Pulmonary Disorders in Connective Tissue Diseases

In This Article

Abstract and Introduction

Abstract

Connective tissue diseases (CTDs) are a heterogeneous group of disorders, acquired or hereditary, involving an autoimmune-mediated inflammation of connective tissues in the whole body. Lung involvement is common with CTDs, and associated with significant morbidity and mortality. Each compartment of the lung may be affected, often simultaneously, depending on the type of CTD. In addition, the lung may show pathological changes related to treatment, such as infection, drug reaction, and neoplasia. A multidisciplinary approach to diagnose these patients is essential and incorporates radiological and clinical as well as pathological data. In this review we describe the patterns of lung disease associated with common CTDs, lung disease in pediatric CTD patients, and newly recognized conditions.

Introduction

Connective tissue diseases (CTDs) are a heterogeneous group of disorders that share similar pathogenetic mechanisms. Different levels of systemic autoimmune-mediated inflammation involve connective tissues in organs throughout the body, including the lungs and the pleura to varying extents. There are several difficulties for pathologists in the assessment of biopsies from these patients.

CTDs show variably strong associations with different histological patterns of lung disease, but these histological patterns can both overlap across CTDs and also show diversity within any particular CTD.
Although the interstitium is often the compartment upon which clinical interest is centered, there is a greater propensity for CTDs to involve multiple pulmonary compartments such as large and small airways, pleura, and pulmonary vasculature. Therefore a combination of patterns, either across compartments or even within the same one (e.g., both organizing pneumonia [OP] and nonspecific interstitial pneumonia [NSIP]), or the presence of lymphoid hyperplasia and/or eosinophilia, should prompt consideration of an underlying CTD. Pathologists should report cases as such, rather than using the fall back of "unclassifiable."
Patients with a known CTD may be on various drugs including immunomodulatory and cytotoxic agents, which can also be associated with pulmonary toxicity and a variety of pathological changes. Many are immunosuppressed, predisposing them to developing lung infections and neoplasia.
Many of the pathologic entities associated with CTD can be diagnosed by noninvasive methods, especially high-resolution computed tomography (HRCT), obviating the need for biopsy, so undertaking biopsy is often quite rare when patients are known to have CTDs. Conversely, biopsy may be the first pointer toward a disease in patient thought to be presenting in an idiopathic setting. Indeed, the lung may be the first organ to be involved, with the CTD manifesting systemically at a later date.

The diagnosis of CTD-related interstitial lung disease (ILD) therefore relies on a multidisciplinary approach, within which the role of the pathologist is often critical. As well as identifying or confirming the presence of CTD-related lung disease, the pathologist may identify patients with an occult CTD, or be called upon to confirm or exclude manifestations of systemic therapy, infection, or a secondary effect of CTD such as aspiration or malignancy (e.g. mucosa-associated lymphoid tissue [MALT] lymphoma in patients with Sjogren's syndrome [SS]). This review will first assess the anatomic compartments of the lung (Table 1) and then review some rare entities.

Table 1. Most frequent histological changes of acquired connective tissue disease ⁵⁷
	Airways	Alveoli	Pulmonary vessels	Pleura	Diaphragm and chest wall
Rheumatoid arthritis	Bronchitis Bronchiectasis Follicular bronchiolitis Constrictive bronchiolitis	Pneumonia Interstitial pneumonia (NSIP, rarely UIP or LIP) Rheumatoid nodules	Hypertension Vasculitis	Pleurisy Empyema
Systemic lupus erythematosus		Interstitial pneumonia (DAD, rarely NSIP, UIP, or OP)	Hypertension Thrombosis Vasculitis Hemorrhage	Pleurisy	"Shrinking" lungs with high diaphragms
Systemic sclerosis		Interstitial pneumonia (NSIP, rarely UIP, DAD, or OP) Aspiration pneumonia			"Hidebound" chest
Sjogren's syndrome	Sicca features	Interstitial pneumonia (NSIP or LIP, rarely UIP, OP or DAD) Lymphoma		Pleurisy
Dermatomyositis and polymyositis		Aspiration pneumonia Interstitial pneumonia (NSIP or OP, rarely UIP, DAD)			Myositis
Ankylosing spondylitis		Upper lobe fibrosis			Costovertebral restriction
Behcet's syndrome	Stenosis Ulceration		Arteritis Aneurysms
Relapsing polychondritis	Stenosis
Rheumatic fever		DAD	Vasculitis		Pleurisy Diaphragmatic paralysis

Abbreviations: DAD, diffuse alveolar damage; LIP, lymphoid interstitial pneumonia; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; UIP, usual interstitial pneumonia.

Table 2. The prevalence of interstitial pneumonias in patients with connective tissue diseases
	RA	SLE	SSc	PM/DM	SS
UIP	++?	+/−	+	+	+/−
NSIP	++?	+?	+++	++	++
LIP/FB	++	+/−	–	–	++
OP	+	+/−	+/−	++	+/−
DAD	+	++	+/−	+/−	–
DIP/RB	+/− ^a	–	+^a	–	–

Abbreviations: DAD, diffuse alveolar damage; DIP, desquamative interstitial pneumonia; DM, dermatomyositis; FB, follicular bronchiolitis; LIP, lymphoid interstitial pneumonia; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; PM, polymyositis; RA, rheumatoid arthritis; RB, respiratory bronchiolitis; SLE, systemic lupus erythematosus; SS, Sjogren's syndrome; SSc, systemic sclerosis; UIP, usual interstitial pneumonia.
Note: ++ = frequent, + = not infrequent, +/− = rare; ? = prevalence currently uncertain.
^aProbable incidental to pulmonary symptoms.

Table 3. Summary of the main histological features of more common CTDs
Rheumatoid disease
Cricoarytenoid arthritis Bronchitis Bronchiectasis Bronchocentric granulomatosis Diffuse panbronchiolitis Follicular bronchiolitis UIP/NSIP/LIP Bronchiolitis obliterans Involvement by systemic amyloidosis	Necrobiotic nodules Pulmonary hypertension Pulmonary vasculitis Carcinoma of the lung Lymphoma of the lung Pleurisy Empyema
Systemic lupus erythematosus (SLE)
Pleuritis, pleural effusion (commonest) Acute lupus pneumonitis Organizing pneumonia Interstitial pneumonia (NSIP pattern) Lymphoid interstitial pneumonia (LIP)	Pulmonary thromboembolism Pulmonary hypertension Pulmonary vasculitis Pulmonary hemorrhage Myopathy in respiratory muscles
Systemic sclerosis (SSc)
Interstitial pneumonia (NSIP) UIP, DAD, bronchiolitis (rare)	Sarcoid granulomas Pulmonary hypertension
Sjogren's syndrome (SS)
Bronchitis Bronchiectasis Bronchiolitis Amyloidosis	Bulla formation NSIP, UIP, LIP, OP Pulmonary hypertension Lymphoma of the lung (MALT)
Polymyositis and dermatomyositis (PM/DM)
NSIP Diffuse alveolar damage Organizing pneumonia Pulmonary hemorrhage	Carcinoma/lymphoma Aspiration pneumonia Respiratory muscle weakness (respiratory failure)