.
Myocarditis is a rare but recognized form of rheumatoid cardiac disease and is a known cause of CHF (50). Its reported prevalence varies in the literature. Rheumatoid myocarditis assumes 1 of 2 patterns: a granulomatous form that is considered specific for RA, or a nonspecific form that may also be observed in other disorders. When present, the granulomas show a predilection for the left ventricle and are morphologically identical to the subcutaneous nodules of RA (38). This differs from the nonspecific inflammatory pattern that is composed predominantly of lymphocytes, plasma cells, and histiocytes, and involves the collagenous interstitium of the heart (38, 51), as was seen in the current case. Both forms of RA myocarditis have been implicated in fatal arrhythmias (48).
We can conclude that the interstitial myocardial inflammation was the cause of this patient's CHF. The CHF itself may have led to the fatal arrhythmia, although it is also possible that RA myocarditis affected the conducting system of her heart, contributing to the patient's fatal arrhythmia and asystole.
Some of the first systematically collected data on the pathology of heart involvement in RA came from autopsy studies performed in the 1960s. In an initial study (38), nonspecific myocarditis was identified in 12 (19.4%) of 62 patients with RA who underwent autopsy. In 10 of the 12 patients without clinically apparent heart disease, an interstitial and focal inflammatory infiltrate consisting of plasma cells, lymphocytes, and histiocytes was noted. Rheumatoid granulomas were found in only 2 (3%) patients, pericardial disease in 18 (29%), and arteritis in 12 (19%). The authors noted that whereas most patients had been labeled on a clinical basis as having arteriosclerotic heart disease, several patients with clinical heart disease had only “lesions of the rheumatoid process present” (38).
Similar findings were encountered in subsequent autopsy studies. Overall, old or fibrinous pericarditis was the most striking finding (52), with incidence rates ranging between 11% and 50% (53). Nonspecific myocarditis, like the one described above, was also an unexpectedly frequent abnormality, found in up to 19% of patients who usually had active arthritis (53).
In more recent publications, pericardial involvement is still encountered as the most frequent finding in autopsy or echocardiographic series, with incidences ranging between 30% and 50% (14), which in most of the cases is not clinically apparent. In contrast, the epidemiology of RA-associated cardiomyopathy/myocarditis is less well explored. A study reported that 7 (25%) of 28 patients with RA had increased myocardial uptake in gallium scintigraphy, possibly consistent with myocardial inflammation (54). In a recent autopsy study of 81 patients with RA who died in the hospital, 13 (16%) died of heart failure, whereas in the age- and sex-matched control group of 243 non-RA patients, only 8 (3%) patients died of heart failure. Variable changes were noted in patients with RA carrying the diagnosis of heart disease prior to death, including pericarditis, myocarditis, angiitis, microinfarcts, granulomatous lesions, and amyloid deposits (55).
Overall and importantly, although postmortem studies report a high prevalence of RA myocarditis in significant percentages, particularly of the nonspecific type similar to the one documented in our patient, it is believed that it seldom becomes clinically apparent.
In summary, it is important to always consider RA as a systemic disease that may significantly contribute to morbidity or mortality from cardiovascular involvement. Although the increased prevalence of atherosclerosis and ischemic and nonischemic CHF has attracted the focus of investigators, myocarditis directly linked to the inflammatory process in the context of the traditionally named rheumatoid heart should still be included in the differential of a patient with RA presenting with CHF (24).
It is possible that increased systemic inflammation (as evidenced by elevated serum inflammatory markers) in our particular patient was not solely reflecting active synovitis but was, at least partially, due to ongoing inflammation in the heart and lungs. One could reasonably speculate that aggressive antiinflammatory or disease-modifying treatment could have a beneficial effect on the myocardial status of patients such as the one presented, although evidence-based confirmation from the literature is lacking in regard to response to therapy for rheumatoid myocarditis.
- 7Hydroxychloroquine-induced cardiotoxicity in a 39-year-old woman with systemic lupus erythematosus and systolic dysfunction. J Am Soc Echocardiogr 2005; 18: 981., , , , , .
- 25Anti-TNF Therapy Against Congestive Heart Failure Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure: results of the Anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003; 107: 3133–40., , , , , and the
- 46Echocardiographic findings, 24-hour electrocardiographic Holter monitoring in patients with rheumatoid arthritis according to Steinbrocker's criteria, functional index, value of Waaler-Rose titre and duration of disease. Clin Rheumatol 1998; 17: 369–77., , .