Scleroderma is a rare disease of the connective tissue in which most, if not all, patients have lung involvement. Scleroderma lung disease includes interstitial lung disease, pulmonary vascular disease and bronchiolitis. Although in the majority of patients scleroderma lung disease is asymptomatic, it is a major cause of morbidity and mortality.

Because of the small number of patients with this disease, the treatment of scleroderma, generally, and of its associated lung disease, specifically, have not been well defined by controlled trials. With the current limited knowledge, a reasonable approach is to treat progressive interstitial lung disease with immunosuppressive drugs such as cyclophosphamide and corticosteroids. Those patients with pulmonary vascular disease have a poor prognosis and therapy is currently limited. However, new treatment strategies are on the horizon, the most promising of which are the recent development of locally administered therapies such as inhaled iloprost, a prostaglandin analogue.

In the US, nitric oxide is only available on a compassionate use basis.Quote


Scleroderma a Rare Syndrome

Scleroderma is a generalised disorder of connective tissue which is characterised by thickening and fibrosis of the skin, abnormalities of the small arteries and microvasculature, and involvement of the internal organs, including the lungs.[1] A relatively rare syndrome, scleroderma has an annual incidence of 1 or 2 cases per 100 000[2] and is 4 times more prevalent in women than men.[1,2]There are 2 major forms of scleroderma: a limited and a diffuse form.[3] Means of classifying scleroderma are shown in table 1. Co-association with other autoimmune syndromes, particularly Sjögren’s syndrome, occurs frequently.[3]

Lung Involvement Common

Lung involvement is common and is often the cause of death from scleroderma.[4] Scleroderma lung disease can be indolent or progressive; the median survival time for patients with progressive disease is around 4 years.[5]Establishing a diagnosis of lung disease in patients with scleroderma is not easy. Respiratory function tests, particularly gas diffusion, are relatively simple and are a sensitive guide to interstitial pulmonary disease.[3] More recently, other investigative procedures including bronchoalveolar lavage, gallium lung scanning and high resolution computerised tomography (CT) of the lung have been used with some advantages.[3] In particular, CT is noninvasive, easy to perform, and is of value in monitoring disease activity.

When evaluating shortness of breath in patients with scleroderma, other aetiologies should be excluded such as cardiovascular disease, anaemia and respiratory tract infection.[3] Moreover, drugs used in the treatment of scleroderma can also cause pulmonary symptoms. For example, ACE inhibitors cause chronic cough, and interstitial lung disease is a rare complication of treatment with methotrexate, cyclophosphamide or penicillamine.[3]

Interstitial Lung Disease Often Subclinical

Interstitial lung disease is reported to occur in up to 74% of patients with scleroderma.[6] However, in the majority of patients, the interstitial lung pathology is subclinical, being completely asymptomatic in the early stages.[3] As the disease progresses, patients develop a dry cough, dyspnoea and diminished exercise capacity.[3] Not only is it important to identify interstitial lung disease, but the presence of any active inflammatory process also needs to be determined as progressive disease is more likely to require treatment.[3]

Poor Prognosis for Pulmonary Hypertension

In patients with scleroderma, pulmonary hypertension may occur secondary to interstitial lung disease or as an isolated primary process affecting the pulmonary vessels, without involvement of lung parenchyma.[3]Isolated pulmonary hypertension is predominantly associated with the limited form of scleroderma.[3] The pathogenesis of isolated pulmonary hypertension in scleroderma involves localised endothelin synthesis which produces pulmonary vasoconstriction and eventually proliferation of smooth muscle.[7,8]

Pulmonary vascular changes have been noted in 30% of autopsies of patients with scleroderma.[9] An isolated depression of gas diffusion has been suggested as an early sign of pulmonary hypertension, and may present in entirely asymptomatic patients.[3]

The prognosis of patients with scleroderma who have isolated pulmonary hypertension is poor, with a 2-year†In the US, iloprost is classified as an investigational drug. survival rate of 40% from the time of diagnosis of pulmonary hypertension.[10]

Most Patients With Bronchiolitis Asymptomatic

Bronchiolitis is classified as a small airways disease in which the terminal and respiratory bronchioles are affected by a chronic submucosal inflammatory infiltrate.[9] Although bronchiolitis occurs in up to 25% of patients,[11,12] the majority of patients with this condition are probably asymptomatic.[3] Penicillamine and smoking are both suggested as risk factors for bronchiolitis[3] but do not seem to account for most cases.

Treatment Limited

In spite of the importance of the pulmonary pathology of scleroderma, there is a lack of well controlled prospective studies of the treatment of this condition, due in part to the relative rarity of scleroderma itself. Currently, only penicillamine has been comprehensively shown to be of benefit in the treatment of patients with scleroderma interstitial lung disease when used for a prolonged period (>2 years).[3] The use of penicillamine is associated with stabilisation or modest improvement in gas diffusion.

Immunosuppressive Drugs for Interstitial Disease?

However, faced with a difficult clinical problem, it would seem reasonable to formulate therapeutic strategies from what is known of disease pathogenesis. Interstitial lung disease is caused by an inflammatory process, triggered by unknown factors, in which continued production of cytokines such as platelet-derived growth factor and transforming growth factor-ß eventually leads to fibrosis.[3] This information as well as data on the therapy of immunopathologically similar diseases and limited data on the therapy of scleroderma itself suggest that the use of immunosuppressive therapy may be of benefit.[3]Immunosuppressive treatment is probably more effective early in the disease process as patients with long-standing disease have established fibrosis and would be expected to respond less favourably to this type of therapy, which appears to be the case according to the results of a study in which patients were treated with cyclosporin.[13] However, because of the toxic nature of the drugs used, these agents should be reserved for serious disease with a decision being based on the presence of active disease with clinical evidence of progression.[3]

Some small uncontrolled studies[14,15] found that cyclophosphamide in combination with prednisone may be beneficial. Treatment with chlorambucil may also be useful in the treatment of interstitial lung disease,[3] but due to limitations of the studies conducted to date no conclusive evidence is yet available.

Skin thickening a surrogate marker? As pathological mechanisms in the skin are similar to those in the lung, it would seem reasonable to extrapolate that a favourable response in the skin may also be associated with a good response in the lung.[3] Methotrexate, interferon-, cyclosporin and antithymocyte globulin have all been shown to have a beneficial effect on skin thickening in patients with scleroderma.[3] However, it has been difficult to draw any conclusions from the studies conducted to date because of limitations in study design.

Locally Administered Vasodilators for Hypertension

In the treatment of isolated pulmonary hypertension, some proven benefit has been shown with calcium antagonists, particularly nifedipine, and anticoagulation with warfarin in patients without contraindications.[10] There is also some evidence that continuous intravenous prostacyclin (epoprostenol) may be beneficial.[3] Continuous ambulatory oxygen therapy is also used.[3]In an effort to maximise pulmonary vasodilatation and minimise systemic adverse effects, the use of local administration of vasodilators is being adopted. Inhaled iloprost, a prostacyclin analogue, has been shown to produce local pulmonary effects without the systemic adverse effects of prostacyclin.[16] Inhaled nitric oxidehas also been shown to be beneficial, although there may be rebound vasospasm.[10]

Endothelin receptor antagonists may prove to be of benefit and are currently undergoing early phase clinical testing.[3]

Bronchiolitis is Corticosteroid-Responsive

Severe bronchiolitis in the absence of interstitial lung disease is unusual. When treatment is necessary patients should be commenced on a dosage of corticosteroid sufficient to suppress symptoms, with a gradual reduction in dosage as time and response allow.[3] In the US, nitric oxide is only available on a compassionate use basis.


Table 1. Aids to classification of scleroderma at presentation[4]

Presenting feature Scleroderma classification
Limited Diffuse
Raynaud’s phenomenon Long duration Short duration
Skin involvement Distal limb and face Proximal limb and trunk
Tendon friction rubs Absent May be present
Nailfold capillaries Dilatation Dilatation and loss
Autoantigen Commonly centromere Commonly topoisomerase I


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