Severe pulmonary hypertension in Anti?Jo?1 ... - Wiley Online Library

Arthritis Care & Research Vol. 62, No. 3, March 2010, pp 425– 429 DOI 10.1002/acr.20109 © 2010, American College of Rheumatology

CASE REPORT

Severe Pulmonary Hypertension in Anti–Jo-1 Syndrome SOUMYA CHATTERJEE

AND

CAROL FARVER

Introduction

Case Report

Antisynthetase syndromes, associated with anti–aminoacyl– transfer RNA (tRNA) synthetase antibodies, are a group of autoimmune diseases characterized by a constellation of manifestations, including inflammatory muscle disease (polymyositis), interstitial lung disease (ILD), mechanic’s hands, fever, Raynaud’s phenomenon, and inflammatory polyarthritis (1). Of these, anti–Jo-1 syndrome (associated with anti– histidyl-tRNA synthetase antibody) is the most well known and also the first one to be identified. As in the other forms of antisynthetase syndrome, ILD is the usual pattern of lung injury in anti–Jo-1 syndrome. Isolated pulmonary arterial hypertension (PAH), similar to idiopathic PAH, can occur in various autoimmune rheumatic diseases such as systemic sclerosis (2), mixed connective tissue disease (3), systemic lupus erythematosus (4), antiphospholipid antibody syndrome (5), primary Sjo¨gren’s syndrome (6), or rheumatoid arthritis (7). Secondary PAH can also develop in patients with significant pulmonary fibrosis (advanced ILD) of any etiology and is associated with substantial morbidity and mortality (8,9). Unlike the autoimmune rheumatic diseases mentioned above, isolated PAH has rarely been reported in patients with polymyositis (10), and in particular in the antisynthetase syndromes. So far, there is only one other reported case of antisynthetase syndrome that developed severe PAH and concomitant ILD. That patient’s disease was associated with anti–PL-12 (anti–alanyl-tRNA synthetase) antibody production (11). Here we report a case of a patient with anti–Jo-1 syndrome who developed severe, relentlessly progressive, and ultimately fatal PAH. To the best of our knowledge, this is the first report of such a case.

Initial presentation. In November 2005, a 56-year-old woman who had never smoked presented with a history of progressive dyspnea and worsening fatigue for two and a half years. She denied any history of fever, weight loss, Raynaud’s phenomenon, joint pain, muscle weakness, or dysphagia. Physical examination revealed dryness and cracking of the skin at the radial margins of her fingers (mechanic’s hands), but there was no sclerodactyly or proximal skin thickening. She had bibasilar rales, a loud pulmonic second sound, and a systolic ejection murmur at the left upper sternal border. There was no clinical evidence of proximal myopathy, although her creatine kinase and aldolase levels were somewhat elevated (Table 1). Antinuclear antibody (ANA) was positive by enzyme immunoassay, but was negative by immunofluorescence assay (Table 1). In addition, anti–Jo-1 antibody was positive. The panel of autoantibodies to specific extractable nuclear antigens (Sm, RNP, SSA, SSB, and Scl-70) was negative. B-type natriuretic peptide (BNP) level was elevated (Table 1). The remaining laboratory tests were all normal. Pulmonary function test indicated restrictive lung disease (Table 1). A high-resolution computed tomography (CT) scan of the lungs showed evidence of bilateral interstitial fibrosis mainly in the periphery and in the lower lobes (Figure 1). The CT scan with contrast indicated bilateral pulmonary artery enlargement, but was negative for the presence of pulmonary emboli. A transthoracic echocardiogram revealed a severely dilated right ventricle with severe systolic dysfunction. There was systolic and diastolic flattening of the interventricular septum consistent with right ventricular pressure and volume overload. Right heart catheterization indicated moderate pulmonary hypertension. The findings of biochemical myopathy, mild to moderate ILD, mechanic’s hands, and Jo-1 antibody were all consistent with a diagnosis of anti–Jo-1 syndrome. Moreover, unlike what has been previously described, she also had evidence of significant PAH, which independently evolved and seemed out of proportion to the degree of pulmonary fibrosis. Based on her oxygen requirements on desaturation study, she was started on continuous home oxygen (2 liters/minute at rest and 6 liters/minute on ex-

Soumya Chatterjee, MD, MS, FRCP(UK), FACP, Carol Farver, MD: Cleveland Clinic, Cleveland, Ohio. Address correspondence to Soumya Chatterjee, MD, MS, FRCP(UK), FACP, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Department of Rheumatic and Immunologic Diseases, Orthopedics and Rheumatology Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk A50, Cleveland, OH 44195. E-mail: chattes@ ccf.org. Submitted for publication July 11, 2009; accepted in revised form September 25, 2009.

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Table 1. Serial recordings of the patient’s clinical parameters, relevant laboratory measurements, pulmonary function test results, and echocardiogram findings over the course of her illness* Observations Heart rate Blood pressure, mm Hg Respirations/minute Pulse oxygen on 6l O2/minute, % Edema FVC, % predicted FEV1, % predicted RV, % predicted TLC, % predicted DLCO, % predicted DL/VA, % predicted 6-minute walk distance, feet RVSP, mm Hg TRV, cm/second BNP, pg/ml (normal range 0–99) CK, units/liter (normal range 30–220) Aldolase, units/liter (normal range 2.0–8.0) ANA by EIA, OD ratio (normal value ⬍1.5) ANA by IFA Jo-1 antibody

November December January 2005 2005 2006 114 120/90 24 86 Negative 40 46 – – – – 925

120 120/75 22 91

120 120/60 30 94

April 2006

May 2006

110 120/80 20 94

86 118/84 22 90

Negative Negative Negative 47 48 47 48 54 51 – 48 59 – 48 53 23 15 16 42 46 45 – 1,532 1,115

June 2006

August September October November 2006 2006 2006 2006

106 119 120/80 137/77 22 24 88 92

110 128/96 24 86

120 124/98 25 88

132 90/60 32 82

Negative – – – – – – –

1⫹ 43 45 33 38 16 48 –

2⫹ – – – – – – –

2⫹ – – – – – – –

3⫹ – – – – – – –

3⫹ – – – – – – –

34 270 126

– – –

– – 36

– – –

– – –

90 462 –

58 – 463

69 369 398

65 360 674

55 356 773

621

114

70

–

184

–

99

79

72

30

16.6

–

–

–

6.7

–

–

5.2

6.8

11

9.0

–

–

–

3.7

–

–

–

–

–

Negative

–

–

–

–

–

–

–

–

Positive

–

–

–

1:160 (speckled) Positive

–

–

–

–

–

* FVC ⫽ forced vital capacity; FEV1 ⫽ forced expiratory volume in 1 second; RV ⫽ residual volume; TLC ⫽ total lung capacity; DLCO ⫽ diffusing capacity for carbon monoxide, DL/VA ⫽ specific diffusing capacity; RVSP ⫽ right ventricular systolic pressure; TRV ⫽ tricuspid regurgitation velocity; BNP ⫽ B-type natriuretic peptide; CK ⫽ creatine kinase; ANA ⫽ antinuclear antibody; EIA ⫽ enzyme immunoassay; OD ⫽ optical density; IFA ⫽ immunofluorescence assay.

ertion). She was also started on treatment for both ILD and PAH: cyclophosphamide 50 mg daily, prednisone 40 mg daily, and sildenafil 20 mg 3 times daily. Subsequent course. Over the ensuing weeks, the cyclophosphamide dosage was gradually increased to 100 mg/ day, whereas prednisone was maintained at 40 mg/day. In April 2006, as her pulmonary function slightly improved, a prednisone taper was initiated. In May 2006, a repeat test for ANA by immunofluorescence assay was positive at 1:160 (speckled pattern) and anti–Jo-1 antibody was detected again. Specific antibodies related to lupus, mixed connective tissue disease, or scleroderma were all negative. An echocardiogram repeated in June 2006 showed normal left ventricular systolic function, severely dilated right ventricle with moderate systolic dysfunction, and estimated right ventricular systolic pressure of 90 mm Hg, consistent with severe pulmonary hypertension (Figure 2). She was hospitalized in August 2006 because her progressive dyspnea (class IV symptoms) had failed to improve with cyclophosphamide 150 mg daily. She had resting tachycardia and significant lower extremity edema. Her plasma BNP level also progressively increased (Ta-

ble 1). A repeat thoracic CT scan showed enlarged right cardiac chambers and main pulmonary artery, but no significant interval change in the bilateral interstitial fibrosis primarily involving the lower lobes and periphery of the lungs. Right heart catheterization indicated worsening pulmonary hypertension: mean pulmonary artery pressure of 52 mm Hg, pulmonary capillary wedge pressure of

Figure 1. High-resolution chest computed tomography scan showing evidence of bilateral interstitial fibrosis mainly in the periphery of the lungs and in the lower lobes.

Pulmonary Hypertension in Anti–Jo-1 Syndrome

427 Histologic examination of the lung parenchyma showed interstitial fibrosis without honeycombing (Figure 3A). The pulmonary arteries were free of thrombi. Connective tissue stains (Movat, Poly Scientific R&D, Bay Shore, NY) on the samples showed medium and small pulmonary arteries with severe intimal fibrosis consistent with pulmonary hypertensive arteriopathy (Figures 3B and C), although no high-grade vascular (plexogenic) lesions were seen. The lung parenchyma (adjacent to the pulmonary artery in Figure 3B) showed mild to moderate interstitial fibrosis, but there was no evidence of severe fibrosis or honeycomb changes.

Discussion

Figure 2. Transthoracic echocardiogram (apical 4-chamber view) showing right ventricular enlargement (RV) and severe right atrial dilation (RA). The left ventricle (LV) was normal in size and systolic function, and the left atrium (LA) was also normal.

16 mm Hg, pulmonary vascular resistance of 250 dynes/ second/cm5, and a cardiac index of 1.7 liters/minute/m2. The patient was started on warfarin, furosemide 40 mg daily, and intravenous treprostinil, the dosage of which was slowly titrated up to 10 ng/kg/minute. She was continued on sildenafil 20 mg 3 times daily. As her white cell count dropped to 3.5 ⫻ 109/liter, the dosage of cyclophosphamide was decreased to 75 mg/day. She continued to have progressive class IV pulmonary hypertension with resting tachycardia, tachypnea, recurrent syncopal episodes, worsening edema, and ascites, with increased bilirubin and BNP levels. When she was readmitted for diuresis and optimization of her pulmonary hypertension management, she was receiving treprostinil 15 ng/kg/minute and sildenafil 50 mg 3 times daily. As her respiratory status declined further, she was intubated in the medical intensive care unit. Throughout the remainder of her hospitalization she was hypotensive, requiring pressor support while her pulmonary artery pressure remained high. During her final days she became hemodynamically unstable. After a long hospitalization, she died in November 2006. An autopsy was performed. Table 1 shows serial recordings of the patient’s clinical parameters, relevant laboratory measurements, pulmonary function test results, and echocardiogram findings over the course of her illness. Significant findings at autopsy. At autopsy, her heart weighed 460 gm (normal weight ⬍400 gm). There was left ventricular hypertrophy (1.3 cm in thickness). The right ventricle was enlarged and dilated (0.7 cm in thickness). The interventricular septum measured 1.5 cm. There were clear, straw-colored bilateral pleural effusions of approximately 2 liters within the pleural cavity. The lungs had pleural adhesions scattered throughout, were congested, and were twice the weight of normal lungs. Gross pathology of the lungs showed a red consolidation, patchy interstitial fibrosis in the mid and lower zones, and some basilar bronchiectasis.

The clinical response to the treatment of ILD was thought to be inadequate in our patient, and she continued to be dyspneic and have declining exercise tolerance. Exploration of other causes of dyspnea unexpectedly revealed the presence of concomitant severe PAH, which has not been previously reported as the dominant pathology in the lung in anti–Jo-1 syndrome. In this case, the exact trigger for the development of such severe PAH is clearly unknown. It would be difficult to hypothesize that this patient’s PAH developed secondary to the ILD associated with her anti– Jo-1 syndrome. Her ILD was not severe and was nonprogressive, as demonstrated on serial spirometry (unchanged forced vital capacity), on a followup thoracic CT scan, and finally at autopsy (Figure 3A), which showed no evidence of severe fibrosis or honeycomb changes in the area of the lung parenchyma adjacent to the involved artery in Figure 3B. Moreover, her respiratory status and hemodynamic parameters continued to deteriorate despite treatment with therapeutic doses of cyclophosphamide and prednisone, indirectly supporting the fact that her pulmonary hypertension relentlessly progressed despite apparently stable ILD. It would also be reasonable to assume that hypoxemia could not be the cause of her progressive pulmonary hypertension, as she had been receiving continuous oxygen based on her oxygen requirements since the early phase of her illness. A case report from 1981 (long before antisynthetase syndrome became known as an entity in 1990) describes a patient with polymyositis who died from the consequences of severe PAH (10). At the autopsy, the patient had severe right ventricular hypertrophy and plexogenic pulmonary arteriopathy, findings that were very similar to our case. It would be reasonable to surmise that that patient also may have had antisynthetase syndrome. The association between ILD and secondary pulmonary hypertension is incompletely understood. In advanced lung disease, pulmonary hypertension generally results from chronic hypoxic pulmonary vasoconstriction and vascular remodeling (12,13). However, pulmonary hypertension can also develop in the absence of hypoxemia and irrespective of its severity. Often, there is no correlation between the degree of ILD and the degree of PAH. In patients with scleroderma or idiopathic pulmonary fibrosis, advanced pulmonary fibrosis can be associated with only mildly elevated or even normal pulmonary artery pressures, whereas patients with relatively mild ILD can

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Figure 3. Histologic examination of the lungs at autopsy. A, Lung parenchyma with diffuse mild to moderate interstitial fibrosis, without severe fibrosis or honeycombing (hematoxylin and eosin stained). B and C, Lung vasculature shows medium (B) and small (C) pulmonary arteries with severe intimal fibrosis consistent with pulmonary hypertensive vasculopathy (Movat stained). D, Autopsy lung in a patient with scleroderma-associated pulmonary arterial hypertension in a smaller-sized arteriole with intimal fibrosis showing characteristic “onion skin” appearance (Movat stained).

have severe pulmonary hypertension. Therefore, it is clear that chronic hypoxic pulmonary vasoconstriction or vascular obstruction or destruction associated with progressive parenchymal fibrosis cannot be the only mechanisms in the pathogenesis of PAH in these patients. An obliterative pulmonary vasculopathy (resulting from proliferation of endothelial and vascular smooth muscle cells) often seems to coexist and plays an important role. This vascular remodeling process involves all layers of the pulmonary arterial wall and includes intimal thickening and medial hypertrophy. In limited scleroderma, an isolated form of PAH can be seen (14). The pathology in this particular form resembles the changes seen in idiopathic PAH. Other possible mechanisms of pulmonary hypertension in ILD include vascular inflammation, perivascular fibrosis, and thrombotic angiopathy (12,13). Abnormal vascular cell phenotypes have been described in a subset of patients with idiopathic pulmonary fibrosis that developed secondary PAH, characterized by a decrease in angiogenic factors and an increase in inflammatory and remodeling genes (9). It is believed that various angiogenic growth factors such as transforming growth factor ␤1 (13,15), vascular endothelial growth factor (13,15,16), basic fibroblast growth factor (16), platelet-derived growth factor (17), and interleukin-6 (15) may play important roles in the pathogenesis of the fibroproliferative and obliterative vasculopathy in idiopathic PAH. The roles of these various growth factors in the pathogenesis of PAH in antisynthetase syndrome are unknown. Similarly, the relative contribution of the endothelium-derived vasoactive factors (endothelin, nitric

oxide, and prostanoids) in modulating the development and progression of the obliterative pulmonary vasculopathy in antisynthetase syndrome is unclear at the present time. Perhaps these should be areas of future research if pulmonary hypertension is believed to play an important role in the pathogenesis of lung disease in subsets of patients with antisynthetase syndrome. In our patient, the vascular pathology leading to progressive luminal narrowing and resultant PAH seemed to involve more proximal pulmonary arterioles, as opposed to the distal and relatively smaller-sized arteriolar involvement in scleroderma-associated PAH (so-called “onion skin” appearance) (Figure 3D) (14). The significance of this difference is not clear, and whether this difference can explain the relative refractoriness of our patient’s PAH to conventional treatment remains to be determined. In order to formulate effective treatment strategies, understanding the pathophysiologic basis of the development of PAH in the antisynthetase syndromes is crucial. The role of early intervention (with conventional therapies for PAH such as prostanoids, endothelin receptor antagonists, and phosphodiesterase inhibitors) and their efficacy in preventing or slowing down the progression of PAH in this subset of patients is unknown. Our patient seemed to have had treatment refractory disease, which was not adequately responsive to a combination of so-called “standard of care” therapies for PAH. In conclusion, progressive shortness of breath despite optimum treatment of ILD in antisynthetase syndrome should prompt the clinician to search for alternative

Pulmonary Hypertension in Anti–Jo-1 Syndrome causes, such as pulmonary hypertension or thromboembolic disease, rather than implicating treatment refractory progressive ILD. This is particularly true if the ILD seems to be mild and nonprogressive, whereas the patient’s symptoms and respiratory parameters continue to decline. It is possible that we have not systematically studied enough cases of antisynthetase syndrome to identify PAH as a complication in subsets of such patients. Further research in this area is clearly necessary. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Chatterjee had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Chatterjee. Acquisition of data. Chatterjee, Farver. Analysis and interpretation of data. Chatterjee, Farver.

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