Pulmonary hypertension in a patient with adult-onset stills disease

Abstract

Pulmonary manifestations of adult-onset Still’s disease (AOSD) include aseptic pneumonitis, pleural effusions, rarely acute respiratory distress syndrome, and restrictive lung disease. Pulmonary arterial hypertension (PAH) occurs with several rheumatologic diseases, however, has only been reported once in AOSD. We describe a 29-year-old woman with a 9-year history of AOSD, who developed PAH without any other obvious cause. Therefore, we conclude that this is likely a result of pulmonary vascular changes related to AOSD.

Adult-onset Still’s disease (AOSD) is characterized by a high spiking quotidian fever, arthralgia and arthritis, pharyngitis, evanescent salmon color maculopapular rash, lymphadenopathy, hepatomegaly, splenomegaly, serositis, anemia, neutrophilic leukocytosis, thrombocytosis, and elevated acute-phase reactants [1]. Cardiopulmonary manifestations include transient pneumonitis, pleuritis, and pericarditis with effusions which rarely progress to acute respiratory distress syndrome, restrictive lung disease, pericardial tamponade, and myocarditis [2].

Pulmonary arterial hypertension (PAH) has been reported in patients with several autoimmune rheumatic diseases (ARD), including systemic sclerosis (SSc), systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), dermatomyositis, polymyositis, primary antiphospholipid antibody syndrome, primary Sjögren’s syndrome (SS), rheumatoid arthritis (RA), and vasculitides such as Wegener’s granulomatosis, polyarteritis nodosa, and Takayasu’s arteritis [3–6]. We describe a patient with AOSD who developed the characteristic clinical and hemodynamic findings of PAH with no obvious alternative explanation.

Case report

A 29-year-old woman with a history of adult-onset Still’s disease (AOSD) for 9 years manifested by high spiking fevers, knee, wrist, ankle, and shoulder joint arthritis, evanescent maculopapular rash, leukocytosis, elevated hepatic enzymes, erythrocyte sedimentation rate (ESR), multiple negative antinuclear antibody and rheumatoid factor serologies, and a ferritin of 10,100 ng/ml (normal <132) was hospitalized with 3 months of progressive exertional dyspnea, orthopnea, lower extremity edema, pleuritic chest pain, and unintentional 20-pound weight loss and was receiving prednisone 60 mg/day. She had been treated with corticosteroids, nonsteroidal antiinflammatory drugs, hydroxychloroquine, methotrexate, and sulfasalazine. She had no history of skin tightness, gastroesophageal reflux, dysphagia, Raynaud’s phenomenon, or sicca symptoms. She denied tobacco, alcohol, illegitimate drug, or weight-loss drug use.

Her physical examination revealed a black woman in mild respiratory distress with a pulse of 120 beats/min, a respiration rate of 28/min, and a blood pressure of 139/99 mmHg, normal lungs, a right parasternal heave, an accentuated pulmonary second heart sound, a 2/6 systolic murmur at left lower sternal border, an elevated jugular venous pressure of 7 cm, a hepatomegaly with a liver span of 16 cm, ascites, 2+ pedal edema, and wrist and ankle joint synovitis. There was no lymphadenopathy, splenomegaly, skin tightness, sclerodactyly, telangiectasias, or calcinosis.

Laboratory investigation showed a white blood cell count of 19.2×10³/μl (normal 3.4–9.2), hemoglobin 9.6 g/dl (normal 11.3–15.4), platelet count 552×10³/μl (normal 142–405), ESR 64 mm/h (normal <20), ferritin 1,270 ng/ml (normal <132), prothrombin time 15 s, INR 1.1, partial thromboplastin time 26.3 s, aspartate aminotransferase 221 μ/l (normal <34), and alanine aminotransferase 354 μ/l (normal <55). Serology tests for hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) were negative. The findings on wrist radiographs were characteristic for adult Still’s disease. A ventilation perfusion scintigraphy and a pulmonary embolism protocol computed tomogram (CT) of the chest were negative for pulmonary embolism. The pulmonary trunk was prominent, and increased right atrial pressure was indicated by posterior bowing of the interatrial septum. A transthoracic Doppler echocardiogram showed right atrial and right ventricular dilatation, tricuspid regurgitation, intact interatrial and interventricular septum, and an estimated pulmonary artery systolic pressure of 61 mmHg, suggesting severe pulmonary hypertension. A right heart catheterization confirmed the presence of pulmonary hypertension, with a main pulmonary artery pressure of 50/24 mmHg (mean 33) (normal <25), but normal capillary wedge pressure of 8 mmHg, cardiac output of 5.7 l/min, and cardiac index of 2.8 l/min/m². The patient had a good response to vasodilator infusion as manifested by a doubling of the cardiac output.

The patient was treated with nifedipine 60 mg/day and continued her prednisone 60 mg daily. Because of her persistently active Still’s disease as indicated by episodic exacerbations of constitutional symptoms, arthritis, and elevated acute-phase reactants despite high-dose steroids, she was started on anakinra 100 mg/day subcutaneously. Her constitutional and articular symptoms improved; however, the right ventricular failure worsened and she died 2 and half months later.

Discussions

We have described a patient with AOSD who presented with severe PAH. The patient’s mean pulmonary pressure was elevated at 33 mmHg at rest (normal <25). Her normal pulmonary artery wedge pressure excludes significant left ventricular dysfunction, and the echocardiogram did not identify mitral stenosis or congenital heart disease. There was no history of sleep-related breathing problems, HIV infection, chronic liver disease, or intake of anorexigens (conditions associated with pulmonary arterial hypertension). Chronic pulmonary thromboembolism as a cause of pulmonary hypertension is unlikely in this case because there was no evidence of thrombus in the venous system or the pulmonary arteries and the perfusion lung scan had no defects. Additionally, the lung parenchyma appeared normal on chest CT, excluding interstitial lung disease as a cause of this patient’s PAH.

Clinically and histologically, PAH in ARD, particularly limited scleroderma, SLE, and MCTD, is often indistinguishable from idiopathic PAH (iPAH). The key histological findings are intimal thickening and media hypertrophy of the small- and medium-sized pulmonary arteries and plexiform lesions. Tuder et al. [7] and Cool et al. [8] have published recently that endothelial proliferation is a hallmark of pulmonary hypertension in both sporadic forms and those associated with rheumatic diseases. The plexiform lesions also consist primarily of proliferating endothelial cells that form channel-like structures indicating an angiogenic process. In addition, proliferation of smooth muscle cells has been reported [9]. These findings suggest that PAH is primarily a proliferative disease. Inflammatory mechanisms appear to play a significant role in some types of pulmonary hypertension including the development of PAH in patients with ARD. Clustering of macrophages and T-lymphocytes around vascular lesions has been reported in PAH and iPAH, and cytokines (especially interleukin-1 and interleukin-6) and growth factors (platelet-derived growth factor or vascular endothelial growth factor) released by these cells have been linked to pulmonary vascular remodeling [10–12]. In in vitro studies, autoantibodies from patients with SLE, SSc, RA, MCTD, and SS (anti-U1-ribonucleoprotein, antidouble-stranded deoxyribonucleic acid antibodies) have been shown to induce upregulation of immunoactive molecules, such as intercellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1, and major histocompatibility complex class II, on human pulmonary endothelial cells, suggesting that such immunologic/inflammatory processes could lead to a proliferative and inflammatory pulmonary vasculopathy [13]. In fact, several case reports describe regression of PAH during immunosuppressive therapy in patients with rheumatic diseases [14]. Large prospective studies are needed to confirm this clinical observation.

The development of PAH in our patient with no apparent parenchymal involvement was thought to be caused by an inflammatory pulmonary vasculopathy probably related to AOSD. To our knowledge, this condition has only been reported once in a Japanese patient with AOSD in 1990 [15]. Therefore, we describe a second case of pulmonary arterial hypertension complicating AOSD.