Sjögren syndrome is a systemic autoimmune disease that mainly affects the exocrine glands resulting in dryness of the mouth and eyes11,28,67. This disease is fairly common, affecting 0.2%-1.4% of the population, principally women18. Sjögren syndrome can be either primary (pSS) or secondary to another connective tissue disease, mainly systemic lupus erythematosus and rheumatoid arthritis. pSS is characterized by a mononuclear infiltration and destruction of salivary and lacrimal glands69. Similar mononuclear infiltrates invading visceral organs or vasculitic lesions can also cause systemic and extraglandular manifestations19,47,53. In a cohort of 400 patients with pSS28, articular involvement was the most frequent extraglandular manifestation, occurring in 37% of patients, followed by Raynaud phenomenon (16%), autoimmune thyroiditis (15%), cutaneous vasculitis (12%), and pulmonary involvement (9%). In this study, as in others67, pulmonary involvement consisted mainly of various form of small airways and interstitial lung diseases54,56. None of these large cohort studies mentioned the presence of pulmonary arterial hypertension (PAH). PAH is a disease of the small pulmonary arteries characterized by vascular proliferation and remodeling, resulting in a progressive increase in pulmonary vascular resistance, and, ultimately, right ventricular failure and death58. By definition, a diagnosis of PAH requires right-heart catheterization, demonstrating an elevated mean pulmonary artery pressure (mPAP) >25 mm Hg at rest or >30 mm Hg during exercise with a normal pulmonary capillary wedge pressure (<15 mm Hg), excluding significant left heart disease with postcapillary pulmonary hypertension45,58. Right-heart catheterization represents the gold standard for PAH diagnosis45,58. As demonstrated in systemic sclerosis, cardiac echo-Doppler is an interesting PAH screening method, but it cannot be accepted as a validated tool to confirm a diagnosis of PAH33. It is noteworthy that a better understanding of PAH pathogenesis has led to novel medical strategies, which in turn have improved the prognosis of idiopathic PAH as well as PAH associated with comorbid conditions such as connective tissue diseases38,40,61.
The association of PAH and pSS is rare; to our knowledge there are only 32 published case reports2,3,5,9,10,14,15,24,25,27,29,31,32,34,36,43,44,48,49,51,52,60,62,68,72,74,75. This contrasts with the much higher frequency of PAH in some other autoimmune connective tissue diseases, such as systemic sclerosis, mixed connective tissue diseases, and systemic lupus erythematosus39,71. Ten of the 32 cases are in Japanese3,25,32,34,44,48,52,60,72,74, and 3 are in Spanish2,31,75, without sufficient data in the abstracts to be fully analyzed. Among the 19 cases in English5,9,10,14,15,24,27,36,43,49,51,62,68, hemodynamic parameters obtained by means of right-heart catheterization are available in only 8 cases5,9,27,36,43,49,62,68.
In the current report we describe 9 new fully characterized PAH cases in patients with pSS. We present PAH and pSS characteristics, complete hemodynamic evaluation, medical management, and outcome. To our knowledge, this represents the first reported cohort of pSS-associated PAH. We also review the 19 cases of PAH in patients with pSS reported in the English literature.
PATIENTS AND METHODS
We retrospectively studied all patients with pSS referred to our institution between January 1995 and January 2007 for PAH management (n = 9). All patients fulfilled the 2002 revised criteria for pSS proposed by the American-European Consensus Group77.
Right-heart catheterization was performed in all patients using standard techniques65. There were no patients who presented between 1995 and 2007 for suspicion of PAH (for example, by echocardiography) who did not undergo right-heart catheterization. Right atrial pressure, mPAP, pulmonary capillary wedge pressure, cardiac index, mixed venous oxygen saturation (SvO2), and total pulmonary resistance (TPR) were measured at rest, and, if necessary, during exercise. PAH was defined by mPAP >25 mm Hg at rest or >30 mm Hg during exercise with mean pulmonary capillary wedge pressure <15 mm Hg during right-heart catheterization45,58. Acute vasoreactivity was tested by inhaled nitric oxide (10 ppm) for 10 minutes. An acute response was defined as a ≥10 mm Hg decrease in mPAP to <40 mm Hg with a preserved cardiac output66.
History of appetite suppressant intake, thyroid hormone level, and human immunodeficiency virus (HIV) serology were collected to rule out other causes of PAH. Cardiac echo-Doppler excluded congenital heart diseases. Abdominal ultrasonography was performed to diagnose portal hypertension, and if necessary a liver biopsy was performed. A ventilation/perfusion lung scan, a spiral computed tomography of the chest, and a pulmonary angiography if necessary were performed to exclude chronic thromboembolic pulmonary hypertension. Pulmonary function tests (PFT) (vital capacity [VC], forced expiratory volume in 1 second [FEV1], and total lung capacity [TLC] >70% of predicted values) excluded significant obstructive or restrictive patterns.
Dilatation of the right atrium and/or ventricle, right ventricle hypertrophy, left atrium dilatation, left ventricle ejection fraction impairment, and pericardial effusion were recorded. All patients were screened for possible congenital heart disease.
PAH Clinical Findings
PAH clinical assessment included New York Heart Association (NYHA) functional class and evaluation of exercise capacity with the non-encouraged 6-minute walk test according to the American Thoracic Society recommendations6 including the Borg dyspnea index12. Age at diagnosis of PAH, age at first symptom of PAH, and presence or history of lipothymia/syncope and right heart failure were recorded.
Treatment and Follow-Up of PAH
We collected the details of medical management including standard PAH therapy (endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, or prostanoids), calcium channel blockers, and/or immunosuppressive therapy and date of the start of treatments. Right-heart catheterization, NYHA functional class, and 6-minute walk test were performed 4 months after each change in therapy or at the end of immunosuppressive therapy (for instance, after the last intravenous [IV] pulse of cyclophosphamide). Afterward, right-heart catheterization, NYHA functional class, and 6-minute walk test were performed yearly. Responders to standard PAH therapy, calcium channel blockers, and/or immunosuppressive therapy were defined as patients with improvement of at least 1 NYHA functional class and hemodynamic improvement compared to baseline data, as described previously61.
Diagnosis of pSS
All patients with secondary Sjögren syndrome were excluded (for example, patients with systemic lupus erythematosus or rheumatoid arthritis). Clinical symptoms of sicca complex, namely subjective xerostomia, subjective xerophthalmia, or recurrent salivary enlargement, were evaluated. Ocular involvement was documented by Schirmer test (abnormal if <5 mm of the filter paper was moistened in 5 min) or Rose Bengal score (keratoconjunctivitis if score was >4 according to the Van Bijsterveld scoring system76). Xerostomia was confirmed by abnormal salivary scintigraphy or unstimulated salivary flow. Biopsy samples of the minor salivary glands were positive if the lymphocytic focus score was equal to or greater than an aggregate of 50 mononuclear cells in 4 mm2 of glandular tissue or if there was an abnormal Chisholm score (higher than 2)16. Screening for autoantibodies to Ro/SSA and La/SSB was performed by ELISA. Screening for other connective tissue diseases was performed in order to exclude all connective tissue diseases except pSS. Exclusion criteria were the following: past head and neck radiation treatment, hepatitis C infection, acquired immunodeficiency disease, preexisting lymphoma, sarcoidosis, graft-versus-host disease, use of anticholinergic drugs or other drugs including sicca symptoms (within a period of <4 times the half-life of the drug). All patients fulfilled at least 4 of the 6 consensus criteria, including minor salivary gland histopathology abnormalities or anti-Ro/SSA and anti-La/SSB antibodies, or 3 of the 4 objective criteria77.
Clinical Findings of pSS
Demographic characteristics and the following data were collected: age at diagnosis of pSS and glandular and extraglandular manifestations (Raynaud phenomenon; articular, muscular, skin, lung, and neurologic involvement; autoimmune thyroiditis; lymphoproliferative disease) at PAH diagnosis. The clinical manifestations were defined as suggested by Garcia-Carrasco et al28, as follows:
Raynaud phenomenon: intermittent attacks of digital pallor followed by cyanosis and/or rubor of the fingers, toes, ears, nose, tongue, induced by exposure to cold, stress, or both, in the absence of any other associated disease or anatomical abnormality.
Articular involvement: arthralgia and/or nonerosive arthritis characterized by tenderness, swelling, or effusion involving 2 or more peripheral joints. We excluded patients with osteoarthritis, nonspecific painful processes, and chronic fatigue.
Muscular involvement: biopsy-proven myositis.
Cutaneous vasculitis demonstrated by cutaneous purpura, rash, and/or cutaneous necrosis.
Peripheral neuropathy: paresthesia, numbness, and/or motor defects of the lower/upper extremities confirmed by electromyography.
Lung involvement: interstitial lung disease on high-resolution computed tomography (HRCT) of the chest.
Autoimmune thyroiditis: altered thyroid function with positive antithyroidal autoantibodies.
PFT were performed following standard protocols. Data on FEV1, slow inspiratory VC, the FEV1/VC ratio, TLC (calculated by adding residual volume to VC), diffusing capacity for carbon monoxide (DLCO), and DLCO adjusted for alveolar volume (KCO) were collected. The predictive values for each subject, based on sex, age, and height, were obtained from standard tables55. For each PFT parameter, results were expressed as percentage of predicted value. PaO2 (mm Hg), SaO2 (%), and PaCO2 (mm Hg) were determined by arterial blood gases.
Immunologic tests included antinuclear antibodies by indirect immunofluorescence using HEP2 cell line as substrate as well as screening for anti-Ro/SS-A, anti-La/SS-B, and anti-RNP (by ELISA) and for anti-dsDNA (by Farr assay) antibodies. Presence and/or levels of anticardiolipin antibodies (ELISA), lupus anticoagulant (coagulation-based test), total complement activity (CH50), total serum gammaglobulin, cryoglobulinemia (measured after centrifugation), antithyroid peroxidase autoantibodies (ELISA), and rheumatoid factor (latex fixation and Waaler-Rose tests) were recorded. Hepatitis B and C serology was performed in all patients.
For the literature review, we performed a MEDLINE (National Library of Medicine, Bethesda, MD) search for PAH in patients with pSS in all articles published in the literature until March 2007. We kept only papers published in the English language. Using data available in these articles, we attempted to record the same data as in our patients. Items searched for and found to be negative were noted as 0; items not reported were noted as not known (NK).
Statistical analysis was performed using Statistica software (Statsoft, Tulsa, OK). Results were expressed as frequencies and percentages for binary and categorical variables and as the mean ± standard deviation (range) for continuous data. We report individual data for our patients and, if available, individual data for the cases reported. Descriptive statistical analysis was performed with data of our patients and also with compiled available data found by the literature review. For comparisons of frequencies of glandular, extraglandular, and immunologic manifestations, we used the 400 patients with pSS described by Garcia-Carrasco et al28 as a control group, except for frequency of hypergammaglobulinemia, which was compared to the cohort of patients reported by Skopouli et al67. The chi-square test was applied to analyze qualitative differences with the Yates correction if necessary. For the analysis of overall survival by the Kaplan-Meier method, the date of diagnosis of PAH was the starting point, and the cutoff date was January 1, 2007. Patients were censored as of the date of the last news.
Our cohort consisted of 9 women with a mean age at PAH diagnosis of 48.9 ± 12.9 years (range, 23-64 yr) (Table 1). Clinical presentation of PAH was severe in most cases: NYHA functional class was IV in 1 patient, III in 7 patients, and II in 1 patient. Mean 6-minute walk distance was low (346 ± 112 m; range, 63-450 m).
At diagnosis of PAH, right-heart catheterization was performed in all 9 patients. In Patient 7, mPAP and pulmonary capillary wedge pressure at rest was 24 mm Hg and 6 mm Hg, respectively, and rose to 33 mm Hg and 8 mm Hg during exercise, respectively. We concluded that this patient had precapillary PAH during exercise. Overall, PAH was severe with a mean mPAP of 47 ± 10 mm Hg (range, 24-57 mm Hg), mean cardiac index of 2.84 ± 0.73 Lmin−1m−2 (range, 1.36-3.88 Lmin−1m−2), and mean TPR of 11.2 ± 5.7 mm HgL−1min (range, 4-25 mm HgL−1min) (Table 2). Acute vasoreactivity testing using inhalation of nitric oxide was performed in all patients, but none was a responder as defined above66.
No PAH associated with history of appetite suppressant intake or HIV infection was found. No thyroid dysfunction was found. A ventilation/perfusion lung scan was performed in all 9 patients and yielded a normal result. Two patients had portal hypertension (Patients 8, 9). Liver biopsy revealed that Patient 8 had nodular regenerative hyperplasia and Patient 9 had liver cirrhosis. No cause of cirrhosis, especially primary biliary cirrhosis, was found despite a thorough examination in Patient 9.
Among the 9 patients, treatment included standard PAH therapy alone in 5 cases: bosentan, n = 3 (Patients 3, 4, 8); IV epoprostenol, n = 1 (Patient 5); sildenafil, n = 1 (Patient 9); or a combination of standard PAH therapy and immunosuppressants in 3 subjects: standard PAH therapy with subsequent addition of immunosuppressants in Patient 1, and immunosuppressants followed by standard PAH therapy in Patients 2 and 6. Patient 7 remained free of standard PAH therapy and immunosuppressants because of mild exercise PAH. All patients except Patient 7 also received diuretics and oral anticoagulant. Response to standard PAH therapy is detailed in Table 3, and response to immunosuppressive therapy in Table 4.
First, among the 6 patients treated with first-line standard PAH therapy, Patients 1 (IV epoprostenol), 4 (bosentan), and 9 (sildenafil) responded at the 3-4 month clinical and hemodynamic evaluation using the criteria of response defined above. At the 1-year evaluation, Patient 4 was still a responder whereas Patient 1 had deteriorated and subsequently died from PAH despite the addition of immunosuppressant (cyclophosphamide). Patient 9 had not undergone the 1-year evaluation yet. Patient 5 had a slight hemodynamic improvement with IV epoprostenol but remained very severe and died from PAH. Patient 3 (bosentan) was not improved. Patient 8 had not been re-evaluated yet at the end of the study.
Second, we studied the effects of immunosuppressive therapy (see Table 4). There was 1 hemodynamic improvement (Patient 2) which was maintained by adding calcium channel blocker, and 1 stabilization (Patient 6) justifying a start of bosentan with a clinical and hemodynamic response. As mentioned, adding immunosuppressants was not successful in Patient 1 after the failure of epoprostenol.
Two patients died from PAH, 21 (Patient 5) and 40 months (Patient 1) after diagnosis of PAH. Estimated survival rates for the 9 patients in the current study were 100% and 83% at 1 and 3 years, respectively (Figure 1).
Demographic and Glandular Features
Diagnosis of pSS preceded diagnosis of PAH in 4 patients. The two diagnoses were made concomitantly in 5 patients. No patients had either clinical manifestations suggesting the presence of systemic sclerosis or systemic sclerosis-associated antinuclear autoantibodies (anticentromere or anti-Scl 70 autoantibodies). Nailfold capillaroscopy was performed in all our patients presenting with Raynaud phenomenon and was normal. To allow comparisons with a large cohort of patients with pSS, we have included in Table 5 demographic and glandular features of 400 patients with pSS reported by Garcia-Carrasco et al28.
Raynaud phenomenon (6/9 patients), cutaneous vasculitis (3/9 patients), and interstitial lung disease (4/9 patients) were frequent in our 9 patients (Table 6). Mean DLCO and mean KCO were low (65% ± 24%; range, 22%-91%; and 69% ± 11%; range, 54%-86%, respectively), and PFT disclosed a restrictive ventilatory defect in 2 patients (Patients 6, 7) (Table 7).
All our patients had antinuclear antibodies with a high frequency of anti-Ro/SSA antibodies (7/9 patients) (Table 8). Hypergammaglobulinemia was also frequent (5/9 patients), with a mean total gammaglobulin level of 23 ± 15 g/L.
DISCUSSION AND LITERATURE REVIEW
We report what is, to our knowledge, the first cohort of pSS patients with a robust diagnosis of PAH based on the gold-standard definition (right-heart catheterization)45,58. Our present cohort comprises 9 patients, and we reviewed 19 additional cases reported in the literature5,9,10,14,15,24,27,36,43,49,51,62,68 for a total of 28 patients. All 9 of our patients were evaluated by right-heart catheterization, compared with only 8 of 19 patients reported in the literature5,9,27,36,43,49,62,68. Therefore, PAH is ascertained in 17 of 28 patients of this cohort. The importance of right-heart catheterization for diagnosis and prognosis evaluation of PAH must be emphasized26,40. Indeed, right-heart catheterization is the only tool that can reliably measure mPAP, pulmonary capillary wedge pressure, and cardiac output, and therefore pulmonary vascular resistance. The low number of cases reported suggests that PAH is a rare complication of pSS, although the current study was not designed to determine the frequency of PAH in pSS. This contrasts with the relatively high frequency of both pSS in the general population18 and PAH in other connective tissue diseases, especially in patients with systemic sclerosis (PAH prevalence is estimated between 8% and 16% in this disease)20,33,39,42 or mixed connective tissue disease71.
Clinical Findings and Hemodynamics
The whole cohort comprised 27 women and 1 man with a mean age at diagnosis of PAH of 50 ± 11 years (range, 23-68 yr). Compared to the study by Garcia-Carrasco et al28, the proportion of female patients was similar in pSS with or without associated PAH (27/28 pSS with PAH, 96% vs. 373/400 pSS without PAH, 93%; p = NS). It is noteworthy that the first symptom of PAH (exertional dyspnea in all 16 available cases except syncope in Patient 16) preceded the diagnosis of PAH by 34.4 ± 50.3 months (range, 2-204 mo). The delay between the first symptom and the diagnosis of PAH was greater than 1 year in 11 of 16 (69%) patients. This late diagnosis is probably due to the rarity of PAH in pSS, where dyspnea is most often explained by other causes such as interstitial lung disease. Moreover, pulmonary hypertension screening is not proposed in pSS in current guidelines, which contrasts to systemic sclerosis where the frequency and severity of PAH require yearly noninvasive screening30. Although rare, PAH should be searched for promptly in patients with pSS with unexplained dyspnea, in order to establish the diagnosis sooner, with presumably a better prognosis39. Of note, 8/18 patients had DLCO >60% and 5 patients among these 8 had normal DLCO. Therefore, DLCO >60% should not lead to exclude PAH in pSS (see Table 7).
Clinical presentation of pSS-associated PAH was severe, with more than 80% of patients presenting with NYHA functional class III or IV and a low mean 6-minute walk distance of 329 ± 109 m (range, 63-450 m) (see Table 1). Nearly half of patients had evidence of right heart failure. All our patients (Table 9) and 14/19 patients in the literature review had echocardiography at the time of PAH diagnosis. Among patients with available data, all but 1 (Patient 8) already had dilatation of the right heart. Pericardial effusion, known to be of bad prognosis in idiopathic PAH26, was present in 4 of the 11 patients with this data available. When performed (n = 17 patients), hemodynamics revealed moderate to severe PAH: mPAP: 44 ± 11 mm Hg (range, 24-60 mm Hg); cardiac index: 2.91 ± 0.72 Lmin−1m−2 (range, 1.36-3.88 Lmin−1m−2); TPR: 11.0 ± 5.2 mm HgL−1min (range, 4-25 mm HgL−1min). Five patients (Patients 1, 2, 4, 5, 13) already had a low cardiac index at PAH diagnosis. The severity of pSS-associated PAH is probably explained in part by the late diagnosis. Among the 10 patients (Patients 1-10) in whom acute vasoreactivity testing using inhalation of nitric oxide was performed, none was a responder as defined above66. Alprostadil (prostaglandin E1 30 ng/kg per min) was used to test vasoreactivity in Patient 27: mPAP fell from 43 mm Hg to 31 mm Hg with a preserved cardiac output. However, the meaning of this acute response remains uncertain, as the testing was not performed with any of the validated short-acting agents recommended in the guidelines (inhaled nitric oxide, IV adenosine, prostacyclin)40.
None of the 9 patients in the current study had a lung biopsy. Histologic examination was available in 6 patients in the whole cohort: 5 postmortem (Patients 11, 12, 15, 19, 28) and 1 lung biopsy (Patient 27) (Table 10). Intimal and medial hypertrophy was common, whereas vasculitis or inflammatory infiltrates were not described. When available, immunofluorescence found deposits of immunoglobulins and complement in the pulmonary arteriolar walls in 2 of 3 patients.
The point to discuss is whether PAH is truly a complication of pSS or if the association could be fortuitous in patients displaying idiopathic PAH or other causes of pulmonary hypertension. Many data favor a true link between PAH and pSS. First, we show that PAH most often occurs in pSS patients with laboratory markers of intense B-cell activation, such as a high frequency of antinuclear antibodies and hypergammaglobulinemia. Second, immunofluorescence studies reveal deposits immunoglobulins and complement in the pulmonary arteriolar walls of patients with pSS-associated PAH. Third, PAH in these pSS patients sometimes responds favorably to immunosuppressive therapy alone, which is not the case in idiopathic PAH. Nevertheless, a fortuitous association, especially in case of pSS without systemic manifestations or immunologic abnormalities, cannot be excluded.
In the current pulmonary hypertension classification64, 5 main categories are identified, corresponding to patients with similar pathologic, pathophysiologic, and therapeutic characteristics. Pulmonary hypertension associated with connective tissue diseases (including pSS) belongs to the first category, namely "pulmonary arterial hypertension." The other conditions reported in this category are idiopathic and familial PAH as well as PAH associated with HIV infection, portal hypertension, congenital systemic to pulmonary shunts, and exposure to drugs and toxins64. Twenty-two of the 28 patients in the whole cohort reported here can be classified in the PAH associated with connective tissue diseases group.
Two patients had portal hypertension (Patients 8, 9). Of note, 2 or more risk factors can be identified in a proportion of PAH patients, as demonstrated by the recent French Registry39, where 4% of the cases had 2 risk factors. No PAH associated with a history for appetite suppressant intake or HIV infection was found. Ventilation/perfusion lung scanning was performed in 16 patients (included our 9 patients) and yielded a normal result in 14 patients. In Patient 13, perfusion lung scanning disclosed nonsegmental patchy uptake throughout the lungs, suggesting a low probability of pulmonary embolism. However, pulmonary angiography was not performed to exclude chronic thromboembolic pulmonary hypertension. Patient 15 had a diagnosis of chronic thromboembolic pulmonary hypertension, on the basis of positive lupus anticoagulant, protein C deficiency, and bilateral multiple perfusion defects. Again, pulmonary angiography was not performed to confirm this diagnosis. Nevertheless, these 2 patients could be classified in the pulmonary hypertension due to chronic thrombotic and/or embolic disease group.
The 2 remaining patients had pulmonary hypertension associated with respiratory diseases and/or hypoxia in the context of significant pSS-related interstitial lung disease. In 1 case (Patient 6), the value of mPAP was very high and out of proportion to the degree of fibrosis, suggesting that significant pulmonary vascular involvement was associated with the chronic respiratory disease. By contrast, mild pulmonary hypertension was diagnosed in the other patient (Patient 7) and could be due only to the interstitial lung disease without out-of-proportion vascular damage. No case was reported of pulmonary veno-occlusive disease in the context of pSS, whereas it seems to be a not-rare finding in systemic sclerosis-associated PAH21,57. Overall, these results suggest that other causes of pulmonary hypertension, especially chronic thromboembolic disease, chronic respiratory disease, and portal hypertension, should be searched for even if pSS is diagnosed. This is of great importance since pulmonary endarterectomy is recommended as the treatment of choice for eligible patients with chronic thromboembolic pulmonary hypertension and should not be missed59. If chronic thromboembolic pulmonary hypertension is diagnosed, a search for antiphospholipid antibodies should be performed.
Among the 19 case reports in the literature, 2 patients (Patients 14, 19) were treated with calcium channel blockers alone. Six patients were treated with immunosuppressive therapy either alone (Patients 18, 20), or preceded by standard PAH therapy (Patients 13, 27) or calcium channel blocker (Patient 16) or followed by standard PAH therapy, which was added in Patient 17. Three patients (Patients 11, 12, 28) remained free of any treatment, and 2 patients were treated with conventional therapy without standard PAH therapy or immunosuppressants (Patient 10 was treated with diuretics and oral anticoagulant and Patient 15 was treated with diuretics, aspirin, oral anticoagulant, digoxin, ticlopidine, and nasal oxygen). In 6 patients (Patients 21-26), no data on treatment were available.
Thus, treatment was heterogeneous in the whole 28-patient cohort, as were the evaluation criteria used to assess treatment efficacy. To investigate response to therapy, we first studied patients who had received standard PAH therapy or calcium channel blockers as first-line treatment (n = 11; Patients 1-9, 13, 14, 16, 19, 27). Three patients were treated with calcium channel blockers (Patients 14, 16, 19), and 8 with standard PAH therapy: bosentan, n = 3 (Patients 3, 4, 8), IV epoprostenol, n = 2 (Patients 1, 5), oral prostacyclin, n = 1 (Patient 27), and sildenafil, n = 1 (Patient 9). For Patient 13, the type of standard PAH therapy was not described. Among the 3 patients who were treated with calcium channel blockers, there was 1 short-term failure (Patient 19), 1 probable stabilization with subsequent degradation and death (Patient 14), and 1 probable short-term response (Patient 16). However, in this last case, the cardiac index was not mentioned, precluding any firm affirmation of hemodynamic improvement, and the long-term effect of calcium channel blocker alone was not assessable because immunosuppressive therapy was added early. It must be underlined that results of acute vasoreactivity testing are not available in these 3 patients. It must be emphasized that current PAH guidelines strongly recommend that calcium channel blockers be used only if acute vasoreactivity testing-mainly by using inhalation of nitric oxide-is positive, which usually concerns a minority of patients with connective tissue disease39,66.
Besides calcium channel blockers, treatment options in PAH have progressed strikingly, with molecules that not only act as potent vasodilators but also have antiproliferative properties on smooth-muscle cells of the pulmonary artery, such as prostacyclin derivatives (epoprostenol, iloprost, beraprost, treprostinil), and more recently endothelin receptor antagonists (bosentan, ambrisentan, sitaxsentan) or oral phosphodiesterase type 5 inhibitors (sildenafil, tadalafil)40. We did not find reports of these PAH treatments used as first-line therapy in pSS-associated PAH in the literature, so we believe the cases reported here are the first reported cases. Indeed, Chen et al15 treated 1 patient with bosentan but as a second-line approach after a relapse of PAH previously treated with immunosuppressants. In this latter patient, bosentan improved dyspnea, 6-minute walk distance, and right ventricular systolic pressure. Patient 27 was treated with first-line oral prostacyclin alone, which was considered a failure, but objective data were not clearly described. Among the 8 patients treated with first-line standard PAH therapy, 3 (1 with bosentan, 1 with sildenafil, and 1 with IV epoprostenol) had clinical and hemodynamic improvement at the first evaluation performed 3-4 months after initiation of the treatment; 1 patient had a slight hemodynamic improvement with IV epoprostenol but remained severe and died from PAH; and 2 patients had short-term failures (1 treated with bosentan and 1 with oral prostacyclin). Overall, these results suggest that standard PAH therapies, like endothelin receptor antagonists, type 5 phosphodiesterase inhibitors, or epoprostenol, can be efficient in pSS-associated PAH but that short-term or long-term treatment failure is possible and should be closely monitored.
Second, we studied the effects of immunosuppressive therapy in Patients 1, 2, 6, 13, 16-18, 20, and 27. Three patients were initially treated with first-line IV cyclophosphamide (and corticosteroids) alone without standard PAH therapy (Patients 2, 6, 17). There was 1 hemodynamic improvement (Patient 2), which was maintained by adding calcium channel blocker; 1 clinical improvement with decrease of right ventricular systolic pressure on echocardiography (Patient 17), which was maintained during 5 years before bosentan was started (with a clinical response and a decrease in right ventricular systolic pressure assessed by echocardiography); and 1 stabilization (Patient 6) justifying a start of bosentan with a clinical and hemodynamic response. One patient was treated with oral azathioprine (and corticosteroids) without standard PAH therapy as first-line therapy (Patient 18), leading to a clinical improvement and decrease of right ventricular systolic pressure, however with subsequent unexpected sudden death. Patient 20 was treated with oral corticosteroids without standard PAH therapy as first-line therapy and had a clear clinical and hemodynamic improvement at the 6-month evaluation. Four patients were treated with immunosuppressive therapy after failure or insufficient effect of standard PAH therapy or calcium channel blocker used as first-line therapy (Patients 1, 13, 16, 27). Adding immunosuppressants was not successful in 2 patients (Patients 1, 13) but led to an improvement in 2 patients (Patients 16, 27). Of note, Patients 1 and 13 had severe PAH before the start of immunosuppressive therapy with a low cardiac output.
Many data favor the use of immunosuppressive therapy in connective tissue disease-associated PAH22,61. It is widely accepted that immune or inflammatory mechanisms could play a significant role in PAH genesis or progression, especially in patients with connective tissue diseases22,46. IgG and complement have been identified in the pulmonary vessel walls from those patients4,80 and also in some patients with pSS-associated PAH, as shown in Table 10. Inflammatory cell infiltrates composed of macrophages and lymphocytes have been detected in plexiform lesions from patients with connective tissue disease-associated PAH17,22,23,73,78. However, it must be emphasized that none of the patients with pSS-associated PAH who underwent autopsy or lung biopsy had such inflammatory cell infiltrates or vasculitis. These patients had rather intimal proliferation, plexiform lesions, and medial hypertrophy, which seem very similar to the histopathologic changes found in idiopathic PAH38. Overexpression of growth factors and chemokines, such as platelet-derived growth-factor A and B37, RANTES/CCL5, and fractalkine/CX3CL1, has been demonstrated in diseased pulmonary arteries of patients displaying severe PAH8,23. Another argument is the higher frequency of immunologic abnormalities in these patients compared with patients with pSS and no evidence of PAH. However, in patients with pSS-associated PAH, effects of immunosuppressive therapy are difficult to analyze because of the heterogeneity of treatments and response criteria. Moreover, it must be emphasized that failure of immunosuppressive therapy is probably underreported in the literature, and therefore underestimated. Among patients treated with first-line immunosuppressive therapy without standard PAH therapy, 4 improved and 1 stabilized. However, during follow-up (available in 4 patients), 1 patient died from PAH, and standard PAH therapy was started in remaining 3 patients with a good clinical and hemodynamic response. These results suggest that immunosuppressive therapy could improve, probably transiently, clinical and hemodynamic status in some patients with pSS-associated PAH. However, the data are both retrospective and too weak at this time. Only prospective studies will be able to answer this question with certainty, which will be difficult considering the rare combination of pSS and PAH.
Finally, we studied the outcome of patients with no treatment at all (Patients 7, 11, 12, 28) or with conventional therapy alone without standard PAH therapy, calcium channel blocker, or immunosuppressant (Patients 10, 15). For patients with no treatment at all, 2 died of PAH (Patients 11, 28) 4 years and 2 years, respectively, after the diagnosis of PAH. For Patient 12, the diagnosis of PAH was made on autopsy. Patient 7, who had mild PAH during exercise, is still alive 6 months after the diagnosis of PAH. Among patients with conventional therapy alone, Patient 10 was treated with oral warfarin and furosemide with initial improvement of exertional dyspnea assessed by walk test (but no further information is available). Patient 15 was treated with diuretics, aspirin, oral anticoagulant, digoxin, ticlopidine, and nasal oxygen, with initial relief of symptoms for about 4 months, but died from PAH thereafter.
Therefore standard PAH therapy and in some cases immunosuppressants can improve pSS-associated PAH, although the best treatment strategy remains to be defined. Recently, we have shown61 that patients with systemic lupus erythematosus- and mixed connective tissue disease-associated PAH who were probably responders to an immunosuppressive therapy alone, had less severe PAH at baseline when compared with patients who were not responders. Therefore, we recommended that patients with systemic lupus erythematosus- or mixed connective tissue disease-associated PAH and in functional class I or II should receive first-line immunosuppressive therapy alone with a clinical and hemodynamic assessment after 3-6 months and subsequent use of standard PAH therapy as add-on therapy in case of failure. Patients with class III or IV may be treated with a combination of immunosuppressant and standard PAH therapy with a strict clinical and hemodynamic follow-up. All patients should receive conventional therapy: oral anticoagulant and, as needed, diuretics and nasal oxygen7,26. We could cautiously suggest a similar strategy in pSS-associated PAH and propose an algorithm of treatment, although with precaution because 1) its validity is not ascertained; with only retrospective and too weak data, it deserves further study, and 2) the improvement of some patients with immunosuppressive therapy could be overestimated in the literature by an underreporting of negative cases (Figure 2). The choice of first-line immunosuppressant is undetermined but should include corticosteroids with or without an immunosuppressive therapy (cyclophosphamide or azathioprine). However, the use of high-dose cyclophosphamide raises some issues because of the risk of severe adverse events and ovarian failure. There are increasing data on the use of alternative and less toxic (especially regarding ovarian failure) immunosuppressive treatment regimens in severe organ involvement in connective tissue diseases. For example, rituximab, a monoclonal anti-CD 20 antibody, is presented as a possible future first-line therapy in some severe systemic manifestations of connective tissue disease including pSS63. As B-cells activation and antibodies formation are thought to play a role in the pathophysiology of pSS-associated PAH, anti-CD 20 could be a therapeutic option in the future.
Information on survival was available for all but 1 of the 28 patients in the whole cohort (Patient 21). Fifteen of 27 patients were alive at the last evaluation (Patients 2-4, 6-10, 16, 17, 20, 22-24, 27). Twelve patients died, 11 from PAH (Patients 1, 5, 11-15, 18, 19, 26, 28) and 1 from pneumonia (Patient 25). Data on date of diagnosis of PAH and date of last news are available in 17 patients (Patients 1-9, 11, 14-20) who were used for the analysis of overall survival. Estimated survival rates were 73% and 66% at 1 and 3 years, respectively, in the whole cohort of patients for whom survival could be studied (see Figure 1). Survival was therefore poor, reinforcing the need for early diagnosis, active treatment (immunosuppressants and/or standard PAH therapy) and strict clinical and hemodynamic follow-up.
Glandular and Extraglandular Features
Diagnosis of pSS preceded diagnosis of PAH in 15 patients (see Tables 5-7). The 2 diagnoses were made concomitantly in 11 patients. The diagnosis of pSS was made after the diagnosis of PAH only in Patient 13 (delay was 10 mo). When all parameters were available, 18/18 (100%) patients fulfilled the 2002 revised European criteria for pSS. No patient had either clinical manifestations suggesting the presence of systemic sclerosis or systemic sclerosis-associated antinuclear autoantibodies (anticentromere or anti-Scl 70 autoantibodies). The nailfold capillaroscopy was performed in all our patients presenting with Raynaud phenomenon and was normal. In the same way, none of the patients fulfilled the international criteria for mixed connective tissue disease1. Glandular manifestations of patients with pSS-associated PAH were similar to those of patients with pSS and no PAH reported by Garcia-Carrasco et al28 except for a lower frequency of subjective xerophthalmia. However, this result has to be interpreted with caution: because some case reports did not mention the presence or absence of subjective xerophthalmia, it may have been underreported, which would explain this difference.
Patients in the current study with pSS-associated PAH had Raynaud phenomenon significantly more frequently compared with the cohort of patients with pSS but without PAH reported by Garcia-Carrasco et al28 (15 of 25, 60%, vs. 62 of 400, 16%; p < 0.0001), and, to a lesser extent, cutaneous vasculitis (5 of 13, 38%, vs. 47 of 400, 12%; p = 0.02). These findings reinforce the probable role of vasculopathy in the pathogenesis of PAH in these patients.
Interstitial lung disease was also more frequently found in the current cohort of patients with pSS-associated PAH compared with the cohort of Garcia-Carrasco et al28 (6 of 23, 26% vs. 37 of 400, 9%; p = 0.03). In the study by Gardiner et al29, interstitial lung disease was found in 8% of pSS patients. Six of the patients in the current cohort had evidence of interstitial lung disease on HRCT of the chest, and 14 had a normal HRCT (and 3 more patients had a normal chest X-ray). Among patients with interstitial lung disease, PFT were available for 4 patients and revealed a significant restrictive pattern in 2 patients (Patients 6, 7). No patient had an obstructive pattern. Concerning diffusing capacity, 13 patients had a decreased DLCO <80% of the predicted value, and 5 had a normal DLCO. Eight among the 18 available DLCO values were higher than 60%. Mean DLCO was low (63% ± 22% of the predicted value; range, 22%-105%). Nine patients had hypoxemia, and mean PaO2 was 9.9 ± 1.8 kPa (range, 6.7-12.3 kPa). Eleven patients had hypocapnia, 2 had normocapnia, and 1 had hypercapnia. Mean PaCO2 was low (4.6 ± 1.7 kPa; range, 3.2-10.1 kPa).
The explanation for this higher frequency of interstitial lung disease is unclear. The first hypothesis is that interstitial lung disease could play a role in the development of pulmonary hypertension, as previously discussed. Indeed, pulmonary hypertension can be a direct consequence of interstitial lung disease because of associated hypoxemia in case of extensive tissue destruction20. However, patients with pSS-associated PAH often had a very high mPAP compared to the degree of pulmonary lung function impairment, indicating that pulmonary hypertension was out of proportion and that a specific vasculopathy presumably played a major role in these cases. Indeed, mPAP in hypoxic pulmonary hypertension is usually moderately elevated with a normal or increased cardiac output, resulting in a modest elevation of pulmonary vascular resistance. For example, it is recognized that 1 of the main characteristics of pulmonary hypertension in chronic obstructive pulmonary disease patients is its mild-to-moderate degree, with a resting mPAP in a stable state of the disease usually ranging between 20 and 35 mm Hg79. However, some patients with hypoxic pulmonary hypertension develop a more severe pulmonary hypertension (mPAP > 40 mm Hg), which is "out of proportion" to the degree of lung function impairment13. These patients are probably important to identify because specific, antiproliferative, pulmonary hypertension treatment could represent a therapeutic option to improve their clinical status. The second hypothesis to explain a higher frequency of interstitial lung disease in patients with pSS-associated PAH is that both conditions share similar pathophysiologic pathways.
When compared to the cohort of Garcia-Carrasco et al28, patients with pSS-associated PAH had antinuclear, anti-Ro/SSA, and anti-RNP antibodies, as well as positive rheumatoid factor, significantly more frequently (see Table 8). Conversely, the frequency of anti-La/SSB antibodies was similar. The presence of hypergammaglobulinemia in pSS was not assessed by Garcia-Carrasco et al28. However, in the cohort of 261 patients with pSS reported by Skopouli et al67, hypergammaglobulinemia was present in 95 of 226 (42%) patients versus 19 of 24 (79%) patients with pSS-associated PAH (p = 0.001). The mean total gammaglobulin level was high in pSS-associated PAH (27 ± 12 g/L). These immunologic findings could suggest both an activation of B-cells and a role of autoantibodies like anti-RNP antibodies41 or other antibodies like anti-endothelial cells antibodies50,70 in the pathogenesis of pSS-associated PAH.
In conclusion, PAH is a rare but severe complication of pSS that should be searched for in case of unexplained dyspnea, lipothymia/syncope, or right heart failure by echocardiography and confirmed by right-heart catheterization. Patients with pSS-associated PAH have Raynaud phenomenon; cutaneous vasculitis; interstitial lung disease; antinuclear, anti-Ro/SSA, and anti-RNP antibodies; and hypergammaglobulinemia more frequently than pSS patients without PAH. This suggests a role for pulmonary vasculopathy and B-cell activation in the pathophysiology of this complication, probably explaining the efficacy of standard PAH therapy and immunosuppressants in some patients.
The authors gratefully acknowledge Pr Jean-Pierre Ducroix (Service de Médecine Interne, CHU Amiens), Pr Jean-Francois Besancenot (Service de Médecine Interne, CHU Dijon), Pr Marie-Françoise Avril (Service de Dermatologie, Hôpital Cochin, Paris), Dr Michel Hiltgen (Service de Cardiologie, CH Argenteuil), Pr Albert Hirsch (Service de Pneumologie, Hôpital Saint-Louis, Paris), Pr Olivier Fain (Service de Médecine Interne, Hôpital Jean-Verdier, Bondy), and Dr Arnold Witte (Service de Médecine Interne, CH Chartres) for referring patients.
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