Could pulmonary arterial hypertension be an active index of systemic lupus erythematosus? A successful case of SLE-PAH cured by methylprednisolone pulse therapy

Introduction

Pulmonary hypertension (PH) is defined as mean pulmonary artery pressure (MPAP) ≥25 mmHg at rest by right heart catheterization (RHC). Pulmonary arterial hypertension (PAH) describes PH with pulmonary artery wedge pressure (PAWP) ≤15 mmHg and a pulmonary vascular resistance (PVR) >3 Wood units (WU), ¹ and is classified as Group I PH. ² PAH associated with connective tissue disease (PAH-CTD) consists a major part of the PAH spectrum, and systemic lupus erythematosus (SLE) has a high frequency in Asian countries as the underlying disease of PAH-CTD patients. Resulting from the increased awareness of PH and easier access to noninvasive screening techniques, earlier detection can be achieved, though prognosis for PAH-CTD is still poor according to several nationwide registries. Treatment for PAH has improved, effective vasodilators are available in many countries and their efficacy have been proven by clinical trials. For PAH-CTD patients, however, the underlying CTD makes it much more complicated for early diagnosis and effective treatment. Some case reports and series raised the clinical question whether immune suppressive therapy is useful, its answer however is still in a controversial dilemma since patients responded differently in observational studies. We admitted an SLE-PAH patient recently in Peking Union Medical College Hospital (PUMCH) who was newly diagnosed with active SLE and PAH simultaneously. Methylprednisolone pulse therapy was effective and the patient’s PAH was totally cured, proven by repeat RHC.

Case report

Our patient, a 35-year-old woman, presented with peripheral edema and progressive dyspnea since March 2013, accompanied by photosensitivity and hair loss. Laboratory results showed leukocytopenia (white blood cells (WBC) 3.65 × 10⁹/l), hematuria with proteinuria (4.58 g/24 h), hypoalbuminemia (Alb 20 g/l), hypocomplementemia (C4 0.006 g/l), positive antinuclear antibody (ANA H-type 1:1000), positive anti-double-strand DNA (anti-dsDNA) antibody and pericardial effusion. Ophthalmology exam showed exudate lesions in the right eye. SLE was diagnosed and systemic involvements included lupus nephritis, pericarditis and retinal vasculitis. The assessment of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was 24. Cardiac ultrasound suggested PAH, with estimated systolic pulmonary arterial pressure (SPAP) of 49 mmHg and right ventricle diameter of 30  cm. She was then transferred to PUMCH for further evaluation.

The New York Heart Association (NYHA) Functional Class (Fc) of our patient at admission was class III, her 6 Minute Walk Distance (6MWD) was 426 m. Brain natriuretic peptide (BNP) was 280 ng/l. Creatine kinase (CK) was 45 U/l, and lactate dehydrogenase (LDH) was 197 U/l. Right heart catheterization (RHC) was performed on June 21, 2013. SPAP, DPAP and MPAP were 55, 27 and 37 mmHg, respectively. Cardiac index (CI) was 2.14 l/min × m². PVR was 7.6 WU (see Table 1). PAH was confirmed by gold standard. Computer tomography pulmonary artery ruled out pulmonary embolism, and pulmonary functional test showed decreased diffusion capacity with DLCO 56% and normal spirometry. Her PAH was classified as SLE associated, and methylprednisolone pulse therapy (1 g/day for three days) was started immediately after RHC performance, followed by prednisone 60 mg/day, plus intravenous cyclophosphamide 0.4 g weekly and combined oral hydroxychloroquine.

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Table 1

Major clinical data related to SLE and PAH

		Week 0	Week 4	Week 24
SLEDAI		24	8	6
BNP (ng/l)		280	12	11
NT-proBNP (pg/ml)		5988	110	50
NYHA Fc		Class III	Class II	Class II
6MWD (m)		426	505	514
Echo	SPAP (mmHg)	49	27	42
	RV (mm)	30	23	21
	LVEF (%)	60	68	63
RHC	SPAP/DPAP/ MPAP (mmHg)	55/27/37	28/16/22	ND
	CI (l/min × m2)	2.14	3.06	ND
	PVR (WU)	7.6	2.5	ND
	PAWP (mmHg)	9	9	ND
Treatment		MP 1 g/d × 3 d →Pred 60 mg/d → tapering →10 mg/day CYC 0.4 g i.v. q.w. HCQ 0.2 g p.o. BID

To our surprise, her repeat RHC four weeks later on July 19, 2013, showed total recovery from PAH, MPAP decreased to 22 mmHg, PVR to 2.5 WU and CI increased to 3.06 l/min × m². Her NYHA Fc was Class II, 6MWD was 505 m. BNP level was back to 12 ng/l and right ventricular size by echocardiogram was normal at 23 cm. Our patient actually achieved normalized hemodynamics and PAH was cured. For her SLE evaluation, WBC elevated to 9.27 × 10⁹/l, albumin 29 g/l, C4 0.075 g/l, and urine protein decreased to 2.89 g/24 h. Anti-dsDNA was negative and cardiac effusion was reabsorbed. She was then discharged home.

The patient was closely followed up in outpatient clinics. At week 24, her prednisone was tapered to 10 mg/day. She has no complaint of dyspnea or edema with only hematuria and positivity of anti-dsDNA.

Discussion

PAH is a severe complication of SLE with high mortality. Echocardiogram is an acceptable screening test, but RHC is the gold standard. ³ The prevalence of PAH in SLE in China was 3.8% according to our recent study in the Chinese SLE Treatment and Research group (CSTAR) registry, based on a multicenter database that covers 104 rheumatology departments from 30 provinces in China. ⁴ SLE-PAH consists of 51% of all CTD-PAH cases in Chinese patients,^5,6 though in European or American registries, systemic sclerosis (SSc)-PAH has a larger percentage. It seems PAH has a higher incidence and prevalence in lupus patients than expected; however, there is no reported worldwide registry of SLE-PAH.

The diagnosis of SLE frequently occurs before the diagnosis of PAH, with a mean delay of 4.9 years ( ± 3.7 years). ⁷ The prognosis of SLE-PAH is poor. Current PAH treatment strategy mainly focuses on supportive treatment and PAH-targeted vasodilators. Idiopathic PAH patients respond well to this therapy regimen, for PAH related to general inflammatory diseases such as SLE, however, inflammation might play a more important role in the process, ⁸ and immunosuppressive treatment might be a priority to benefit patients. Several experimental effective therapies with immunosuppressives for SLE-PAH have been published;^9–11 but there are no randomized clinical trials that can validate the efficacy of immunosuppressive treatment, and complete normalization of hemodynamic parameters is very rare, as well.

When should immunosuppressive therapy be initiated and who would benefit from it? In 2002, Tanaka et al. reviewed 12 SLE and overlap cases in Japan, and reported the efficacy of corticosteroids plus cyclophosphamide for PAH associated with SLE immediately after the diagnosis of PAH. They deduced long-standing PAH patients might have irreversible pathologic changes of pulmonary vessels. ¹² In 2006, Sanchez et al. gathered 28 PAH-CTD patients and found that eight responders to immunosuppressive therapy out of the total 28 patients were less severe than those non-responders in terms of World Health Organization (WHO) Fc, CI and PVR, which hinted that responders were at an earlier phase of the disease. ¹³ Two years later in 2008, Jaïs et al. in the same group suggested a combined therapy strategy of corticosteroids and cyclophosphamide in SLE or mixed connective tissue disease (MCTD) patients with WHO Fc I/II or III with CI>3.1 l/min × m². Responders to immunosuppressive therapy tend to have a higher frequency of positive anti-dsDNA antibody and a higher SLEDAI score, according to their experience. ¹⁰

However, the recommendations are based on large doses of prednisone, and very few cases in the literature focused on the efficacy of steroid pulse therapy, which is a common treatment strategy for life-threatening conditions in SLE and has a much stronger suppression on the human immune system. In 2005, one PAH-MCTD patient from Japan was reported to be a responder to methylprednisolone pulse treatment, but she was at the same time on the medication sildenafil. Our SLE patient was diagnosed with PAH early in the disease course and totally recovered through methylprednisolone pulse treatment without any vasodilator drugs, proved by repeat RHC. This is the first simultaneously diagnosed, totally recovered, gold standard-proved SLE-PAH case ever reported.

Apart from the mentioned characteristics of good responders to immunosuppressive therapy, such as early phase, better cardiac function and high disease activity, in our case, we would like to consider the patient’s PAH as an active index of SLE, and she benefited from steroid pulse treatment since the PAH itself was a sign of inflammation. Very few studies mentioned the relationship between PAH and activity of underlying CTD. In 2011, Johnson and Granton proposed in a review article that SLE-PAH could be classified into three subsets. One subset may be those prone to thromboembolic disease and would benefit from anticoagulation therapy. A second subset may be those with a pulmonary vasculopathy similar to SSc-PAH who may be associated with anti-ribonucleoprotein antibody and non-inflammatory vascular remodeling. A third subset is one with an immune-mediated vasculopathy leading to pulmonary vasculitis, and may be reversible with immunosuppression. ⁷ Patients who present with PAH in the early phase of SLE and have high disease activity might be classified as the third subset, and PAH could be the best evidence for inflammation. We believe that more research on the relationship between PAH and disease activity could provide a better understanding on CTD-PAH and a better treatment choice.

The treatment goal of PAH was recently defined as the following criteria: ¹⁴ (1) modified NYHA Fc I or II, (2) 6MWD ≥380 to 440 m, (3) BNP level toward normal, (4) echocardiograph and/or cardiac magnetic resonance imaging demonstrating normal/near-normal right ventricular size and function, (5) cardiopulmonary exercise test-measured peak oxygen consumption >15 ml/mon/kg and ventilator equivalent for carbon dioxide <45 l/min/l/min, (6) hemodynamics showing normalization of right ventricular function with right atrial pressure <8 mmHg and cardiac index >2.5 to 3.0 l/min/m². ¹⁴ Our patient is a rare cured case. However, if PAH might be a consequence of a systemic inflammatory reaction, we would also suggest the ultimate goal for SLE-PAH is a total cure with normal hemodynamics.