Abstract
Antisynthetase syndrome is characterised by the association of interstitial lung disease and myositis with different anti-tRNA-synthetase antibodies. The occurrence, aetiology and prognosis of pulmonary hypertension have not yet been evaluated.
Among 203 consecutive patients, transthoracic echocardiogram and right heart catheterisation results were retrospectively analysed in the light of clinico-biological, morphological and functional parameters. Definitions of pulmonary hypertension were based on the European Society of Cardiology/European Respiratory Society 2009 guidelines, with severe pulmonary hypertension being defined by a mean pulmonary arterial pressure >35 mmHg.
Pulmonary hypertension was suspected by transthoracic echocardiogram in 47 (23.2%) cases, corresponding to pulmonary hypertension “possible” (n=27, 13.3%) or “likely” (n=20, 9.9%). Right heart catheterisation was performed in 21 patients, excluding pulmonary hypertension in five and confirming pre-capillary pulmonary hypertension in 16 (7.9%). Although related to interstitial lung disease in all cases, pre-capillary pulmonary hypertension was severe in 13 (81.3%) patients (mean±sd pulmonary arterial pressure 46±9 mmHg), frequently associated with low cardiac index (mean±sd 2.3±0.8 L·min−1·m−2) and high forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio (2.5±0.6). Pulmonary hypertension was significantly associated with a lower survival rate (p<0.001), with a 3-year survival rate of 58%.
The occurrence of pulmonary hypertension in antisynthetase syndrome is significant and dramatically worsens the prognosis. Although systematically associated with interstitial lung disease, pulmonary hypertension was usually severe, suggesting a specific pulmonary vascular involvement.
Abstract
PH in antisynthetase syndrome significantly worsens the prognosis, suggesting a specific pulmonary vascular involvement http://ow.ly/okXyG
Introduction
Antisynthetase syndrome (ASS) was first described in 1990 as a heterogeneous connective tissue disease, characterised by the association of an interstitial lung disease (ILD) and/or inflammatory myositis with the presence of anti-aminoacyl-tRNA-synthetase antibodies (anti-ARS) [1]. Different anti-ARS specificities have been described, with anti-histidyl(Jo1)-tRNA-synthetase antibodies being the most common (20% of the polymyositis and dermatomyositis patients). The other antibody specificities, including anti-alanyl(PL12), anti-threonyl(PL7), anti-isoleucyl(OJ) and anti-glycyl(EJ)-tRNA-synthetase antibodies are less commonly found (each antibody being <5% of the of the polymyositis and dermatomyositis patients). Although the anti-ARS could be associated with other anti-extractable nuclear antigen antibodies, including anti-Ro/SSA or anti-La/SSB antibodies, they are mutually exclusive in most cases. Aside from myositis and ILD, other unspecific symptoms are quite commonly reported in ASS and include arthritis, mechanic's hands and Raynaud's phenomenon. Associated symptoms of Sjögren’s syndrome or systemic sclerosis (SSc) have also been reported in different proportions [1–4].
Pulmonary hypertension (PH) is, by itself, a severe life-threatening disorder, and is complicated with variable frequency with connective tissue diseases [5, 6], among which SSc is the most common [7, 8]. In inflammatory myositis [9], and in ASS in particular, the occurrence of PH has never been systematically evaluated and its description rests only upon isolated case reports [10–12]. PH comprises many causes, including pulmonary arterial hypertension (PAH), left heart disease, chronic lung diseases, chronic thromboembolism and others [13]. However, although rarely reported, PH in ASS patients could be related to any of these aetiologies, the most common of which would theoretically be PH due to ILD (PH-ILD) and PAH. Indeed, ILD is the most frequent manifestation of ASS and some patients with ASS may present signs of SSc [1, 2, 14], which often causes PAH or PH-ILD [7, 8, 15, 16]. Conversely, specific left heart dysfunction seems rare in myositis [17].
The knowledge of PH prevalence and its mechanism is important, as it implies different investigations, such as echocardiography for positive screening and right heart catheterisation (RHC) for a precise positive and aetiological diagnosis. Moreover, certain causes require specific treatments. These treatments could be essential, as the long-term prognosis and the survival of patients with ASS, based on retrospective studies, showed a clear correlation with lung involvement [2, 18–20]. However, to date, the influence of cofactors associated with ILD, such as PH, has rarely been evaluated in large series. This led us to conduct this large multicentre study of 203 ASS patients, our aim being to evaluate the prevalence of PH in ASS and to describe more specifically patients with pre-capillary PH attested by a RHC, in order to identify both the causes of PH and the features associated with PH development.
Patients and methods
Patients
This 2008–2012 retrospective study was conducted in nine French university hospitals. Identification of the patients (n=258) was performed in each centre through the Laboratory of Immunology databases for each institution. We included 203 patients who met the following inclusion criteria: 1) two successive positive tests for anti-ARS, including LUMINEX-100 system (Luminex, Austin, TX, USA), ENA-LISA-kit (Biomedical Diagnostics, Marne-la-vallée, France) and IMMUNO-DOT (Euroimmun AG, Lübeck, Germany or Diasorin, Saluggia, Italy); 2) clinical involvement in accordance with ASS, including ILD, muscle or rheumatic involvements [21]; and 3) realisation of at least one echocardiography during the follow-up period. All patients were anonymously reported, and this study was approved by the institutional review board of each participating centre.
Data collection
Demographic information, comorbidities, clinical history of ASS, imaging findings (including thoracic high-resolution computed tomography (HRCT) scan and echocardiography), pulmonary function tests, RHC, biological data and detailed medical treatment were collected. Data collection was compiled by B. Hervier, A. Meyer and C. Dieval using the same form.
Definitions
The onset of ASS was defined by the first occurrence of pulmonary, muscular or rheumatic symptoms. ILD was defined by the results of HRCT and abnormal pulmonary function tests (forced vital capacity (FVC) <70% predicted and/or diffusing capacity of the lung for carbon monoxide (DLCO) <70% predicted). The characterisation of the ILD pattern was made by radiologists experienced in ILD assessment, and was based on the international consensus [22]. The HRCT scans of 15 out of 16 patients with PH on RHC were retrospectively reviewed in consensus by B. Hervier, D. Launay, D. Montani, E. Hachulla and P. Grenier. The extension of the ILD was evaluated by two different methods, as previously described [23, 24]. In addition to the extension scores, a coarseness score was assigned where a reticular pattern was identified (grade 1: fine intralobular fibrosis predominating; grade 2: microcystic pattern with airspaces <3 mm; and grade 3: large cysts >3 mm. Scores were then summed, with a maximum score of 15).
Experienced cardiologists from each tertiary care centre measured the echocardiographic parameters. PH was suspected on echocardiography and diagnosis was confirmed by RHC according to the judgement of each experienced physician in charge of the patient (on the basis of the European Respiratory Society/European Society of Cardiology guidelines [25]). By echocardiography, PH was “possible” when systolic pulmonary artery pressure (PAP) was 37–50 mmHg, and/or tricuspid regurgitation velocity 2.8–3.4 m·s−1. PH was “likely” when tricuspid regurgitation velocity was >3.4 m·s−1, and/or estimated systolic PAP was >50 mmHg. By definition, the time of the diagnosis of PH was retrospectively based on the first positive echocardiographic screening.
Pre-capillary PH was defined during RHC as mean PAP ≥25 mmHg and pulmonary capillary wedge pressure (Ppcw) ≤15 mmHg [25]. In the presence of an ILD and as previously described [16], pre-capillary PH was classified as PH-ILD. In patients with PH-ILD and a mean PAP≥35 mmHg, the PH was considered severe [26]. Thromboembolic PH was defined by pre-capillary PH, past medical history of pulmonary embolism and positive 99Tc ventilation/perfusion scintigraphy (n=9) and/or angio-CT (n=7).
According to the American College of Rheumatology [27], signs and symptoms suggestive of associated SSc are sclerodactyly, skin sclerosis and digital ulcers. Raynaud's phenomenon and ILD, as part of the ASS, were not considered to be SSc symptoms.
Statistical analysis
For the bivariate analysis, quantitative data were described as mean±sd and qualitative data as numbers and percentages. The t-test or nonparametric Mann–Whitney tests were used for comparison of continuous variables while the Chi-squared test was used for comparison of categorical variables. The Kaplan–Meier method and log rank tests were used to compare survival between groups. A multivariate model using Cox regression analysis was built to identify the variables independently associated with the survival. A p-value <0.05 was considered significant. All the analyses were performed using SAS software (version 9.3; SAS Institute, Inc., Cary, NC, USA).
Results
Overall cohort description
Among the 203 patients, 150 were females and 53 were males (female/male ratio 2.7). The mean±sd age at onset was 49±15.2 years and the mean±sd follow-up was 78±67 months. Over the course of the disease, ILD (n=174, 86%) was the most common ASS manifestation, followed by inflammatory myositis (n=148, 73%) and arthralgia/arthritis (n=122, 60%). The immunological analyses of the patients’ sera showed five different anti-ARS, anti-Jo1 being the most common (occurring in almost 66% of the patients), whereas anti-OJ and anti-EJ were unusual in this population, which was mostly Caucasian (n=159, 78%).
Prevalence of PH and pre-capillary PH in ASS
Of the included patients, 47 (23.2% of the whole cohort) were positively screened for PH (mean systolic PAP 53±16 mmHg), with 27 (13.3%) patients being classified as PH “possible” and 20 (9.9%) as PH “likely” (fig. 1). Left ventricular ejection fraction was normal in 38 out of these 47 patients (81%). After echocardiographic screening of “possible or likely PH”, RHC was performed in only 21 (45%) of the cases and was mostly performed in patients who were classified as “PH likely” (55%). RHC confirmed the diagnosis of pre-capillary PH in 16 patients (7.9% of overall population) and was normal at rest in the five remaining cases. Of note among the patient with pre-capillary PH confirmed by RHC, 48% were screened by echocardiography as PH “possible” and 52% as PH “likely”. It is noteworthy that, on RHC, no patient had post-capillary PH (Ppcw at rest <15 mmHg in all cases).
Prevalence of pulmonary hypertension (PH) in the cohort of patients with antisynthetase syndrome according to echocardiography and right heart catheterisation results. Pre-capillary PH was defined during right heart catheterisation as mean pulmonary artery pressure ≥25 mmHg and pulmonary capillary wedge pressure ≤15 mmHg. Pre-capillary PH related to interstitial lung disease (PH-ILD) was observed by high-resolution computed tomography. Thromboembolic (TE)-PH was defined by the association of pre-capillary PH, past medical history of pulmonary embolism and positive 99Tc ventilation/perfusion scintigraphy or angio-computed tomography.
Comparisons of patients with pre-capillary PH and patients without PH on echocardiography
Clinico-biological features of patients with pre-capillary PH confirmed by RHC were then compared with patients who were PH “unlikely” (based on normal echocardiographic screening). As shown in table 1, arthralgia/arthritis were less common at diagnosis in patients developing pre-capillary PH than in patients without PH (38 versus 65%; p=0.028). This was the only phenotypic difference between the two groups of patients. Although systematic at the steady state of the disease in patients with pre-capillary PH, the occurrence of ILD was not significantly higher than in patients without PH (100 versus 81%; p=0.059). The ILD was clinically not more severe at diagnosis (New York Heart Association (NYHA) functional class III or IV) in patients developing pre-capillary PH than in patients with ILD but without pre-capillary PH (n=127). However, the initial DLCO and the FVC/DLCO ratio were significantly different from those in patients without PH (39±18% versus 53±18% predicted, p=0.0015, and 2.1±1.0 versus 1.4±0.5, p=0.009, respectively). In contrast, FVC at the ASS diagnosis was similar in both groups. The distribution of the different ILD patterns on HRCT was statistically equivalent in patients without PH and in those with pre-capillary PH. The distribution of anti-ARS and other associated auto-antibodies was similar in both groups.
Severity among patients with pre-capillary PH
The patients with pre-capillary PH confirmed by RHC (n=16) were mostly females (n=15, 94%) (table 2). The diagnosis of pre-capillary PH was made 86±60 months after the onset of ASS symptoms. At this time, nearly 69% (n=11) of the patients complained of severe dyspnoea (NYHA functional class III or IV). Echocardiographic data are listed in table 2. RHC showed an increase in mean PAP (43.5±10 mmHg) and normal Ppcw (9±4 mmHg). Acute vasodilator testing with nitric oxide was performed in 10 patients and no acute response was observed.
All the patients with pre-capillary PH presented an ILD on HRCT and were diagnosed as “PH-ILD”. However, one patient had a mixed PH (patient 9), with a possible chronic thomboembolic PH. No other cause of PH was found in the other patients.
Among these 16 patients, PH was considered as severe (mean PAP >35 mmHg) in 13 cases (81%), with a mean PAP of 46±9 mmHg. Moreover, the cardiac index (mean±sd 2.3±0.8 L·min−1·m−2) of these patients was significantly decreased and pulmonary vascular resistance was dramatically increased (mean±sd 11.5±19.2 Wood units). These haemodynamic parameters contrasted with the mild severity of the parenchymal lung involvement. As shown in figure 2, the ILD pattern was a more or less fibrosing nonspecific interstitial pneumonia in most patients (n=13, 81%) with a median coarseness score of 8 (ranging from 4 to 12). Although ILD was frequently extensive (n=13/14, 93%) [23], the median extension score [24] was 19% (3.5–45%). The decrease of the FVC (mean±sd 66%±13% predicted) and the DLCO/alveolar volume ratio (mean±sd 53±11%), were moderate, whereas the decrease of the DL,CO (mean±sd 28%±6%) was dramatically more severe. Moreover, the FVC/DLCO ratio was increased in these most severe patients (mean±sd 2.5±0.6). Importantly, PaCO2 was normal in all these cases at time of diagnosis of PH.
Representative thoracic computed tomography images of the interstitial lung disease (ILD) in patients with severe pulmonary hypertension associated with ILD. High-resolution computed tomography images of the ILD in three different patients, a) patient 10, b) patient 15, and c) patient 16, with a fibrosing nonspecific interstitial pneumonia pattern, showing predominant reticular opacities more or less associated with ground glass opacities and traction bronchiectasis or bronchiolectasis. The lesions were bilateral and mainly localised to the posterior and basal areas of the lungs (lower lobes).
Management of patients with pre-capillary PH
The median follow-up of the 16 patients after PH diagnosis was 43±50 months. PAH-specific treatment was started in 13 out of the 16 patients (81%) at a mean of 23±43 months after the PH diagnosis. As shown in table 3, in all but two cases, a monotherapy was initiated. However, in seven cases, an initial (n=2) or sequential combined therapy (n=5) was proposed. Specific PAH therapies included endothelin receptor antagonists (n=13), phosphodiesterase 5 inhibitors (n=7) and prostanoid (n=3). Due to other symptoms of ASS and independently of the PH diagnosis, steroids and/or immunosuppressive drugs were also given to 15 patients (94%). During the follow-up period, one patient underwent lung transplantation and seven patients died due to acute or chronic respiratory or heart failure.
Survival analyses
When comparing survival from the onset of ASS between patients developing pre-capillary PH confirmed by RHC and patients without PH on echocardiography (n=156), pre-capillary PH was associated with a dramatically lower long-term survival rate (hazard ratio 6.8, 95% confidence interval 3.6–73.6; p<0.001). A similar result is also found when comparing patients for whom the PH was only suspected by echocardiography (n=26; hazard ratio 10.0, 95% confidence interval 2.9–34.4; p<0.001) with patients without PH on echocardiography. As all the patients with pre-capillary PH presented an ILD, we also compared the survival rate of these patients with ASS patients displaying ILD without PH on echocardiography (n=127) (fig. 3). As shown in table 4, five parameters were associated with the survival, including severe dyspnoea (NYHA III or IV) at diagnosis and pre-capillary PH confirmed by RHC. Importantly, the multivariate analysis showed that pre-capillary PH correlated independently of the other variables with a lower survival (hazard ratio 5.1, 95% confidence interval 1.1–24.9; p=0.042), suggesting that the occurrence of pre-capillary PH in patients with ILD was by itself a dramatic aggravating factor of ASS. Indeed, in the patients with pre-capillary PH confirmed by RHC, the 3-year survival rate after PH diagnosis was 58%.
Kaplan–Meyer survival curve (from antisynthetase syndrome diagnosis) comparing patients with interstitial lung disease (ILD) but without pulmonary hypertension (PH) (n=127, ILD alone, systolic pulmonary arterial pressure (PAP) <37 mmHg on transthoracic echocardiogram) with patients with pre-capillary PH confirmed by right heart catheterisation (RHC) (n=16, all with ILD). Pre-capillary PH was defined during RHC as mean PAP ≥25 mmHg and pulmonary capillary wedge pressure ≤15 mmHg. ILD was defined by the results of high-resolution computed tomography and/or abnormal pulmonary function tests (forced vital capacity <70% predicted and/or diffusing capacity of the lung for carbon monoxide <70% predicted). Log rank test was used to compare the survival rate between groups.
Discussion
Based on RHC, the prevalence of PH in this retrospective study is 7.9%. However, as 21% of the patients from this series were not screened for PH by transthoracic echocardiography and as only 45% of the patients positively screened by echocardiography underwent a RHC to confirm the PH, this prevalence could have been underestimated. Nevertheless, these data suggest that, although rarely reported, occurrence of PH during ASS is not a rare complication. Furthermore, this prevalence is similar to other connective tissue diseases, such as systemic lupus [5, 6], but is slightly lower than SSc [7, 8]. Similarly to SSc, dyspnoea in ASS has many causes, including ILD, PH or anaemia. Moreover, in ASS, muscle involvement impacts on both breathing and exercise capacity, leading to specific difficulties in diagnosing dyspnoea and its aetiology. According to these data, it could be recommended to perform echocardiography in patients with ASS, particularly in the presence of unexplained or severe dyspnoea. Additionally, echocardiography should be repeated throughout the course of the disease, and especially when the severity of the dyspnoea seems to be “out of proportion” to the severity of the ILD itself.
By comparing the patients without PH to the patients with pre-capillary PH, as confirmed by RHC, the analysis showed how difficult it was to distinguish which patients were at risk of developing pre-capillary PH. Indeed, only a few clinical and biological features present at diagnosis or during the course of the disease were associated with the occurrence of pre-capillary PH. These patients systematically showed an ILD and rarely complained of arthralgia/arthritis. It is therefore important to carefully analyse the HRCT (ILD pattern and extension) and pulmonary function test results, as the patients with pre-capillary PH had a lower DLCO (or higher FVC/DLCO ratio) upon first investigation. Furthermore, diagnosing PH in such a context is of particular importance, as it could require specific management and could impact on the patient outcome.
When analysing the group of patients with pre-capillary PH confirmed by RHC, we observed that the time between ASS and PH onset was quite long (a mean of >7 years). However, it is difficult to determine whether this delay, which is similar to that found in series of SSc patients [15, 28], was caused by a late progression of the disease or a late diagnosis. However, as most of the patients were severe at PH diagnosis (based on the NYHA functional class and haemodynamic parameters), and because suspecting PH in the presence of ILD is very challenging, we could consider that the diagnosis of PH was delayed. These data should also encourage clinicians to perform echocardiographies early on and repeatedly over the course of the disease.
As the 16 patients with pre-capillary PH on RHC suffered from ILD, the retained mechanism of pre-capillary PH was PH-ILD. However, 81.3% of these patients with PH-ILD disclosed a severe PH (mean PAP >35 mmHg), which could be considered “out of proportion” according to lung parenchymal involvement. Moreover, a FVC/DLCO ratio >1.8, a possible marker of pulmonary vascular disease in SSc [15], was frequently observed (n=14, 88% of the patients). These parameters suggest that ASS-associated PH may be at least in part the consequence of a specific pulmonary vascular involvement. Furthermore, in the patients from the current series, pre-capillary PH was frequently associated with Raynaud's phenomenon, capillaroscopic abnormalities (data not shown) and dramatic increase in pulmonary vascular resistance. It is also of note that it has been shown that sera from patients with anti-Jo1 Abs positive ASS can activate endothelial cells in vitro [29]. Altogether, these data reinforce the hypothesis that in the context of ASS, PH-ILD may be associated with specific pulmonary vascular involvement. In this series, most PH-ILD patients (n=10, 63%) displayed a low cardiac index (median 2.4, range 1–6), which is a classic haemodynamic parameter of severity in all forms of PH. Interestingly, the mean cardiac index herein was quite similar to the values previously reported in PH-ILD related to SSc [7, 15]. In these patients with pre-capillary PH, no signs pointing to a left ventricular dysfunction (due to a specific inflammatory myocarditis and/or a proximal coronaropathy) were reported. This myocardial involvement could therefore be related to an involvement of the cardiac microvasculature leading to a worse cardiac adaptation to PH (as reported in SSc [30]).
Although some small retrospective studies suggested that specific PH therapy may be discussed in the presence of “out-of-proportion” due-to-lung-disease PH [16, 25], the clinical benefit of this therapy still has not been rigorously demonstrated in this setting. Then, in regards to the current guidelines, no specific treatment in PH related to any chronic lung disease, including ILD, is as yet recommended. Nonetheless, most of the patients from the current series received specific PAH therapy because of the severity of the pre-capillary PH. As ILD was systematic and as both PH and ILD evolutions are closely linked, different immunosuppressive drugs were also given in association with PAH treatments. For these reasons and due to the retrospective nature of this study it was not possible to rigorously determine the impact of such treatments in these patients. Indeed, further prospective studies are needed to confirm the benefit/risk ratio of this strategy in ASS patients.
Similarly to what has been reported for idiopathic pulmonary fibrosis [31], or other underlying diseases [7, 15, 16, 32], the survival analyses confirmed that PH in ASS worsened the prognosis, independently of both its confirmation by RHC and of its supposed mechanism. These data clearly show the need for a systematic PH screening by transthoracic echocardiography and also for a RHC confirmation in all the suspected cases.
However, the 3-year survival of the patients with PH confirmed by RHC (58%) could appear slightly better than previously reported in these diseases [16, 31], but the diagnosis of PH in this study was based on the first positive echocardiograph rather than on the RHC. Unlike what has been reported for SSc [15, 32], we were unable to find individual factors associated with a poor outcome among patients with pre-capillary PH, due to the small number of patients. Larger series, and series comparing the prognosis of ASS patients with patients suffering from other connective tissue diseases, such as SSc, or idiopathic pulmonary fibrosis with PH, would be of interest.
In summary, this series showed for the first time that pre-capillary PH is not a rare complication of ASS. PH is mainly related to ILD and is associated with a poor outcome. Clinically diagnosing PH in this condition is particularly difficult, but is important. Altogether these data should encourage clinicians to perform a screening of PH by echocardiography in the context of ASS, to do so early on, more systematically and more regularly, and to rigorously confirm pre-capillary PH by RHC.
Acknowledgments
We thank all other physicians in charge of the ASS patients, including pneumologists: E. Quoix and B. Geny (Strasbourg, France), B. Wallaert and I. Tillie-Leblond (Lille, France), D. Valeyre (Bobigny, France), D. Lauque (Toulouse, France), P. Delaval (Rennes, France), P. Camus (Dijon, France), and O. Sanchez and L. Parent (Paris, France); internists: J.F. Besancenot, B. Bonnote and B. Lorcerie (Dijon), S. Morell-Dubois, G. Prevot, H. Maillard-Lefebvre, M. Lambert and P.Y. Hatron (Lille), B. Couret, D. Adoue and P. Arlet (Toulouse), C. Durant, A. Masseau and J. Connault (Nantes), P. Blanco and M. Longy-Boursier (Bordeaux), and N. Costedoat-Chalumeau, C. Cacoub, D. Saadoun, R. Stanciu and A. Rigolet (Paris); rheumatologists: J.M. Berthelot (Nantes), B. Fautrel (Paris), and B. Lorcerie, B. Bonotte and J.F. Besancenot (Dijon); immunologists: L. Musset and J.L. Charuel (Paris), S. Dubucquoi (Lille), N.O. Olsson (Dijon), M. Audrain (Nantes), and I. Bahon-Riedinger (Rennes); and pathologists: J.M. Mussini (Nantes), and O. Dubourg and T. Maisonobe (Paris).
Footnotes
Conflict of interest: None declared.
- Received October 2, 2012.
- Accepted January 7, 2013.
- ©ERS 2013
References
