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(Chest. 2006;130:182-189.)
© 2006 American College of Chest Physicians

Immunosuppressive Therapy in Connective Tissue Diseases-Associated Pulmonary Arterial Hypertension*

Olivier Sanchez, MD; Olivier Sitbon, MD; Xavier Jaïs, MD; Gérald Simonneau, MD and Marc Humbert, MD, PhD

* From the Centre National de Référence de l’Hypertension Artérielle Pulmonaire, UPRES EA2705, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, Assistance Publique Hôpitaux de Paris, Université Paris-Sud, Clamart, France.

Correspondence to: Marc Humbert, MD, PhD, Service de Pneumologie et Réanimation, Hôpital Antoine Béclère, 157, rue de la Porte de Trivaux, 92140 Clamart, France; e-mail: marc.humbert{at}abc.aphp.fr

Abstract

Study objective: Immune and inflammatory mechanisms could play a significant role in pulmonary arterial hypertension (PAH) genesis or progression, especially in patients with connective tissue diseases. Immunosuppressive therapy should be better evaluated in this setting.

Study design: Monocentric retrospective study.

Patients: We reviewed the clinical and hemodynamic effects of immunosuppressants administered as first-line monotherapy to 28 consecutive patients with connective tissue disease-associated PAH.

Interventions: All patients received a monthly IV bolus of cyclophosphamide, 600 mg/m2, for at least 3 months, and 22 of 28 patients received systemic glucocorticosteroids. Responders to immunosuppressive therapy were defined as patients who remained in New York Heart Association (NYHA) functional class I or II with sustained hemodynamic improvement after at least 1 year of immunosuppressive therapy without addition of prostanoids, phosphodiesterase type 5 inhibitors, or endothelin receptor antagonists.

Results: Eight of 28 patients (systemic lupus erythematosus [SLE], n = 5; mixed connective tissue disease [MCTD], n = 3) [29%] were responders. These patients had a significantly improved 6-min walking distance (available in five patients) and a significant improvement in hemodynamic function. No patients with systemic sclerosis responded, while 5 of 12 patients with SLE and 3 of 8 patients with MCTD did respond. Survival analysis indicated that responders had a better survival than nonresponders. Patients with a lower baseline NYHA functional class and better baseline pulmonary hemodynamics (p < 0.05) were more likely to benefit from immunosuppressive therapy.

Conclusion: PAH associated with SLE or MCTD might respond to a treatment combining glucocorticosteroids and cyclophosphamide.

Key Words: connective tissue diseases • cyclophosphamide • immunosuppressive therapy • pulmonary hypertension

Pulmonary arterial hypertension (PAH) is due to chronic obstruction of small pulmonary arteries resulting from sustained pulmonary vasoconstriction and lumen obliteration of small- and medium-sized arteries and arterioles in association with the formation of plexiform lesions and in situ thrombosis, and concentric thickening of pulmonary arteries resulting from excessive proliferation of endothelial and smooth-muscle cells.12 In addition, it is widely accepted that immune and/or inflammatory mechanisms could play a significant role in PAH genesis or progression, especially in patients with connective tissue diseases, including limited and diffuse systemic scleroderma, systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), polymyositis, Sjögren syndrome, and rheumatoid arthritis. Inflammatory cell infiltrates composed of macrophages and lymphocytes have been detected in plexiform lesions from PAH patients,3456 and anti-nuclear antibody, rheumatoid factor, IgG, and complement have been identified in the pulmonary vessel walls from patients with connective tissue diseases-associated PAH.78 More than 20% of patients with idiopathic PAH have either circulating anti-nuclear antibodies9 or elevated serum levels of proinflammatory cytokines (interleukin-1 and interleukin-6).1011 The overexpression of growth factors such as platelet-derived-growth-factors A and B12 and chemokines RANTES/CCL5 and fractalkine/CX3CL1 have been demonstrated in diseased pulmonary arteries of severe PAH patients.511

The above information pleads in favor of an inflammatory component in a significant proportion of PAH patients, especially in the context of connective tissue diseases. Moreover, improvements of connective tissue diseases-associated PAH have also been reported with glucocorticosteroid and/or immunosuppressive therapy131415161718 but analysis of the available literature is difficult because most of the articles are case reports, and unpublished negative data are presumably more common. It is difficult to evaluate the true effects of immunosuppressive therapy alone because of the frequent combination with specific PAH therapy including prostaglandins, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors.19 We therefore reviewed the clinical and hemodynamic effects of immunosuppressive therapy administered as first-line monotherapy to 28 consecutive patients with connective tissue diseases-associated PAH referred to the French PAH reference center.

Materials and Methods

Patients
Between February 1991 and January 2001, 112 patients with connective tissue disease were referred to our institute for PAH management (systemic scleroderma, n = 61; SLE, n = 24; MCTD, n = 17; polymyositis, n = 2; Sjögren syndrome, n = 4; rheumatoid arthritis, n = 4). Among them, 28 patients (25%) were not previously treated with either PAH-specific therapies (IV, subcutaneous, inhaled, or oral prostacyclin derivatives, endothelin receptor antagonists, or phosphodiesterase type 5 inhibitors) or immunosuppressants and received first-line immunosuppressive therapy. At baseline, these patients had no immunosuppressive or glucocorticosteroid therapy either because PAH revealed the systemic disease or that the systemic disease was regarded as quiescent with no obvious indication for this therapy for extrapulmonary involvement at referral. These 28 patients are analyzed in the present retrospective study. Connective tissue diseases were classified according to the American College of Rheumatology classification,202122 and corresponded to SLE (n = 13), MCTD (n = 8), limited systemic sclerosis (n = 5), diffuse systemic sclerosis (n = 1), and rheumatoid arthritis (n = 1). Individual clinical and hemodynamic characteristics of these patients are summarized in Table 1 . There were no difference between responders and nonresponders for organ involvement or other inflammation parameters. The diagnosis of PAH was established by right-heart catheterization and defined by mean pulmonary artery pressure (mPAP) > 25 mm Hg at rest and mean pulmonary capillary wedge pressure < 15 mm Hg. Other causes of pulmonary hypertension were excluded by ventilation/perfusion lung scanning and/or pulmonary angiography, CT of the chest, Doppler echocardiography, and lung function tests. All patients tested negative for HIV, and none had evidence of portal hypertension, congenital heart disease, or chronic thromboembolic pulmonary hypertension. No patients had significant pulmonary parenchymal disease, as demonstrated by pulmonary function tests (total lung capacity, vital capacity, and FEV1 of at least 60% of predicted values) and high-resolution CT of the chest (either normal or showing mild interstitial disease).


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  		Table 1. Patient Characteristics*

 
According to French legislation, the agreement of an ethics committee is not required for retrospective collection of data corresponding to current practice. However, the database was made anonymous and complied with the restrictive requirements of the Commission Nationale Informatique et Liberté, the organization dedicated to privacy, information technology, and civil rights in France.

Right-Heart Catheterization and Exercise Capacity
Right-heart catheterization was performed in all patients using standard techniques. Mean right atrial pressure, mPAP, mean pulmonary capillary wedge pressure, cardiac index, mixed venous oxygen saturation (SvO2), and pulmonary vascular resistance (PVR) were measured. All patients had negative acute vasodilator test results with inhaled nitric oxide, IV epoprostenol, or both. Clinical assessment included New York Heart Association (NYHA) functional class and evaluation of exercise capacity with the 6-min walk test. Patients who were unable to walk because of severe PAH were assigned a value of 0 m. Right-heart catheterization, NYHA functional class, and 6-min walk test were performed at baseline and every 3 to 6 months after initiation of immunosuppressive therapy.

Treatment
All patients received conventional therapy (oral anticoagulation, diuretics, and supplemental oxygen if needed) and monthly IV bolus of cyclophosphamide, 600 mg/m2, for at least 3 months. In addition, 22 of 28 patients received oral glucocorticosteroid therapy consisting of 0.5 to 1 mg/kg/d of prednisone (after three IV pulses of 500 mg of methylprednisolone during 3 consecutive days in 5 of 22 patients). Patients with a positive response to immunosuppressive therapy (responders) were defined as patients in NYHA functional class I or II with sustained hemodynamic improvement after at least 1 year of immunosuppressive therapy without addition of prostanoids, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, or transplantation.

Statistical Analysis
Data were analyzed with a personal computer-based data spreadsheet (StatView 5.0; SAS Institute; Cary, NC). Data are presented as mean ± SD. A nonparametric Mann-Whitney test was used for clinical and hemodynamic comparisons between responders and nonresponders to immunosuppressive therapy. A nonparametric Wilcoxon test was used for clinical and hemodynamic comparison between baseline values and those obtained after initiation of immunosuppressive therapy. For survival analysis, we used the beginning of immunosuppressive therapy as the starting point to determine the survival duration. The Kaplan-Meier method was used to estimate the proportion of patients surviving at each time point.

Results

Baseline Characteristics
Individual baseline demographic and hemodynamic parameters are summarized in Table 1. Most patients were female (82%), with a mean age of 40 ± 17 years. PAH was severe (Table 1), with a mean 6-min walk distance of 256 ± 109 m, and 75% of the patients were in NYHA functional class III (57%) or IV (18%).

Response to Immunosuppressive Therapy
Eight of 28 patients (29%) were responders to immunosuppressive therapy, as defined above. Five of eight responders had SLE (62%), and the remaining three responders had MCTD (38%). Clinical and hemodynamic characteristics before and after immunosuppressive therapy are summarized in Table 2 and Figure 1, 2 . Six-minute walk test results were available before and after therapy in five of nine responders. These patients had a significant improved 6-min walking distance (294 ± 118 m vs 449 ± 118 m; p < 0.05) and a significant fall of mPAP (49 ± 16 mm Hg vs 34 ± 11 mm Hg; p < 0.05) and pulmonary vascular resistance (PVR) index (15.6 ± 4 Wood U/m2 vs 10.1 ± 4 Wood U/m2; p < 0.05).


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  		Table 2. Clinical and Hemodynamic Characteristics of Patients Who Responded to Immunosuppressive Therapy*

 

Figure 1
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  		Figure 1. Comparison of NYHA functional class before and after treatment in responders and nonresponders to immunosuppressive therapy (IT).

 

Figure 2
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  		Figure 2. Comparison of PVR before and after treatment in responders and nonresponders to immunosuppressive therapy. A significant improvement of PVR was observed only in responders. PVRI = PVR index. See Figure 1 legend for expansion of abbreviation.

 
Survival
Eleven of the 20 patients (55%) who did not respond to immunosuppressive therapy subsequently died 0.6 to 59 months after initiation of immunosuppressive therapy, as compared with no deaths in responders. The causes of death were end-stage right-heart failure (n = 6), sepsis (n = 2), stroke (n = 2), and sudden death (n = 1). Survival analysis indicated that a positive response to immunosuppressive therapy was associated with significantly better survival. In patients who responded to immunosuppressive therapy, the survival rates at 1, 2, 3, and 5 years were 100%, as compared with 70%, 65%, 65%, and 38%, respectively, in patients who did not respond (p = 0.0069, Mantel-Cox log-rank test) [Fig 3 ].


Figure 3
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  		Figure 3. Survival of patients with PAH associated with connective tissue diseases treated with immunosuppressive therapy. The survival rates at 1, 2, 3, and 5 years were 100% in patients who responded to immunosuppressive therapy as compared with 70%, 65%, 60%, and 38% in patients who failed to respond (p = 0.0069, Mantel-Cox log-rank test). Vertical bars indicate 95% confidence interval at each event.

 
Need for Second-Line PAH-Specific Therapy
One of the eight patients (12%) who initially improved with first-line immunosuppressive therapy was subsequently treated with continuous IV epoprostenol 28 months after the last cyclophosphamide pulse because of persistent severe PAH. In contrast, 15 patients (75%) who did not respond to first-line immunosuppressive therapy required second-line PAH-specific therapy corresponding to IV epoprostenol (n = 8), subcutaneous treprostinil (n = 2), inhaled iloprost (n = 3), or oral bosentan (n = 2).

Complications of Immunosuppressive Therapy
Minor complications related to the use of cyclophosphamide (leukoneutropenia, thrombopenia, nausea, and vomiting) were infrequent. Two life-threatening septic complications occurred. One patient died of severe cellulitis due to Pasteurella sp, and one patient died of Staphylococcus aureus septicemia.

Comparison of Baseline Characteristics of Patients Who Responded and Who Did Not Respond to First-Line Immunosuppressive Therapy
There was no difference in terms of age and sex ratio between the two groups. No patients with systemic sclerosis benefited from immunosuppressive therapy. In contrast, 5 of 13 patients with SLE-associated PAH (38%) and 3 of 8 patients with MCTD-associated PAH (37%) improved with immunosuppressive therapy (Table 3 ). Patients with a lower baseline NYHA functional class were more likely to benefit from immunosuppressive therapy (NYHA classes I/II/III/IV, 0%/33%/67%/0% in responders vs 0%/21%/53%/26%, in nonresponders; p < 0.05). No NYHA functional class IV patients improved significantly with immunosuppressants. In addition, we observed a baseline cardiac index (3.1 ± 0.5 L/min/m2 vs 2.6 ± 0.7 L/min/m2; p < 0.05) and lower baseline PVR index (15.6 ± 4.0 Wood U/m2 vs 21.4 ± 8.0 Wood units/m2; p < 0.05) [Table 3]. The 6-min walk distance in responders was 294 ± 118 m, vs 240 ± 107 m in nonresponders (p = 0.26).


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  		Table 3. Comparison of Patients Who Responded and Did Not Respond to First-Line Immunosuppressive Therapy*

 
Discussion

Pulmonary hypertension is a major complication of connective tissue diseases. In some patients, pulmonary hypertension is due to either significant left-heart disease or chronic respiratory failure with hypoxemia, requiring specific management.2324 However, in many cases, the degree of pulmonary hypertension is not due to pulmonary fibrosis or left-heart disease and corresponds to chronic obstruction of small pulmonary arteries characteristic of PAH.2526 Advances in the understanding of the molecular mechanisms involved in this disease suggest that endothelial dysfunction plays a key role in the genesis and progression of PAH. Chronically impaired production of vasoactive mediators, such as nitric oxide and prostacyclin, along with prolonged overexpression of vasoconstrictors such as endothelin-1, not only affect vascular tone but also promote vascular remodeling.27 Thus, these substances represent logical pharmacologic targets that had been evaluated in several placebo-controlled trials.28293031 However, increasing evidence supports that inflammatory mechanisms contribute to the genesis or progression of connective tissue diseases-associated PAH. Thus, immunosuppressive therapy should be better evaluated in that setting.

In the present study, we report that 8 of 28 patients with connective tissue diseases-associated PAH responded clinically and hemodynamically after a treatment combining monthly cyclophosphamide IV pulses and glucocorticosteroids. We defined responders to immunosuppressive therapy as patients who remained in NYHA functional class I or II with sustained hemodynamic improvement after at least 1 year of immunosuppressive therapy without addition of prostanoids, phosphodiesterase type 5 inhibitors, or endothelin receptor antagonists. This criteria was in part used to define chronic responder to calcium-channel blockers in idiopathic PAH.32 This end point is probably subjective for an open-label retrospective study. However, responders to immunosuppressive therapy had a significant improvement of the 6-min walk distance as compared to baseline, when it was available before and after therapy, and they had a significant improvement of mPAP and PVR, highlighting the relevance of an improvement of NYHA functional class in these patients. Moreover, the significantly better observed survival in responders as compared to nonresponders corroborates these results. The clinical relevance of NYHA, 6-min walk distance, and hemodynamics has been previously emphasized as major end points in PAH. Indeed, these three parameters have a strong association with mortality in patients with PAH.1933 However, we cannot exclude that this survival "benefit" may be due to the lesser severity of the responders at baseline.

The present treatment regimen (IV cyclophosphamide pulse plus glucocorticosteroids) was selected after analysis of the available literature343536 revealing that it appeared to be the most effective treatment to date. Interestingly, no responders had systemic sclerosis, highlighting the fact that there is no clue in favor of immunosuppressive therapy in scleroderma-associated PAH. This is in agreement with the medical literature131415161718373839 reporting cases of PAH improvements mostly in patients with SLE or MCTD but not with systemic sclerosis. Tanaka et al13 reported the effects of immunosuppressive therapy in a series of eight patients with PAH associated with SLE. One patient was treated with oral glucocorticosteroids alone, four patients received oral and IV pulses of glucocorticosteroids, and three patients received glucocorticosteroids and cyclophosphamide.13 Seven of eight patients had a marked or moderate clinical and hemodynamic response, including two patients who later relapsed and subsequently improved with corticosteroids and cyclophosphamide.13 In addition, these authors13 suggested that immunosuppressive therapy for PAH may be less effective in patients with long-standing PAH in whom pathologic changes of pulmonary vessels have already become irreversible, as six of seven responders were treated immediately after the diagnosis of PAH. Analysis of our case series shows that patients who responded to immunosuppressive therapy were less severe than patients who did not respond in terms of NYHA functional class, cardiac index, and PVR index. These results may suggest that these patients were at an earlier phase of the disease. However, the mean delay between PAH diagnosis and initiation of immunosuppressive therapy, and the mean time between diagnosis of connective tissue diseases and PAH were identical in responders and nonresponders to immunosuppressive therapy (20 ± 43 months vs 14 ± 24 months and 77 ± 65 months vs 73 ± 95 months, respectively).

Our study has several limitations. First, this is a monocentric retrospective study analyzing a selected population of patients referred to a PAH referral center. In this population, a majority of patients were already treated with either immunosuppressants or PAH-specific therapy prior to referral and thus could not receive first-line immunosuppressive therapy. In addition, it is likely that possible responders to immunosuppressive therapy would not be referred to our center if they had a complete and excellent response to these agents. Second, the variable clinical course of PAH and the fact that some patients might remit spontaneously without treatment have been described previously40; thus, we cannot exclude the possibility of a spontaneous remission that occurred coincidentally with immunosuppressive therapy, at least in some patients. Nevertheless, there was a close temporal relationship between treatment and disease remission. Last, most patients described in our present series only had a partial response to immunosuppressive therapy and may require second-line PAH-specific therapy. This is the case of one of eight patients at this time. Indeed, complete reversibility of PAH is exceptional even in the setting of SLE-associated PAH responding to immunosuppressive therapy. Long-term follow-up pleads in favor of a persistent significant pulmonary vascular disease in most cases, confirming that there is still no cure for most if not all PAH patients.

In conclusion, in the absence of a large placebo-controlled study, it is difficult to provide guidelines on immunosuppressive therapy in the management of PAH associated with connective tissue diseases. Our study shows that some patients with PAH associated with SLE or MCTD might respond to a treatment combining glucocorticosteroids and cyclophosphamide. In addition, concordant data suggest that patients with scleroderma-associated PAH should not receive such treatments. Strict clinical and hemodynamic criteria are necessary to evaluate the efficacy of such treatments. In our clinical practice, we recommend that patients with SLE- or MCTD-associated PAH in NYHA functional class I or II should receive first-line glucocorticosteroids and cyclophosphamide for 3 to 6 months. In the absence of a clear clinical and hemodynamic improvement after 3 to 6 months of therapy, the immunosuppressive therapy should be stopped because of possible life-threatening adverse events including infections that occurred in two patients in this series, as well as in another report.13 Patients presenting in NYHA functional class III or IV may be treated with a combination of immunosuppressants and PAH-specific therapy. However, it remains to be demonstrated whether combining immunosuppressive therapy with PAH-specific therapy at diagnosis could provide additional benefits to a subset of PAH patients.

Footnotes

Abbreviations: MCTD = mixed connective tissue disease; mPAP = mean pulmonary artery pressure; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PVR = pulmonary vascular resistance; SLE = systemic lupus erythematosus; SvO2 = mixed venous oxygen saturation

This study was supported by grants from Université Paris-Sud, Legs Poix, and Institut des Maladies Rares.

Received for publication September 5, 2005. Accepted for publication December 23, 2005.

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