Systemic lupus erythematosus and pulmonary arterial hypertension: links, risks, and management strategies

Figures & data

Table 1 Independent predictors of PAH in SLE

Variable	Patients (n)	Hazard ratio	95% CI	Reference
Disease duration	111	1.12	1.03–1.21	Huang et al^Citation13
Raynaud’s phenomenon	41	3.204	1.291–7.949	Lian et al^Citation14
Pleuritis	74	3.061	1.602–5.85	Li et al^Citation18
Pericarditis	111	21.3	4.1–110.6	Huang et al^Citation13
	74	4.248	2.261–7.98	Li et al^Citation18
Interstitial lung disease	111	17.03	3.6–80	Huang et al^Citation13
Anti-RNP antibodies	111	12.4	3.6–42.9	Huang et al^Citation13
	74	2.559	1.312–4.993	Li et al^Citation18
	41	5.393	2.073–14.028	Lian et al^Citation14
Anti-SSA/Ro antibodies	111	4.84	1.7–14	Huang et al^Citation13
Anticardiolipin antibodies	41	3.753	1.532–9.197	Lian et al^Citation14

Abbreviations: CI, confidence interval; PAH, pulmonary arterial hypertension; RNP, ribonuclear protein; SLE, systemic lupus erythematosus; SSA/Ro, Sjogren’s Syndrome related antigen A.

Figure 1 A schematic representation of the pathogenesis of PAH in SLE.

Notes: Pulmonary and cardiac involvement as well as disequilibrium between vasodilators (prostacyclin, PGI2) and vasoconstrictors (ET-1 and, TXA-2) will lead to hypoxia and vasoconstriction. Hyperexpression of HIF and EPO will drive impaired smooth muscle, endothelial, and adventitial cell proliferation and apoptosis. In parallel, the accumulation of inflammatory cells into the elastic lamina of the pulmonary arteries and the secretion of certain cytokines and growth factors will lead to abnormal vascular remodeling, and thus increased PVR. In selected cases, thrombosis of the pulmonary circulation in the presence of antiphospholipid antibodies and other prothrombotic factors, will also contribute to increased PVR and PAH. The role of the anti-endothelial cell antibodies AECA and other immune mediators has not been clarified yet.
Abbreviations: PAH, pulmonary arterial hypertension; SLE, systemic lupus erythematosus; ET-1, endothelin-1; TXA-2, thromboxane A2; HIF, hypoxia-inducible factor; EPO, erythropoietin; PVR, pulmonary vascular resistance; AECA, anti-endothelial cell antibodies.

Table 2 Studies with immunosuppressive medications for SLE-PAH

Reference	Year	N (SLE)	Baseline characteristics			Intervention	Outcome	Notes/side effects
Tanaka et al^Citation46	2002	12	Age RVSP	38.3±14.2 years 55.5±10.7 mmHg		8/12 received corticosteroids and/or CYC	7/8 responded (significant decrease in RVSP), 2/7 relapsed (treated with corticosteroids plus CYC successfully)	Retrospective, four patients had SLE + SSc overlap syndrome One patient died due to sepsis, one developed hemorrhagic cystitis
GonzalezLopez et al^Citation47	2004	34	Age mPASP	38± 11 years 39±6 mmHg		IV CYC (500 mg/m^2/month × 6 months) n= 16 vs enalapril 10 mg/day for 6 months, n=18 + oral prednisone < 15 mg/day	1. Significant reduction in PASP in both groups (13 mmHg for CYC, 8 mmHg for enalapril) 2. CYC performed better in moderate PAH (initial PASP >35 mmHg), enalapril was not effective 3. NYHA functional class improved only with CYC	Randomized controlled trial, PAH defined as RVSP >30 mmHg by TTE Patients on CYC had more infections and gastrointestinal side effects
Sanchez et al^Citation48	2006	28 (12)	Age mPAP PVR NYHA 6MWD	29 years 54 mmHg 19 WU II, III 370 m		IV CYC (600 mg/m^2/month ×3 months) + oral prednisone (0.5–1 mg/kg for 4 weeks, then slow tapering) 22/28	5/12 SLE patients responded (mPAP decreased from 49±16 to 34±11 mmHg, PVR from 15.6±4 to 10.1 ±4 WU) Responders had improved survival (100% vs 38% at 5 years)	Patients with MCTD and SSc were also included Two of 28 patients died due to sepsis; minor side effects (leukopenia, thrombocytopenia) were infrequent
Jais et al^Citation49	2008	23 (13)*	Age mPAP PVR NYHA 6MWD	IS =9 31 ±10 years 48±12 mmHg 8.6±3.5 WU II, III 347±80 m	IS+ VD =4 38±9 years 58±10 mmHg 14.3± 1.3 WU III, IV 381 ±71 m	IV CYC (600 mg/m^2/month ×6 months) + oral prednisone (0.5–1 mg/kg for 4 weeks, then slow tapering) + VDs + supportive treatment (diuretics, anticoagulants)	1. Patients with less severe PAH (NYHA class I or II) may respond to IS alone 2. Patients with more severe disease may benefit from the addition of VDs	Patients with MCTD were also included in the analysis Only minor side effects (leukopenia, thrombocytopenia) were reported
Miyamichi- Yamamoto et al^Citation50	2011	13 (7)	Age mPAP PVR NYHA 6MWD	42±8 years 39.5±9.2 mmHg 8.75±5.43 WU I, II, III 442±54 m		IV CYC (500 mg/month ×10 months) + oral prednisone (1 mg/kg for 1 month, then slow tapering) + VDs (more than one could be used in a single patient)	1. mPAP significantly decreased from 39.5±9.1 to 28.9±11 mmHg 2. PVR: trend for decrease (700±434 to 481 ±418 dynessec/cm^5) 3. Improved long-term prognosis	Analysis for 13 patients with CTDs. Among seven SLE patients, five responded quickly (in months) Two patients developed mild liver dysfunction
Kommireddy et al^Citation51	2015	24	Age mPASP NYHA 6MWD	25.4±8 years 59.3±18.7 mmHg I, II, III, IV 312 m		IV CYC (500–1,000 mg/m^2/month ×3 months) + oral prednisone (0.5–1 mg/kg for 4 weeks, then slow tapering) + PDE5 inhibitors in 20/24	11/24 responders PASP reduced from 59.3±18.7 to 43.3±20.9 mmHg at 6 months	Retrospective, PAH defined as RVSP >30 mmHg by TTE 2/24 deaths, one from resistant PAH and one from septic shock

Note:

* Within the 13 SLE patients of this study, 9 received immunosuppressive treatment and 14 vasodilators.

Abbreviations: IV, intravenous; mPAP, mean pulmonary artery pressure; SLE-PAH, SLE-associated PAH; SLE, systemic lupus erythematosus; PAH, pulmonary arterial hypertension; PDE5, phosphodi-esterase type 5 inhibitors; RVSP, right ventricular systolic pressure; CYC, cyclophosphamide; SSc, systemic sclerosis; PASP, pulmonary artery systolic pressure; mPASP, mean PASP; TTE, transthoracic echocardiogram; PVR, pulmonary vascular resistance; NYHA, New York Heart Association; IS, immunosuppressive; VD, vasodilator; 6MWD, 6-minute walk distance; MCTD, mixed connective tissue disease; WU, Woods units.

Table 3 Studies with PAH-targeted therapy medications for SLE-PAH

Reference	Year	N (SLE)	Baseline characteristics		Intervention	Outcome	Notes/side effects
Robbins et al^Citation53	2000	6	Age mPASP PVR NYHA	26–35 years 57±9 mmHg 14±7 WU III, IV	IV epoprostenol	Significant improvement in hemodynamics (PAP reduced by 38±21%, PVR reduced by 58±12%), and NYHA functional class from III–IV to I–II for all patients	SLE relapsed in one patient
Rubin et al^Citation43	2002	213 (16)	Age mPAP PVR NYHA 6MWD	49± 16 years 55 ±16 mmHg 12.7±8.5 WU III, IV 330±74 m	Bosentan	Significant improvement in exercise capacity (6MWD increased by 36 m in cases, decreased by 8 m in controls), NYHA functional class (42% in bosentan group), and time to clinical worsening	Double-blind, placebo-controlled trial No significant differences in side effects between groups
Oudiz et al^Citation45	2004	90 (25)	Age mPASP NYHA 6MWD	54±2 years 52 ±2 mmHg II, III, IV 280±13 m	SC treprostinil	Improved exercise capacity (6MWD increased by 25 m), dyspnea, hemodynamics (PVR decreased by 4±2 WU), and trend toward improved quality of life	Double-blind, placebo-controlled trial Patients with MCTD and SSc were also included Minor side effects (infusion site pain) only
Mok et al^Citation56	2007	4	Age mPAP PVR NYHA 6MWD	42±8 years 39.5±9.2 mmHg 8.75±5.43 WU I, II, III 442±54 m	Bosentan	6MWD significantly improved in 3 (+24.8 m), 6 (+26.2 m), 9 (+54 m), and 12 (+62.7 m) months	Liver toxicity in one patient, PASP assessed with TTE
Badesch et al^Citation44	2007	284(19)	Age mPAP PVR NYHA 6MWD	53±15 years 47±11 mmHg 10.1 ±5.5 WU II, III, IV 342±76 m	Sildenafil 20, 40, or 80 mg/d	Patients with CTD-associated PAH had improved exercise capacity (6MWD increased by 42 m in cases and decreased by 13 m in controls), hemodynamics, and NYHA functional class (29%–42% improvement, 5% for placebo) after 12 weeks of treatment with sildenafil 20 mg/day	12-week double-blind study (SUPER-1) Subgroup analysis of 84 patients with CTD-associated PAH Patients with SSc and other CTDs were also included in the analysis No significant side effects
Shirai et al^Citation54	2013	16 (6)	Age mPAP PVR NYHA	43 ±14 years 56 ±9 mmHg 21 ±9 WU III, IV	IV epoprostenol	mPAP (26% reduction from baseline), PVR (41% reduction from baseline), and functional class were improved after 6 months. Treated patients had better survival (3-year survival 55% vs 6%)	Patients with MCTD and SSc were also included All patients had treatment-related side effects (headache, flushing, diarrhea) Seven of 16 patients had catheter-related infections and required admission

Abbreviations: IV, intravenous; PAP, pulmonary artery pressure; mPAP, mean PAP; PAH, pulmonary arterial hypertension; SLE-PAH, SLE-associated PAH; SLE, systemic lupus erythematosus; SC, subcutaneous; SSc, systemic sclerosis; PASP, pulmonary artery systolic pressure; mPASP, mean PASP; PVR, pulmonary vascular resistance; NYHA, New York Heart Association; 6MWD, 6-minute walk distance; CTD, connective tissue disease; MCTD, mixed CTD; TTE, transthoracic echocardiogram; WU, Woods units.

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