Management and long-term outcomes of sarcoidosis-associated pulmonary hypertension

Athénaïs Boucly; Vincent Cottin; Hilario Nunes; Xavier Jaïs; Abdelatif Tazi; Grégoire Prévôt; Martine Reynaud-Gaubert; Claire Dromer; Catherine Viacroze; Delphine Horeau-Langlard; Christophe Pison; Emmanuel Bergot; Julie Traclet; Jason Weatherald; Gérald Simonneau; Dominique Valeyre; David Montani; Marc Humbert; Olivier Sitbon; Laurent Savale

doi:10.1183/13993003.00465-2017

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FIGURE 1
Patient disposition and initial therapy. RHC: right heart catheterisation; PAH: pulmonary arterial hypertension; ERA: endothelin receptor antagonist; PDE-5i: phosphodiesterase type 5 inhibitor.
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FIGURE 2
Box plots of change in 6-min walk distance (6MWD) and pulmonary vascular resistance (PVR) according to a, b) radiological stage of sarcoidosis or c, d) severity of restrictive physiology (forced vital capacity (FVC)). a) Change in 6MWD according to radiological stage of sarcoidosis (stage IV versus others): +5±49% versus +21±49%; p=0.11. b) Change in PVR according to radiological stage of sarcoidosis (stage IV versus others): –24±29% versus –22±32%; p=0.73. c) Change in 6MWD according to FVC (≤50% versus >50% predicted): –1±56% versus +14±45%; p=0.10. d) Change in PVR according to FVC (≤50% versus >50% predicted): –22±32% versus –27±25%; p=0.57. Box plots indicate the mean, standard deviation and extreme values.
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FIGURE 3
Kaplan–Meier analysis of the overall survival in patients with severe sarcoidosis-associated pulmonary hypertension. Survival at 1, 3 and 5 years was 93%, 74% and 55%, respectively.
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FIGURE 4
Proposed algorithm for the management of sarcoidosis-associated pulmonary hypertension. This algorithm must be read with caution because it relies on retrospective and open-label data, and must therefore be confirmed by future randomised controlled trials. HRCT: high-resolution computed tomography; V/Q: ventilation/perfusion; ¹⁸F-FDG: ¹⁸F-2-fluoro-2-deoxy-d-glucose; PET: positron emission tomography; mPAP: mean pulmonary artery pressure; CI: cardiac index; PAH: pulmonary arterial hypertension.

TABLE 1

Demographics and baseline characteristics of patients with newly diagnosed severe sarcoidosis-associated pulmonary hypertension

Patients	126
Male/female	65 (52)/61 (48)
Age years	57.5±10.6
BMI kg·m⁻²	25.5±6.6
Tobacco exposure	42 (33)
Time between sarcoidosis and pulmonary hypertension diagnosis months	204 (59–313)
Radiological stage
I	6 (5)
II	22 (17)
III	7 (6)
IV	91 (72)
WHO/NYHA functional class
I–II	21 (17)
III	79 (63)
IV	26 (20)
6MWD m	319±143
Borg dyspnoea scale	4.9±2.3
Haemodynamics
RAP mmHg	7±5
mPAP mmHg	46±10
PAWP mmHg	9±4
Cardiac index L·min⁻¹·m⁻²	2.6±0.8
PVR Wood units	8.8±4.3
S_vO₂ %	63.4±8.9
Lung function tests
FVC % pred	64±21
FEV₁ % pred	55±22
K_CO % pred	54±23
Long-term oxygen therapy	68 (54)

Data are expressed as n, n (%), mean±sd or median (interquartile range). BMI: body mass index; WHO: World Health Organization; NYHA: New York Heart Association; 6MWD: 6-min walk distance; RAP: right atrial pressure; mPAP: mean pulmonary artery pressure; PAWP: pulmonary arterial wedge pressure; PVR: pulmonary vascular resistance; S_vO₂: mixed venous oxygen saturation; FVC: forced vital capacity; FEV₁: forced expiratory volume in 1 s; K_CO: transfer coefficient of the lung for carbon monoxide.

TABLE 2

Effects of pulmonary arterial hypertension-targeted therapy on World Health Organization (WHO)/New York Heart Association (NYHA) functional class, exercise capacity and haemodynamics at first follow-up visit in patients with severe sarcoidosis-associated pulmonary hypertension^#

	Baseline	First follow-up visit^¶	Difference	p-value
WHO/NYHA functional class I–II/III/IV	11/52/18	26/45/10		0.01
6MWD m	311±127	324±138	+13 m	0.33
RAP mmHg	7±4	6±4	−14%	0.007
mPAP mmHg	48±9	42±11	−13%	<0.00001
Cardiac index L·min⁻¹·m⁻¹	2.6±0.8	2.9±0.8	+12%	<0.00001
PVR Wood units	9.7±4.4	6.9±3.0	−29%	<0.00001

Data are expressed as n or mean±sd, unless otherwise stated. 6MWD: 6-min walk distance; RAP: right atrial pressure; mPAP: mean pulmonary artery pressure; PVR: pulmonary vascular resistance. ^#: n=81; ^¶: median (interquartile range) 4.5 (4.0–6.7) months.

TABLE 3

Evolution at 6 months of individual and haemodynamic parameters in patients treated with initiation or escalation of immunosuppressive therapy alone

Patient	Sex	Age years	Extrinsic pulmonary artery compression	Increased ¹⁸F-FDG uptake in PET scan	Radiological stage	FVC %	WHO/NYHA functional class		6MWD m		mPAP mmHg		Cardiac index L·min⁻¹·m⁻²		PVR Wood units		Immunosuppressive therapy
Patient	Sex	Age years	Extrinsic pulmonary artery compression	Increased ¹⁸F-FDG uptake in PET scan	Radiological stage	FVC %	T0	T6	T0	T6	T0	T6	T0	T6	T0	T6	Immunosuppressive therapy
1	Male	66	Yes (lymph nodes)	Yes	1	96	III	II	490	540	38	29	3.1	3.7	3.2	1.9	Methotrexate
2	Female	40	Yes (lymph nodes)	Yes	1	100	III	II	ND	420	51	29	2.1	2.2	11.7	4.2	Prednisone 60 mg·day⁻¹
3	Female	55	Yes (fibrosing mediastinitis)	Yes	1	42	III	II	190	195	46	30	3.3	2.6	7.4	6.5	Prednisone 60 mg·day⁻¹
4	Male	67	Yes (fibrosing mediastinitis)	No	4	57	II	II	550	530	42	46	2.8	1.9	6.3	10.6	Prednisone 30 mg·day⁻¹
5	Female	58	Yes (fibrosing mediastinitis)	ND	4	40	III	III	390	367	48	39	2.8	2.9	7.3	8.4	Prednisone 30 mg·day⁻¹
6	Female	45	No	ND	4	77	III	III	449	462	39	28	2.8	2.9	6.5	4.8	Prednisone 60 mg·day⁻¹
7	Male	41	No	ND	4	52	II	IV	525	270	39	45	2.3	ND	7.7	ND	Prednisone 60 mg·day⁻¹
8	Male	64	No	ND	2	63	III	III	388	377	42	30	4.3	2.6	4.9	4.7	Prednisone 60 mg·day⁻¹
9	Female	68	No	ND	4	65	III	III	242	ND	44	25	3.3	4.0	7.0	3.6	Azathioprine 100 mg·day⁻¹
10	Female	65	No	ND	4	108	II	III	410	310	48	38	4.1	3.3	6.5	6.6	Prednisone 40 mg·day⁻¹
11	Male	79	No	ND	4	48	III	III	509	ND	56	46	2.3	2.4	9.3	9.5	Prednisone 60 mg·day⁻¹

¹⁸F-FDG: ¹⁸F-2-fluoro-2-deoxy-d-glucose; PET: positron emission tomography; FVC: forced vital capacity; WHO: World Health Organization; NYHA: New York Heart Association; 6MWD: 6-min walk distance; mPAP: mean pulmonary artery pressure; PVR: pulmonary vascular resistance; T0: baseline visit; T6: 6-month visit; ND: no data available.

TABLE 4

Univariate analysis relating survival time to selected baseline variables

	Hazard ratio (95% CI)	p-value
Sex (female)	1.017 (0.573–1.806)	0.954
Age	1.004 (0.977–1.031)	0.794
WHO/NYHA functional class IV	2.010 (1.052–3.840)	0.034
6MWD	0.995 (0.993–0.997)	<0.001
RAP	0.930 (0.861–1.005)	0.066
mPAP	0.997 (0.968–1.027)	0.834
Cardiac index	1.401 (0.994–1.976)	0.054
PVR	0.966 (0.898–1.039)	0.350
FVC	0.984 (0.969–0.999)	0.042
K_CO	0.982 (0.968–0.996)	0.013
Radiological stage IV	1.845 (0.954–3.559)	0.069
PAH-targeted therapy	0.845 (0.526–2.650)	0.684

WHO: World Health Organization; NYHA: New York Heart Association; 6MWD: 6-min walk distance; RAP: right atrial pressure; mPAP: mean pulmonary artery pressure; PVR: pulmonary vascular resistance; FVC: forced vital capacity; K_CO: transfer coefficient of the lung for carbon monoxide; PAH: pulmonary arterial hypertension.