It is estimated that approximately 3% of all patients with scleroderma are children. Children under 10 years account for less than 2% of all cases. The patients between 10-20 years make up from 1.2% to 9% depending on the study involved (1). In the children with childhood scleroderma, lung involvement occurs in quite a high percentage of patients. Lung involvement many cause the most mortality now in scleroderma. Of those who die with scleroderma, 50% die of pulmonary hypertension (PHT) and 25% with pulmonary fibrosis (2). Pulmonary disease usually involves either pulmonary blood vessels and tissue including predominantly interstitial fibrosis with gradual obliteration of the blood vessels, combined pulmonary tissue and vascular lesions, or predominant pulmonary blood vessel involvement associated with rapidly lethal right ventricular failure. Pulmonary disease is almost universal in diffuse scleroderma, although frequently asymptomatic. Symptoms may not occur until 60% of the pulmonary function is compromised. The patients often have a dry, hacking cough or shortness of breath on exertion. Occasionally, rales or pleural friction rub are present on examination (1). The main histological abnormality in the lungs is diffuse alveolar, interstitial, and peribronchial fibrosis. The thickened walls may result in reduction of alveolar space. Extensive bronchiolar hyperplasia, arteriolar endothelial proliferation, fibrous pleuritis, and pleural adhesions are also present (1).

Initial evaluation of a child for possible childhood scleroderma and lung involvement should include a complete blood count (CBC), urinalysis, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), comprehensive metabolic panel to measure liver and kidney function tests and muscle enzymes (CPK and aldolase). Immunologic studies should include a rheumatoid factor, antinuclear antibody (ANA) looking for a speckled, nucleolar, or centromere pattern on immunofluorescence, and specific antibodies for DNA topoisomerase-1 (anti-Scl 70 antibody) or centromere. If available, testing for antibodies to PM-Scl and RNA polymerase III may be indicated. The presence of these antibodies indicate a greater possibility of lung involvement. The original evaluation of the child will also include pulmonary function tests (PFTs), echocardiogram, and high resolution computerized tomography (CT) of the lung. Pulmonary diffusion and spirometry are sensitive measures if restrictive changes are present in the respiratory tract in childhood scleroderma. If restrictive changes are present, characteristic findings include a decrease in the forced vital capacity (FVC) and forced expiratory flow, an early decrease in diffusion capacity (DLCO), and an increase in functional residual volume (3, 4). A two dimensional echocardiogram is important in confirming early PHT by documentation of a dilated right ventricle with thickening of the ventricular wall and straightening of the septum, and measuring right ventricular pressure. The one-dimensional M-mode echocardiogram is characterized by changes in the mid-systolic movement of the pulmonary valve. Right heart catheterization provides definitive confirmation of PHT (1). High-resolution CT of the lungs may give more involved information in evaluating the patient with childhood scleroderma.

Interstitial fibrosis of the lung in childhood scleroderma is a severe, fibrotic process without a lot of involvement in the blood vessels. The way to determine if inflammation of the breathing sacs of the lung (alveolitis) is present is the high-resolution CT scan (2). A bibasilar, peripheral, ground-glass appearance on the CT scan correlates very nicely with progression of fibrosis, changes in PFTs, and also with improvement after treatment. The patients with antibodies to Scl-70 (topoisomerase) or nucleolar pattern on their ANA have a high risk of developing pulmonary fibrosis. To determine if significant alveolitis should be treated, a combination of potential findings including a decrease in FVC, a 10% decrease in DLCO, and a ground-glass appearance on high-resolution CT should be noted. Dr. Steen’s studies (2) have shown only the use of cyclophosphamide had significant improvement in these patients over a two-year period with stabilization and improvement of their FVC. Another possible drug that may be helpful is that of bosentan, an endothelin-1 antagonist. Endothelin is a profibrotic peptide and possibly bosentan will prevent further development of fibrosis.

Pulmonary vascular disease in scleroderma can be a very lethal complication. Blood vessels show diffuse intimal proliferation with occlusion of lung vessels similar to narrowing of the digital blood vessels (2). Severe PHT is unrelated to severe fibrosis. The patients with PHT have minimal fibrosis or restrictive disease with an FVC of 80% predicted similar to the patients without PHT. However, at the time of diagnosis, the DLCO may be very low. The risk factors for isolated PHT include long duration of Raynaud’s, limited scleroderma, and the presence of anticentromere antibodies (2). The patients with PHT tend to have a high frequency of pericardial effusions including tamponade (5). Pulmonary systolic pressure on echocardiogram higher than 35 mm Hg is compatible with early PHT. However, interpreting the significance of the level of pulmonary artery pressure sometimes has problems with echocardiograms as a screening tool (2). The physician specifically needs to request to measure pulmonary artery pressures. To confirm PHT, a right heart catheterization may need to be performed. If the pressure is greater than 45 mmHg, there is a 90% correlation with the right heart catheterization. The patients with longstanding disease, anticentromere antibody, low DLCO, and a pulmonary artery pressure greater than 40 mm Hg are suspect for PHT. The patients with primary PHT sometimes have a positive response to nitric oxide, a short-acting inhaled vasodilator (6). This may indicate a possible good response to high-dose calcium channel blockers, such as nifedipine. However, childhood scleroderma patients may have low systemic blood pressures and usually cannot tolerate these medications because of dizziness and hypotension as side effects. Newer treatments such as epoprostenol, bosentan, and treprostinil sodium have now been approved for PHT in both primary and scleroderma PHT (2). The problem with epoprostenol is that it is a continuous intravenous effusion, which has many complications and is extremely expensive. Treprostinil, a continuous subcutaneous infusion, has some side effects such has nausea, headache, and jaw pain, and a very painful local site reaction that occurs in 85% of the patients, and is also extremely expensive. Bosentan, the endothelin antagonist, is an oral agent, well-tolerated, and is a very potent vasoconstrictor. It decreases pulmonary artery pressures and improves right ventricular mass. Increased liver function tests are the main complication and monthly laboratory tests are required.

Lung disease is very common in childhood scleroderma. It is a very serious disease and requires a careful evaluation of risk factors, laboratory studies, PFTs with DLCO, high-resolution CT scans, and echocardiograms to determine the primary type of lung disease and the most appropriate treatment.

References

1) Cassidy JT, Petty RE: The systemic sclerodermas and related disorders. In Cassidy JT, Petty RE (eds): Textbook of Pediatric Rheumatology, Philadelphia, W.B. Saunders Co, 2001, pp 507-533.
2) Steen VD: The lung in systemic sclerosis. J Clin Rheumatol 2005; 11: 40-46.
3) Garty BZ, Arthreya BH, Wilmott R, et al: Pulmonary functions in children with progressive systemic sclerosis. Pediatrics 1991; 88: 1161-1167.
4) Falcini F, Pignane A, Matucci-Cerinic M, et al: Clinical utility of noninvasive methods in the evaluation of scleroderma lung in pediatric age. Scand J Rheumatol 1991; 21: 82-84.
5) Steen V. Medsger TA: Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 2003; 48: 516-522.
6) Rich S, Kaufmann E, Levy PS: The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327: 76-81.

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