Section 4 -

Difficult to Characterize Patterns of ILD – Collagen Vascular Diseases Allen R Gibbs Department of Histopathology Llandough Hospital Penarth, Wales, UK

CVDs are frequently associated with acute and chronic manifestations which can affect airways, alveoli, pulmonary vessels, pleura and chest wall. It has been estimated that interstitial lung disease (ILD) associated with collagen vascular diseases (CVD) accounts for about 1600 deaths per year in the USA, which comprises about 2% of all respiratory deaths. References 1 to 3 are useful reviews [1, 2, 3]. The five CVDs most commonly associated with ILD are : rheumatoid arthritis (RA) progressive systemic sclerosis (PSS) systemic lupus erythematosus (SLE) polymyositis-dermatomyositis (PM-DM) Sjogren's syndrome The histological patterns of interstitial disease seen in CVDs include : diffuse alveolar damage, organizing pneumonia, UIP, NSIP, respiratory bronchiolitis-associated interstitial lung disease, DIP and LIP. Estimations of prevalence are difficult because of variations in diagnostic criteria, imprecise histopathological characterization, co-existance of several patterns, failure to control for smoking and overlap with drug induced pulmonary disease. NSIP appears to be the most common histological pattern associated with CVD [4, 5]. In many cases two or more pulmonary pathologies coexist which result in problems for determining the predominant process, important in deciding treatment. It has been recommended that where biopsies show NSIP or LIP-follicular bronchiolitis or a combination of patterns the patient should be investigated for CVD [6]. The patients are usually younger than those with idiopathic ILD. It has been estimated that in those patients with lung involvement the onset of respiratory disease may precede the systemic disease : in about a third of cases with PM-DM [7], in 20% of those with RA [8], and less commonly in PSS. The main symptoms are shortness of breath and cough. Physical examination reveals bilateral basal inspiratory crackles, finger clubbing and signs of cor pulmonale. Radiologically a variety of changes can be seen depending on the nature of the associated lung disease : reticular opacities, airway-associated abnormalities, ground glass opacities, nodular opacities and honeycombing. Prognosis depends on the severity of the disease but is generally better, when matched for disease severity, than in those with lone interstitial lung disease [9] . The good prognosis of treated organizing pneumonia is not invariable in CVDs, some progress to respiratory failure and death. A study has shown that patients with CVD associated UIP have fewer fibroblastic foci than those with lone UIP and a better survival [10]. Drug induced lung disease is not uncommon in collagen vascular diseases and since the histopathological patterns are similar to those seen in association with CVDs per se this can pose substantial diagnostic problems. In the acute (diffuse alveolar damage) and subacute (organizing pneumonia) disorders infection has to be excluded. Rheumatoid Arthritis Rheumatoid arthritis is a chronic systemic disease characterized by symmetrical arthritis and associated with various serological abnormalities. It is more common in women than men but pulmonary complications are more frequent in men. Lung disease occurs clinically in 14% and subclinically in 44% [11]. It usually occurs in patients with diagnosed disease but may precede articular manifestations [12] It appears to be more frequent in those with subcutaneous nodules. On biopsy the majority of the changes are similar to the idiopathic forms of ILD. In a recent study the UIP pattern was most frequent, followed by NSIP and then organizing pneumonia [13]. Pointers to the changes being related to rheumatoid arthritis include the presence of lymphoid follicles with germinal centres located around terminal airways (follicular bronchiolitis) or in the pleura, chronic pleuritis, vasculitis and necrobiotic nodules. In RA biopsies taken in the context of developing symptoms suspected to be related to drugs or infection may be very difficult to interpret because of the overlap of morphological patterns with CVD associated ILD. Progressive Systemic Sclerosis PSS is a rare systemic disease with fibrosis involving the skin and internal organs which affects mainly women with Raynaud's phenomenon. Respiratory disease is now the leading cause of mortality. Since PSS is often diagnosed because of the presence of lung disease it is not unexpected that pulmonary fibrosis is found in 75% of autopsies [14] and lung function impairment in 90% [15]. Diffuse lung disease is clinically overt in about 30% [8]. UIP, NSIP and organizing pneumonia appear to be the predominant patterns [5, 16]. Pulmonary hypertensive changes, without interstitial fibrosis, may be present and these are a major cause of mortality. Chronic aspiration may result from disturbances of oesophageal motility. Systemic Lupus Erythematosus SLE is a chronic systemic disease characterized by arthropathy, cutaneous lesions, renal disease and serositis and it is associated with autoantibodies against nuclear antigens and immune complex deposition. Acute lung injury, characterised by the changes of diffuse alveolar damage or diffuse alveolar haemorrhage, is a rare but well recognized complication. Pulmonary fibrosis is comparatively rare in SLE but pleurisy/effusion is common and more frequent than in other CVDs. When interstitial lung disease occurs it is usually NSIP or organizing pneumonia [17]. Infection is the most frequent pulmonary complication mainly because of the use of immunosuppressive drugs. Polymyositis – Dermatomyositis PM-DM is an idiopathic inflammatory process of the skin and skeletal muscle. Mean onset of symptoms is in the sixth decade and women are more frequently affected than men. Pulmonary involvement occurs in about 5 to 20% and it is the most frequent cause of death in PM-DM. Many show the patterns of UIP, NSIP or organising pneumonia [18]. A rapid course of disease with diffuse alveolar damage sometimes in association with organizing pneumonia can occur. Aspiration pneumonia may result from respiratory muscle weakness and it is the most frequent pulmonary complication. Sjogren's Syndrome SS is an autoimmune disorder characterised by a triad of dry eyes, dry mouth and arthritis. It can occur alone or in association with other autoimmune diseases. Lung involvement has been estimated at between 9 to 90% of patients. The most frequent patterns of lung involvement are chronic bronchiolitis [5] and a spectrum of lymphoid lesions icluding follicular bronchiolitis, LIP, nodular lymphoid hyperplasia and malignant lymphoma [19, 20]. Other interstitial patterns are infrequent but include NSIP, OP and UIP. References Fukuoka J, Leslie KO. Chronic diffuse lung diseases. Leslie KO and Wick MR. Practical Pulmonary Pathology. 181-258. 2005. Philadelphia, Churchill Livingstone. Ref Type: Generic Connective tissue and inflammatory bowel diseases. Travis WD, Colby TV, Koss MN, and et al. Non-neoplastic disorders of the lower respiratory tract. First series, fascicle 2, 291-320. 2002. Washington, DC, The American Registry of Pathology. Ref Type: Generic Wells AU. Lung disease in association with connective tissue diseases. Olivieri O and du Bois RM. Interstitial Lung Diseases. European Respiratory Monograph 5[Monograph 14], 137-64. 2000. Sheffield, UK, European Respiratory Society Journals Ltd. 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