Pulmonary arterial hypertension in idiopathic inflammatory myopathies

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Introduction
Pulmonary arterial hypertension (PAH) is a rare condition characterized by a proliferation and remodeling of the small pulmonary arteries, leading to a progressive increase in pulmonary vascular resistance and right heart failure. [1] Categorized as group 1 in the pulmonary hypertension (PH) classification, PAH can be idiopathic, heritable, and associated with drug exposure or with an underlying disease. [2] Connective tissue diseases (CTDs) are the most frequent associated causes of PAH. [1] Among them, PAH is a well-known complication of systemic sclerosis (SSc) [3] , systemic lupus erythematosus (SLE), [4] and mixed connective tissue disease (MCTD). [5] Although more scarce, the occurrence of PAH has also been documented in primary Sjögren syndrome (SjS) [6] and antiphospholipid syndrome. [7] Idiopathic inflammatory myopathies (IIMs) are a group of disorders classified within the CTD and characterized by an immune-mediated muscle injury. [8] These disorders include mainly dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). [8] Occurrence of PH due to chronic respiratory diseases (group 3 PH) has been well-documented in the context of IIM associated with antisynthetase syndrome (ASS), in a recent work by our group. [9] Conversely, the association of PAH and IIM without extensive ILD has rarely been reported so far [10][11][12][13][14][15] ; and in most cases, other causes of pulmonary hypertension (notably overlap syndromes with another CTD; and group 3 PH) could not be formally excluded.
Using data from the French PH prospective Registry, we conducted a nationwide search for cases and report here the first cohort of fully characterized IIM-PAH patients.

Inclusion and exclusion criteria
Eligible patients were identified through screening of the French PH Registry, which gathers all PAH cases prospectively enrolled by 27 referral hospital centers across France between 2002 and 2015 (as previously described [1] ).
They were included in the study if they fulfilled all the following criteria: a diagnosis of PAH according to the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines, [2] defined by a mean pulmonary arterial pressure (mPAP) ≥25 mm Hg, a pulmonary vascular resistance (PVR) ≥3 Wood units (WU), and a pulmonary artery wedge pressure (PAWP) 15 mm Hg, measured during a resting right-heart catheterization (RHC); a definite diagnosis of IIM, according to Dalakas criteria [16] (for PM and DM), or Griggs criteria [17] (for IBM); an age above 18 years old.
Patients were excluded if they met one of the following criteria: an overlap syndrome with another CTD (SSc, SLE, MCTD); an extensive ILD, defined by an extent of lung parenchymal involvement >20% on high-resolution computed tomography (HRCT) of the chest and/or a forced vital capacity (FVC) <70% of the predicted value on pulmonary function tests (PFTs); another plausible cause of PH (heritable mutation, drug or toxic exposure, HIV infection, portal hypertension, congenital cardiomyopathy, left heart disease, chronic lung disease, chronic thromboembolic PH).
The study was approved by local ethic committees and complied with the requirements of the "Commission Nationale de l'Informatique et des Libertés," in accordance with current French legislation. This study followed the recommendations of the Helsinki Declaration of 1975, as revised in 1983.

Constitution of a control cohort
To study statistical associations of IIM characteristics with PAH occurrence, a control cohort was retrospectively designed and recruited from all consecutive patients referred to our Depart- They were included in the cohort if they fulfilled the same criteria as described above (ie, a definite diagnosis of IIM, an age above 18 years old, no overlap syndrome, no extensive ILD, and no condition associated with PH) and if they displayed no sign suggestive of pulmonary hypertension on TTE.

Statistical analysis
Data are expressed as number (percentage), mean (standard deviation), or median (interquartile range). The associations of IIM characteristics with PAH occurrence were evaluated using Fisher exact or Mann-Whitney tests. No statistical comparison was done for dichotomous variables with less than 3 patients per group. A 2-tailed P < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS software, package 22.

Results
Among the 5223 PH patients registered in the Registry, 34 had a diagnosis of IIM. Among them, 31 met an exclusion criterion, mostly because of an extensive ILD and/or an overlap syndrome ( Fig. 1 Antinuclear antibodies were positive in all 3 patients. Patient #2 was positive for anti-Ku antibodies, but displayed no sign of SSc. In patients #1 and #3, no IIM-specific or associated antibody was identified; anti-SSA antibodies were mildly positive, but none of them exhibited signs of SjS or SLE (Table 1).
Therapeutic management of DM included corticosteroids (3/ 3), either alone (1/3) or in combination with azathioprine (2/3) and/or hydroxychloroquine (1/3). Skin and muscle involvements improved in patients #2 and #3; however, patient #1 needed monthly injection of intravenous immunoglobulins to control the disease. After 3 to 8 years of follow-up, none of them developed any features of overlap syndrome ( Table 2).

PAH characteristics in IIM-PAH patients
Pulmonary arterial hypertension always developed after IIM onset. All patients were referred for severe dyspnea, associated with syncope and/or clinical signs of right-heart failure, which developed while their DM was still active. Precapillary PH was diagnosed by RHC, as recommended by guidelines, [2] in all cases (patient #1: mPAP 27 mm Hg, PVR 4.0 WU; patient #2: mPAP 46 mm Hg, PVR 12.4 WU; patient #3: mPAP 49 mm Hg, PVR 7.8 WU) ( Table 1). All of them had a severe PAH and functional impairment (NYHA class III; 6MWT distance between 64% and 72% of predicted value).
In each case, other causes of dyspnea and differential diagnoses of PH were excluded: RHC demonstrated precapillary PH, and TTE showed no sign of myocarditis or left heart failure; V/Q lung scan and helical CT of the chest excluded thromboembolic pulmonary disease; chest HRCT did not show evidence of extensive ILD (only patient #3 presented a limited ILD, as illustrated in Fig. 4); PFT displayed no obstructive or restrictive pattern.
All patients were started on PAH therapy (Table 2). In patient #1, oral tadalafil was introduced and allowed a rapid improvement of dyspnea and hemodynamic parameters. However, 6MWT distance decreased during follow-up, probably because IIM remained active. Patient #2 was treated with intravenous epoprostenol, which led to an increase of cardiac index and functional capacity. Patient #3 had a positive acute vasodilator response with inhaled NO and was started on nifedipine. As this treatment rapidly failed, it was switched to bosentan after 1 month. Three months later, tadalafil was added to bosentan, because of insufficient response to monotherapy. This sequential combination therapy allowed functional and hemodynamic

Identification of IIM characteristics associated with PAH occurrence
To determine whether certain IIM characteristics were associated with PAH occurrence, our 3 original observations were pooled with 6 previously reported cases [10][11][12][13][14][15] (Table 3) and compared with a control cohort of 35 IIM patients without PH. Other reports were identified, [18][19][20][21][22] but were not included in the analysis because of insufficient patient information. Characteristics of IIM patients with PAH and without PH are described in Table 4. Sex ratio and age at diagnosis were similar between the 2 groups. Remarkably, a diagnosis of DM was significantly associated with PAH occurrence: 78% of the patients with PAH had DM compared with 46% of the non-PH patients (P < 0.05). As such, presence of skin involvement was also associated with PAH (87% vs 43%; P < 0.05). Muscle features were comparable between the 2 cohorts, but IIM-PAH patients tended to have lower CPK levels (P = 0.11). Interestingly, a trend for an association between PAH and peripheral vascular disorders was found (83% vs 36%; P = 0.06). Finally, anti-SSA antibodies, but not IIM-specific autoantibodies, were a more frequent finding in PAH patients (50% vs 15%; P = 0.05).

Therapeutic modalities in IIM-PAH patients
Among the 9 identified IIM-PAH cases, treatment data are available in 8 patients ( Table 3). Four of them (patients #1, #2, #3, and #9) were under therapy for IIM at the time of PAH occurrence, mostly by corticosteroids and/or immunosuppressants; and the 4 others were treatment-naïve.
After PAH diagnosis, 3 patients (#1, #2, and #5) were started on a mixed regimen combining PAH-specific treatments with corticosteroids and/or immunosuppressants: a clinical, echocardiographic, and/or hemodynamic improvement was observed in all of them (Table 3). The 5 remaining patients were managed by introduction or intensification of IIM treatment only: with 1 notable exception (patient #7), this strategy was associated with a deterioration of functional, TTE, and/or RHC parameters (patients #3, #6, #8, and #9). A PAH-specific treatment was then introduced in 2 patients (patient #3 after 1 month; patient #6 after 12 months) and led to an overall improvement. The last 2 patients (# 8 and #9) did not receive any PAH therapy and died rapidly.

Discussion
To our knowledge, this is the first study describing prevalent cases of IIM-PAH patients in a nationwide prospective PH registry. [23] Our results can be summarized as follows: PAH is a very rare, but possible complication of IIM; among IIM characteristics, DM subtype, skin involvement, peripheral microangiopathy, and anti-SSA antibodies might be associated with PAH occurrence; IIM treatment alone might not be sufficient to stabilize PAH.
Our study benefited from a national recruitment of patients and a prospective collection of PAH data. Interestingly, only 3 patients out of 5223 prevalent PH cases were identified. This result confirms the empirical impression that, conversely to other CTDs, [1] occurrence of PAH during the course of IIM is an exceptional event. Considering that PAH and IIM are rare conditions, a coincidental association, although possible, seems unlikely.
So far, PH in the context of IIM has been mainly described in patients with extensive ILD. [9,18,19,[26][27][28][29][30][31][32][33] Recently, our team identified 16 cases of hemodynamically-proven PH among 203 consecutive patients presenting with ASS, a condition characterized by the presence of anti-tRNA synthetase antibodies and associated with IIM and ILD. [9] Almost all of them had extensive ILD according to Goh criteria, [34] with marked limitation of functional capacities (NYHA functional class II-III; mean 6MWT distance ± standard deviation: 59%± 19% of predicted value). The occurrence of PH considerably worsened the prognosis, with a 3-year survival rate of 58%. Similarly, Minai [26] reported a series of 3 PM-DM patients who developed severe PH during the course of an ILD. All of them had a major restrictive lung disease (with a FVC ranging between 36% and 58%) and severe functional impairment (NYHA class IV, 6MWT distance between 65 and 346 m). Despite initiation of off-label PAH therapy, 2 patients died after a 12 and 21-month followup, respectively. Interestingly, our report indicates that IIM-PAH patients were more likely to have a DM diagnosis (a condition whose prime pathophysiological target is thought to be endothelial cells, and not muscle fibers), [8] skin manifestations, and possibly signs of peripheral microangiopathy. This suggests that IIM-PAH may be the result of a specific microvascular disease, as observed in the muscles and skin of DM patients. Indeed, in an early autopsy series of IIM, histological features of pulmonary vasculitis were found in 5 out of 65 patients, [35] one of which had been previously diagnosed with PAH. [15] Remarkably, the pathological aspects of the microvascular inflammation (active necrotizing or chronic proliferative vasculitis, with lymphomononuclear and plasmacytic infiltrates) were very close to those encountered during SSc and SLE. [35] Similarly, Grateau et al [14] reported the case of an IIM-PAH patient who died from right heart failure: post mortem histologic examination revealed pathological features that resembles idiopathic PAH (thickening, fibrosis, and massive hyalinization of the wall of small pulmonary arterioles). More recently, we noted that most patients with ILD-PH in ASS had severe hemodynamic alterations in regard to their lung parenchymal involvement, [9] and we speculated that this might be due to an underlying microvascular disease. [36] The occurrence of PAH in IIM without extensive ILD, as demonstrated in our present study, tends to support this hypothesis and suggests a possible benefit of PAH-specific therapy. [37] Given the few number of identified cases, defining the best therapeutic strategy for IIM-PAH is challenging. However, by carefully analyzing patient data under treatment, it seems that 2 distinct trends can be identified: either patients were treated with a mixed regimen (combining IIM and PAH therapy) and seemed to stabilize or improve (patients #1, #2, and #5); either they were treated by IIM therapy alone and seemed to deteriorate (patients #3, #6, #8, and #9). This observation tends to suggest that, conversely to PAH associated with SLE and MCTD, [38] IIM-PAH might not respond to corticosteroids and/or immunosuppressants alone, whereas PAH-specific therapy appeared to stabilize the disease.
Our study has several limitations. As all clinicians are not familiar with the possibility of PAH occurring during IIM, and since other causes of dyspnea are frequent in these diseases, those patients might have been underdiagnosed. Moreover, our statistical analysis should be interpreted with caution, as it could  be biased by the low number of patients in each group and by the retrospective collection of IIM data.
In conclusion, our study suggests that PAH is a rare but possible complication of IIM. It should be considered in case of unexplained dyspnea, syncope, or right heart failure, especially in patients with DM subtype, skin involvement, peripheral microangiopathy, and anti-SSA antibodies. The pathogenesis of IIM-PAH is unclear and might involve a specific microvascular disease. The best therapeutic modalities for these patients remain to be defined. Table 3 Individual data for the IIM-PAH cohort (study population and previously reported cases).