The case history is described of a young woman who presented with primary pulmonary hypertension and non-specific inflammatory signs. The patient received prolonged immunosuppressive treatment with low dose methotrexate and prednisone without any vasodilator agent. After one year the pulmonary artery pressure fell from a mean value of 47 mm Hg to 30 mm Hg and there was a corresponding clinical response. This case suggests that, in patients with pulmonary hypertension of unknown origin, immunopathogenetic factors should be sought in order to consider the utility of immunosuppressive therapy.
- pulmonary hypertension
- transforming growth factor β
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Primary pulmonary hypertension (PPH) is a rare disease of unknown origin that should be suspected in any young patient who presents with unexplained effort dyspnoea and electrocardiographic signs of right ventricular hypertrophy in the apparent absence of any underlying cause.1 Pulmonary hypertension clinically and histologically similar to PPH has been described in association with connective tissue diseases and other immunological disorders, also in the absence of any parenchymal lung involvement.2Primary forms usually show a rapidly progressive course despite treatment, with a mean survival of 2.5 years.3
We describe a patient with PPH who, after treatment with immunosuppressive therapy, showed a clinical improvement.
A 25 year old woman was admitted in December 1994 because of the recent onset (less than six months) of rest dyspnoea (NYHA class III), cough, cyanosis, hypotension (80/60 mm Hg), tachycardia (120–130 bpm), and congestive heart failure. She had a five year history of recurrent mild temperature elevation, asthenia, myalgia, arthralgia, transient diffuse lymphoadenomegaly, neutrophil leukocytosis, and persistent elevation of acute phase reactants, despite anti-inflammatory therapy. Tests for antinuclear (ANA and ENA) and antiphospholipid antibodies, rheumatoid factor, ANCA and other autoantibodies, HIV and other infectious agents were always negative. The patient had never been pregnant nor used appetite suppressants or any other drug potentially able to induce pulmonary hypertension.1 There were no signs suggestive of connective tissue disease.
Laboratory tests gave the following results: erythrocyte sedimentation rate, 29 mm/h; fibrinogen, 5.32 g/l (normal 2.0–4.0 g/l); antithrombin III 1.42 IU/ml (normal 0.8–1.2); positive indirect antiglobulin test; serum IgE, 1.817 kU/l (normal <200) with negative RAST; serum IgG, 19.30 g/l (normal 8.0–15.0 g/l); serum IgA, 0.32 g/l (normal 1.00–4.90 g/l); ferritin, 1808 ng/l (normal 4–233 ng/l); positivity for HLA-DR4 antigen; moderate increase in peripheral blood CD8+ lymphocytes. Other routine tests were negative or normal.
Lung scans with 99m-technetium labelled albumin macroaggregates and 133-xenon gas and deep vein Doppler ultrasonography of the lower extremities were normal. The electrocardiogram, which had been normal six months earlier, showed signs of right ventricular (RV) pressure overload. The chest radiograph showed normal lung fields and a marked distension of the main pulmonary artery. Echocardiography revealed moderate RV hypertrophy and dilatation, with an RV ejection fraction of 39%, mild tricuspid incompetence, and an estimated pulmonary pressure of 75 mm Hg. Spirometric findings were normal: FEV1 2.43 l (94% of predicted normal) and FVC 2.60 l (119% of predicted normal), FRC 2.08 l, TLC 4.16 l (101% of predicted normal). Arterial blood gas tensions on room air were Pao 2 94 mm Hg (12.5 kPa), Sao 2 97%, pH 7.41, Paco 2 40 mm Hg (5.3 kPa); Tlcowas 23.5 ml CO/min/mm Hg. Right heart catheterisation showed a pulmonary arterial pressure of 65/30 (mean 47) mm Hg, pulmonary capillary wedge pressure of 3 mm Hg, cardiac output 3.6 l/min, and vascular resistance of 12.2 Wood units. Mean values of pulmonary arterial and capillary wedge pressures and vascular resistance were substantially unaffected by prolonged intravenous infusion of diltiazem (15 mg/kg/min for four hours) or supplemental oxygen.
Open lung biopsy specimens showed diffuse involvement of small arteries and arterioles, intimal fibrocellular proliferation and severe luminal narrowing; there were no signs of inflammatory, thromboembolic, or pulmonary veno-occlusive disease, suggesting the diagnosis of PPH.4 Immunofluorescence staining for immunoglobulins, complement, and fibrinogen was negative.
Given the rapid progression of the disease, the lack of any acute reactivity to vasodilator agents, and the suspicion of an immune mediated pathogenetic mechanism because of the persistent signs of systemic inflammation, immunosuppressive therapy with oral prednisone (1.5 mg/kg/day for one month gradually tapering to 5 mg/day over six months) and methotrexate (7.5 mg/week over 36 hours followed by low dose folinic acid, 2.5 mg/week) was administered for one year with the patient’s informed consent.
The patient received only immunosuppressive treatment without any vasodilator or anticoagulation. She became completely asymptomatic in a few weeks, the inflammatory indices steadily returning to within normal ranges. The patient’s quality of life improved dramatically (NYHA class I), enabling her to perform even some sports. A right heart catheterisation control after 12 months showed a marked reduction in both pulmonary arterial pressure (43/18 mm Hg, mean 30) and vascular resistance (4.36 Wood units) with a cardiac output of 5.5 l/min. The electrocardiographic signs of RV overload were no longer present and RV function appeared normal on echocardiography.
After 30 months methotrexate has been discontinued and the patient, who is still taking prednisone, 5 mg/day, remains well.
In this patient immunosuppressive therapy alone produced a significant decrease in pulmonary vascular resistance, steadily reducing the right heart overload and leading to the complete remission of any sign or symptom of pulmonary hypertension. The variable clinical course of PPH and the fact that some patients will remit spontaneously without treatment have been described previously5 so we cannot theoretically exclude the possibility of a spontaneous remission that occurred coincidentally with immunosuppressive treatment. Nevertheless, there is a close temporal relationship between immunosuppression and disease remission (fig 1).
It has recently been shown that plexogenic arteriopathy may result from deregulated endothelial cell growth.6 Functionally activated immunocompetent cells surrounding the pulmonary vessels, even in small numbers, may be responsible for the production of local mediators that could favour abnormal endothelial proliferation. In fact, lymphocyte and macrophage released cytokines and growth factors, in addition to the appearance of systemic manifestations, seem also to be involved in pulmonary vascular remodelling.7 8 Both the release of immunologically derived factors such as interleukin 1 and transforming growth factor β, and of endothelium derived vasoconstrictive factors (thromboxane and endothelin) together with the impaired production of vasodilator molecules (prostacyclin and nitric oxide), might equally account, at least in some cases, for the pathogenesis of PPH.1 Thus, pulmonary hypertension and pulmonary vascular remodelling are linked and are mutually self-sustaining.8
In patients with NYHA class III or IV and no response to oral calcium channel blockers or a moderate to minimal fall in pulmonary vascular resistance in response to short acting vasodilators, anticoagulation and long term epoprostenol infusions are currently recommended as a possible bridge to lung transplantation.1 Although immunosuppressive agents are not usually used in these patients, their rational use may be appropriate in some instances. Indeed, by inhibiting the production of pro-inflammatory and proliferative fibrogenic cytokines, and by controlling both immunologically induced intimal hyperplasia and the general immune response, immunosuppression might theoretically arrest and even relieve vascular obstruction and systemic symptoms, interrupting the vicious circle of “cell growth-vasomotor coupling”.9 Favourable effects have been anecdotally reported in patients with pulmonary hypertension associated with autoimmune disorders who have been treated with other immunosuppressive agents such as cyclophosphamide or cyclosporin A.2 10-12However, the possible efficacy of methotrexate and prednisone in PPH observed in our patient needs to be confirmed.
Since a recent study reported that a subset of patients with PPH may have an immune mediated disease,13 we suggest that even minor signs of immune activation should be carefully evaluated in patients with pulmonary hypertension of unknown origin in order to assess the pathogenetic responsibility of immune factors. We suggest further study of the effect of immunosuppressive treatment in the subgroup of patients with severe and uncontrollable PPH, candidates for lung transplantation, to test the hypothesis of a direct drug induced beneficial effect that is not coincident with spontaneous remission.
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