Anti-PL-7 antibody antisynthetase syndrome can lead to the development of pulmonary hypertension including pulmonary arterial hypertension.

Dear Editor Myositis-specific autoantibodies are closely associated with distinct clinical subsets of idiopathic inflammatory myopathies (IM). Anti-PL-7 (threonyl) antibody, a subtype of anti-aminoacyl-tRNA synthetase (ARS) antibodies, is found in only 2–5% of IM patients [1]. Clinical features are essentially consistent with anti-ARS syndrome, while relatively milder myositis compared with anti-Jo-1 antibody-positive patients and concomitant SSc have been described as unique [2, 3]. However, there is a paucity of reports on the association between anti-PL-7 antibody and pulmonary hypertension (PH). We present a case of anti-PL-7 antibody positive antisynthetase syndrome diagnosed after the onset of PH and right-sided heart failure.

A 53-year-old Japanese woman with a 2-year history of Raynaud syndrome and skin sclerosis presented to a general hospital with dyspnoea, weight gain and oedema of the lower extremities. She suffered from respiratory failure and required oxygen supplementation. Chest X-ray and CT showed cardiomegaly, reticular shadows and traction bronchiectasis in a non-specific interstitial pneumonia pattern (Fig. 1A and B). Transthoracic echocardiography revealed a tricuspid regurgitation pressure gradient (TRPG) of 48 mmHg and dilated right ventricle with pericardial effusion (Fig. 1C). Of note, elevated creatinine kinase (CK) levels and anti-ARS antibody were newly detected. The patient was referred to our hospital with suspected connective tissue disease (CTD) and PH.

Radiologic images, echocardiography, and clinical course of the patient

(A) Chest X-ray demonstrating cardiomegaly and reticular shadows in both lower lung fields. (B) High-resolution CT scan demonstrating reticular shadows (arrow) and traction bronchiectasis (arrowheads). (C) Parasternal short-axis view of the heart showing the characteristic D-shape of the left ventricle (arrows) and pericardial effusion (arrowheads). (D) BNP, TRPG and CK in response to the treatment. Because the patient had signs of right-sided heart failure, combination therapy with vasodilators proceeded to immunosuppressive therapy. The combination therapy alone promptly improved BNP and TRPG. After the initiation of PSL followed by tacrolimus and IVCY, CK levels were finally normalized. 6MWD: 6-min walking distance; BNP: brain natriuretic peptide; CK: creatinine kinase; DOB: dobutamine; HOT: home oxygen therapy; IVCY: intravenous cyclophosphamide; PSL: prednisolone; RHC: right heart catheterization; TRPG: tricuspid regurgitation pressure gradient.

On admission, physical examination revealed no musculoskeletal findings or rash typical of dermatomyositis. Laboratory results showed elevated C-reactive protein (2.26 mg/dl), CK (943 U/l), brain natriuretic peptide (BNP) (844.3 pg/ml), and Krebs von den Lungen‐6 levels (928 U/ml). Also, antinuclear antibodies characterized only by a cytoplasmic pattern were reported as positive and anti-PL-7 antibody was positive as well. Electromyography showed low amplitude and short duration motor unit potentials. Muscle biopsy showed variation in fibre size and some central nuclei with focal inflammatory cells infiltrating the perivascular reions. Collectively, the patient was diagnosed with anti-PL-7 antibody antisynthetase syndrome overlapping with SSc.

Simultaneously, a diagnostic workup for PH was performed. The 6-min walking distance (6MWD) was 223 m. Lung function test showed a restrictive pattern with reduced diffusion. Right heart catheterization (RHC) revealed mean pulmonary artery pressure (mPAP) 47 mmHg, pulmonary arterial wedged pressure (PAWP) 9 mmHg, pulmonary vascular resistance (PVR) 5.8 Wood units, and cardiac index (CI) 2.9 l/min/m2. These results were compatible with pre-capillary PH [4]. Above all, the severity and CTD activity suggested not only lung interstitial involvement but also pulmonary arterial hypertension (PAH).

Figure 1D shows the clinical course. Because the patient had signs of right-sided heart failure [WHO functional class (FC) IV], PH treatment was prioritized. Dobutamine was initiated at 2 µg/kg/min. Sildenafil was then started, followed by tadalafil, macitentan, selexipag and riociguat (to replace the sildenafil and tadalafil). These agents were sequentially added and dosages increased with up-titration of each agent. The combination therapy promptly ameliorated the symptoms to WHO-FC II and improved BNP levels and echocardiographic parameters. After the diagnosis of CTD, oral prednisolone (PSL) was administered at 30 mg/day for myositis. Because the myositis did not respond sufficiently to PSL, tacrolimus and monthly intravenous cyclophosphamide (IVCY) (500 mg/body) were administered. IVCY was withdrawn due to infection, but CK levels were finally normalized. The CT findings of interstitial lung disease (ILD) remained stable and lung function test unchanged. After about 90 days of therapy, her haemodynamic parameters were stabilized (mPAP 25 mmHg, PAWP 11 mmHg, PVR 2.1 Wood units, CI 4.15 l/min/m2) and 6MWD was remarkably improved (428 m). She was discharged with home oxygen therapy. The clinical course was uneventful for the following 2 years.

Up to now, PH associated with anti-PL-7 antibody antisynthetase syndrome has been reported only in three cases [5, 6], the pathogenesis of which was considered to be slowly progressive ILD-associated PH. To our knowledge, this is the first case of anti-PL-7 antibody antisynthetase syndrome with severe and acute haemodynamic changes mainly caused by PAH, and it is also notable that unlike previous cases, the combination therapy for PAH with three classes of agents responded well. Meanwhile, regarding the beneficial effect of the immunosuppressive therapy for PH, because the patient maintained the haemodynamic stability without worsening disease activity after the immunosuppressive therapy, it might play a potential role in the long-term stability of the PAH component.

The use of combination therapy is already common in current management strategies for PAH associated with CTD [4], although, because of pathological complexity and clinical heterogeneity, initial upfront combination therapy is not always recommended. As this case shows, PAH with other component causes (e.g. PH associated with SSc) should be initially treated with a single agent and second or third agents introduced with a gradual up-titration of each agent in a sequential fashion [7].

In conclusion, PH, including PAH, can develop in anti-PL-7 antibody antisynthetase syndrome. Combination therapy with vasodilators, followed by immunosuppressive therapy might result in a favourable outcome.

Patient consent: The patient presented in this report gave her informed consent prior to her inclusion.

Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.

Disclosure statement: All authors declare no conflicts of interest.

The data underlying this article will be shared on reasonable request to the corresponding author.

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