This site is intended for healthcare professionals as a useful source of information on the diagnosis, treatment and support of patients with lupus and related connective tissue diseases.

KEY POINTS:

• Lupus causes a number of acute and chronic lung diseases.

• Lupus of the lung is common and can be important in prognosis.

• Symptoms are similar to other serious pathologies e.g. PE or pneumonia.

Introduction

Intrathoracic lupus is common and may involve the pleura, lung parenchyma, vasculature or respiratory muscles, presenting as: Pleuritis and effusions; Pneumonitis (acute and chronic); Bronchiolitis obliterans; Pulmonary vasculitis; Opportunistic infections; Pulmonary haemorrhage, Pulmonary hypertension, Pulmonary embolus (particularly with anti-phospholipid syndrome) and "Shrinking lung syndrome".

It is important to remember that in addition to primary lupus-induced pleuropulmonary pathology, respiratory symptoms may also be secondary to lupus acting on other organs or due to the side effects of systemic steroid or cytotoxic treatment.

This chapter summarises key clinical features and likely treatments of such conditions, commenting where relevant, on how diagnosis can be focused with investigation – whilst this is often radiological, detailed reviews of this nature are to be found elsewhere. Lung findings in lupus have been correlated with clinical symptoms and serological markers for other rheumatological syndromes e.g. Scleroderma or Raynaud’s and also Anti-Ssa/anti-Jo-1 antibodies but the lack of evidence supporting their role in diagnosis renders them outside the scope of this chapter. Ultimately, diagnosis and management of lupus lung disease is complex and often requires expert management in a specialist centre.

Pleural disease

Up to 60% of patients with lupus experience pleuritic chest pain at some point. Some are associated with a serous/serosanguinous pleural effusion, typically exudative with a high protein and lactate dehydrogenase (LDH) versus serum (LDH here is, however, lower than in Rheumatoid Arthritis and glucose is higher).

Given that chest signs and symptoms can be relatively common, the decision to investigate will depend on the severity of symptoms and whether they present alongside other features that arouse suspicion of new, significant intrathoracic disease. For example, diagnostic aspiration of a new effusion in the presence of elevated CRP is likely to be useful, more so than in an individual with recurrent lupus related pleurisy which has responded well to anti-inflammatory medications. Pleural biopsy is less useful, being poorly specific and, therefore, rarely performed. It should also be remembered that the presence of lupus does not preclude the presence of thoracic disease of other aetiologies.

Lupus associated pleuritis responds to NSAIDs in mild cases or, where severe, may require increased dose corticosteroids. Anti-malarials are useful for refractory cases. Colchicine may also be useful in acute pleuritis.

Pulmonary Infection

Pleural disease is often complicated by infection, particularly since lupus patients are generally more susceptible to infection, which can account for considerable morbidity and mortality.A number of hypotheses explain this increased susceptibility: defective macrophage antibacterial activity; complement deficiency impairing opsonisation and immune presentation of bacterial antigens; immunosuppression with corticosteroids and DMARD’s; oedema and poor clearance of respiratory secretions providing a fertile environment for bacterial colonisation. Unusual and more aggressive, opportunistic organisms e.g. Aspergillus, Cryptococcus, Pneumocystis jirovecii (carinii), CMV and Nocardia are, therefore, more likely. Hypocomplementaemic patients also have increased sensitivity to more common organisms such as Streptococcus pneumoniae and Neisseria meningitidis, both of which may result in fatal infection and should be considered even in low activity.

Tuberculosis (TB) is also more common in lupus and should be excluded if haemoptysis,weight loss or fever persist.TB may also give rise to isolated pleural involvement (see above) and suspicion should be high where systemic upset occurs in ‘at-risk populations’ and those in contact with individuals with AFB (Acid-Fast Bacilli) positive sputum. A chest radiograph may identify multiple opacities or nodular (potentially cavitating) masses.

In any infection, accurate early diagnosis, with microbiological identification of organisms and sensitivities are crucial, and whilst infection in the presence of other lupus-related lung disease can be difficult to diagnose, this may be aided by a high CRP which, in lupus, is generally not elevated, even in the presence of active inflammation. Prompt "appropriate" treatment is essential to rapid recovery, particularly in septicaemia where "Surviving Sepsis" guidelines should be followed. In hypocomplementaemic patients who suffer recurrent infection there is also an argument for prophylactic antibiotics.

Pulmonary Embolus

Sudden onset pleuritic chest pain with acute respiratory compromise should also arouse suspicion of pulmonary embolus (PE), particularly if the ECG shows sinus tachycardia or right heart strain (classically "S1Q3T3"). The incidence of thromboembolic events is increased in rheumatological diseases and particular vigilance is required in the presence of antiphospholipid antibodies (aPL) which strongly predispose to venous thrombosis.

Lupus anticoagulants are so named because in vitro clotting is inhibited. In vivo, paradoxically, thrombotic events are more common. This occurs due to their activity against plasma proteins such as prothrombin. aPTT is unreliable in these patients, being prolonged in only half of those with lupus anticoagulant and often not at all in the presence of anticardiolipin antibodies (aCL). More reliable tests (such as ELISA for aCL or dRVVT for lupus anticoagulant) should be ordered early in patients with suspected antiphospholipid syndrome or where there are unexplained thrombotic events.

Standard risk factors e.g. smoking, oral contraceptive, malignancy, surgery and immobility may also co-exist in lupus and should be considered when establishing probability of venous thrombosis. Corticosteroids also increase the risk of venous thromboembolism, both acutely and chronically.

Patients in whom there is a high clinical suspicion of PE in the presence of preexisting lung disease and/or serological risk factors (LAC or high titre aPL), should be anticoagulated pending further investigation (CTPA is usually preferred due to a higher specificity when there is previous/chronic lung damage that renders V:Q scanning less accurate). Long term anti-coagulation is generally recommended in patients with high titre aPL who have had a pulmonary embolus.

Acute Pneumonitis (ALP)

This acute, non-infective, inflammatory lung lesion has been reported in up to 9% of lupus patients and with symptoms such as fever, pleuritic chest pain, dyspnoea and cough is readily confused with other acute lung disease unrelated to lupus, including pulmonary embolus and acute infection. ALP tends to affect the young but may complicate CILD (see below) in older patients. The chest radiograph findings may include lower zone alveolar infiltrates, elevated diaphragm or pleural effusion.

Exclusion of infective aetiologies is crucial and it is often favourable to cover with broad spectrum antibiotics where there is any suspicion of an infective component, pending microbiological culture results (whenever possible cultures of blood, sputum etc. should precede antibiotics). Chills and rigors favour infection and a raised CRP is atypical in lupus and also suggests infection. However, such elevation in CRP may also be absent in viral infections. ALP would also be more likely during a generalised lupus flare such that diagnosis is supported by the presence of nephritis, arthritis, pericarditis and pleuritis. Distinguishing an acute lupus pneumonitis from that of an infective origin can be difficult (see below). Systemic prednisolone is the most common therapy. In-patient assessment in a specialist centre is, however, always indicated.

Acute Alveolar Haemorrhage

Pulmonary haemorrhage complicating lupus is almost identical to acute pneumonitis and may represent the same spectrum of disease. This disease is rare and can range from a mild sub-clinical chronic form to massive life-threatening haemorrhage with a mortality of up to 90%. Patients may have haemoptysis at presentation (one study reported 42%), but sometimes manifestations can be clinically non-specific and include unexplained anaemia, cough and dyspnoea. Risk factors include known lupus, high levels of anti-DNA antibodies and active extrapulmonary disease. Glomerulonephritis is also often present in these patients.

Important differential diagnoses include anti-GBM disease and ANCA associated vasculitis (e.g.Wegener’s Granulomatosis or Churg-Strauss Disease). Pulmonary function test results showing increased diffusing capacity for carbon monoxide is a sensitive test for acute alveolar haemorrhage although it can be technically challenging to perform in severe cases. Increasingly, blood stained samples from bronchoalveolar lavage or progressive chest radiograph in association with a fall in haemoglobin are highly suggestive. Lung biopsies show capillaritis with immunoglobulin or immune complex deposition although, clinically, these are rarely indicated. Treatment options include high dose steroids and cyclophosphamide and, in severe cases, plasma exchange, although the latter can be hazardous in the presence of thrombocytopenia or coagulation disorders.

Pulmonary function tests in Lupus – do they help?
TLC
FVC
PEFR
FEV1
FEV1/FVC
TLCO
Restrictive/Intrinsic
Decreased
Decreased
Normal or (decreased)
Decreased or normal
Normal
Decreased
Extra pulmonary
Decreased
Decreased
Normal
Decreased or normal
Normal
Normal
Obstructive/COPD
Normal or increased
Normal or increased
Usually decreased
Decreased
Decreased
Normal (may be low in emphysema volume loss)
Asthma
Normal
Normal
Decreased
Decreased
Decreased
Normal to high

Subacute interstitial Lung disease

Bronchiolitis obliterans (which may comprise an organising pneumonia - BOOP) presents with more sub-acute symptoms of cough, dyspnoea, fever and constitutional un-wellness. Middle-aged women are most typically affected.

Airflow limitation arises from submucosal oedema with peribronchiolar inflammation and fibrosis, primarily involving respiratory bronchioles in the absence of diffuse parenchymal disease, thought to arise from plugs of fibrous tissue in bronchioles and alveolar ducts. Prognosis is better than that for those with a standard interstitial pneumonia, particularly when BOOP is the diagnosis since there is often an excellent response to corticosteroids.

Whilst chest radiographs in BOOP may show focal alveolar infiltrates with striking air bronchograms, there are often no changes in pure BO where the lung parenchyma is spared. Pulmonary function tests show a restrictive defect.

Clinical and serological markers may also correlate with such chronic lung disease in lupus. Both Scleroderma-like symptoms (e.g. Raynaud’s) and Anti-SSa (Ro) antibody seem to be more common with restrictive defects and a reduction in transfer factor. Another important differential is anti-Jo-1 associated myositis/lung disease.

All such patients should be assessed in a specialist centre.

Chronic Interstitial lung disease

Chronic interstitial lung disease (CILD) is well recognised in connective tissue disorders yet, in lupus, is thought to be clinically significant less often than in, for example, RA, Scleroderma or complex myositis associated syndrome. Symptoms include progressive dyspnoea and non-productive cough that may develop insidiously ‘de novo’ or progress from acute pneumonitis.

The chest X-ray shows coarse reticulonodular densities in the lower zones but, as with lung function tests, cannot easily differentiate between this chronic picture of fibrosis (due to either cause) and an acute alveolitis – this requires serial investigations. High-resolution CT images can detect such progressive parenchymal change more readily.
‘Ground glass’, focal alveolar opacities, imply active inflammation, potentially treatable with steroids, whereas macroscopic, honeycomb-like cysts are more consistent with end-stage irreversible fibrosis. CT may, therefore, have a greater Prognostic significance and correlate more closely with abnormal lung function tests, although not necessarily clinical severity. CILD associated with connective tissue disease may be indistinguishable from idiopathic fibrosis, but the former is generally less severe and may respond well to steroids and immunosuppressive therapy.

Pulmonary hypertension

Pulmonary hypertension is defined as elevated pulmonary artery pressure (>25mmHg at rest/30mmHg on exertion) and can be of primary origin or secondary to the conditions described above e.g. interstitial lung disease or pulmonary emboli. Pulmonary hypertension is seen more frequently with scleroderma, mixed connective tissue disease and rheumatoid arthritis rather than lupus, however, the increased presence of the antiphospholipid syndrome/anti-cardiolipin antibodies in lupus predispose to a thromboembolic aetiology and the incidence of pulmonary hypertension is also increased in the presence of Raynaud’s phenomenon.

Symptoms including lethargy, fatigue, angina, syncope and dyspnoea on exertion are relatively non-specific. Diagnosis is, therefore, aided by the presence of distended jugular veins (with prominent a and v waves), right ventricular heave, fixed split S2, hepatomegaly, ascites and peripheral oedema. Investigations should include ECG (changes are consistent with right ventricular hypertrophy) and CXR (cardiomegaly combined with prominent pulmonary arteries can lead to straightening of the left heart border on the background of oligaemic lung fields). Whilst echocardiographic measurement of pulmonary artery pressures may be suggestive, formal diagnosis requires right heart catheterisation which may be accompanied by vasodilator challenge.

Treatment requires specialist supervision and often includes control of any underlying activity of interstitial lung disease with steroids and cytotoxic agents, combined with vasodilators. Prognosis is generally poor but is improved in secondary pulmonary hypertension if an underlying cause can be identified and reversed.

Shrinking lung syndrome (SLS)

Initial lung function measurement in patients with lupus showed that 30% had unexplained shortness of breath with lung volume restriction and sluggish, raised diaphragms. Hence, in 1965 Hoffbran & Beck proposed the "Shrinking Lung" syndrome. Pathophysiology of this disease is still poorly understood and possibly relates to respiratory muscle weakness (predominantly the diaphragm), caused by an unknown myopathic process without documented abnormality of other lung tissue. There is, however, insufficient evidence to support this.

SLS should be considered when lupus patients present with unexplained dyspnoea or chest pain in the presence of reduced lung fields but this diagnosis is thought to be rare and remains a diagnosis of exclusion.
Dr Richard W Lee
Academic Clinical Fellow
Allergy & Respiratory Medicine
Guy’s and St Thomas’ Hospitals
London
Prof Kevin A Davies
Professor of Medicine & Honorary Consultant Rheumatologist
Brighton & Sussex Medical School
University of Sussex
Brighton
East Sussex BN1 9PX