Chapter 53 Connective Tissue Diseases
Connective tissue diseases (CTDs) are generally referred to as a group of systemic disorders with abnormalities in the tissues containing collagen and elastin. Usually, CTDs are characterized by overactivity of the immune system from unknown causes resulting in production of autoantibodies. Pathologic changes are often seen in the lungs of these patients and may be the site of initial manifestation of the systemic disease. All compartments of the respiratory system can be involved, from pleura, airways, and alveolar parenchyma through the pulmonary vasculature. These anatomic regions can be affected either in isolation or in combination, producing a variety of clinical presentations. Furthermore, the pulmonary manifestations of CTDs need to be separated from the effects of therapy (drug reactions, opportunistic infections).
• Polymyositis/dermatomyositis (PM/DM) is relatively rare, affecting 2 to 10 per 1 million people; has a bimodal age distribution, with an early peak at 5 to 15 years and a later peak at 50 to 60; and occurs three to four times more often in women.
• Mixed connective tissue disease (MCTD) has a prevalence that has not been precisely defined but probably approximates 1 in 10,000 people. Mixed disease is more common in women, and most patients present in the second or third decade of life.
• Sjögren syndrome (SS) has a prevalence of 0.5% to 1% in the general population for primary SS and of 10% to 30% in patients with other autoimmune disorders (secondary SS). SS predominantly affects middle-aged women.
Estimates of the prevalence of pulmonary involvement in CTDs vary widely, depending on the investigated cohort and the methods used to detect lung abnormality. For parenchymal disease, the highest prevalence is seen in histologic or autopsy studies and high-resolution computed tomography (HRCT), which often demonstrates abnormalities not seen on chest radiography.
Systemic sclerosis shows the highest prevalence of interstitial pneumonia (IP) (±80% nonspecific) and vascular disease among the CTDs. Autopsy studies indicate that at least some degree of pulmonary fibrosis is present in up to 75% of SSc patients, and vascular disease occurs in approximately 30%. RA and PM/DM also show relatively high prevalence of certain degrees of lung fibrosis, but clinically overt disease occurs less often and is similar to SSc (~5%). Compared with SSc patients, those with RA or PM/DM complicated by lung fibrosis show higher frequency of usual interstitial pneumonia (UIP) and organizing pneumonia (OP). Of all pulmonary manifestations in CTDs, pleural disease is probably the most common, especially in RA and SLE. Table 53-1 summarizes the relative frequencies of the major respiratory complications, including IP subtypes, across the various CTDs.
There is increasing evidence of a genetic predisposition for CTDs. For example, RA is strongly associated with the major histocompatibility complex (MHC) Class II gene product HLA-DR4; up to 70% of patients with definite RA express HLA-DR4 versus 28% of control subjects. Evidence for genetic factors in SSc is supported by familial clustering, increased prevalence in twin studies, the high frequency of autoimmune disorders and autoantibodies in family members of SSc patients, and differences in prevalence and clinical manifestations among different ethnic groups. Strong genetic associations have been found between HLA-DRB1*11 and HLA-DPB1*1301 and diffuse SSc, and some evidence suggests an amino acid motif shared by the different MHC Class II susceptibility alleles that may be pivotal in predisposing to autoantibody formation.
In SSc and RA in particular, several genetic factors are specifically associated with pulmonary complications. In SSc, carriage of HLA-DRB1*11(04) and DPB1*1301 alleles is associated with lung fibrosis and DRB1*04 and DRB1*08 with pulmonary hypertension, related to the presence of anticentromere autoantibodies (ACAs). ACA positivity has also been shown to associate with carriage of a functional tumor necrosis factor promoter variant (TNF-863A). This and other genetic findings as yet have no clinical implication, although in the case of TNF-α, they suggest a different pathogenetic role of this cytokine across different SSc subsets. In RA, there is an association between obliterative bronchiolitis (OB) and the expression of histocompatibility antigens HLA-B40 and DR1, which implicates a genetic risk factor.
In CTDs the current concept is that interstitial fibrosis occurs in response to a persistent inflammatory stimulus, causing extended or repetitive tissue damage, and that fibrosis can be considered as an inappropriate response to injury or excessive wound healing. Activation and interaction of both the innate and the adaptive immune system and interaction with extravascular tissue promote the production and secretion of inflammatory mediators, including free radicals, cytokines, and chemokines. Along with growth factors and proteolytic enzymes, together these mediators modulate mesenchymal cell phenotypes and induce synthesis, deposition, and accumulation of extracellular matrix components within the affected tissues. As part of the regulatory process, there is often an upregulation of connective tissue matrix protein breakdown enzymes (e.g., collagenase) and other metalloproteinases and serine proteases (e.g., elastase), which can cause damage to the original architecture. Over time, these processes cause extensive tissue remodeling, with scar tissue substituting for normal tissue architecture and structures.
Numerous lines of evidence suggest that autoimmune antibodies play a key role in the inflammatory process that precedes the development of fibrosis. Reactivity to the nuclear autoantigen topoisomerase I (Scl70) is rarely seen other than with SSc and is strongly associated with lung fibrosis. Recently, the serum of SSc patients was found to contain stimulatory antibodies to the platelet-derived growth factor receptor, which can selectively induce intracellular transcription factors and reactive oxygen species and stimulate type I collagen-gene expression and myofibroblast phenotype conversion in normal human fibroblasts.
Pulmonary vessels may be involved by inflammation (vasculitis) or by concentric fibrosis formation. Vasculitis can affect all levels of the pulmonary circulation. Pulmonary capillaritis usually manifests as diffuse alveolar hemorrhage. The exact pathogenesis of vasculitis is not known, but in some syndromes such as SLE, it is thought to result from immune complex deposition.
Concentric fibrosis of small arterioles will give rise to pulmonary artery hypertension. The pathogenesis of pulmonary hypertension in CTDs is complex, with no single unifying hypothesis at present. Potential etiologies are autoimmune antibodies (e.g., antifibrillarin, antiendothelial, or anticentromere antibodies) and enhanced vasoreactivity. Several reports suggest that dysregulation of the pulmonary vascular tone may contribute to CTD-related pulmonary hypertension (“pulmonary Raynaud’s hypothesis”). The observation of decreased nitric oxide (NO) production in the lungs of patients with SSc and pulmonary hypertension supports that endothelial dysfunction contributes to altered regulation of pulmonary vascular tone and development of pulmonary hypertension. Other etiologies might be involved as well, including increased endothelin-1 (ET-1), platelet activation, and oxidant stress.
The CTDs may affect all parts of the airways. Usually, the pathology is characterized by diffuse inflammatory infiltrates in and around the walls of the larger and smaller airways and sometimes in their lumina. It is usually chronic in nature but may be a mixture of acute and chronic. Persistent inflammatory activity can cause damage to normal airway structures, which may induce wound-healing responses that lead to the accumulation of scar tissue in and around airways. In some conditions, such as relapsing polychondritis, specific anatomic structures may be involved.
Chronic bronchitis or bronchiolitis refers to a variable, intense, nonspecific chronic inflammatory cell infiltrate within the bronchial or bronchiolar walls. In SS the infiltrate tends to involve the seromucinous glands, leading to glandular atrophy and a “dry” trachea.
Follicular bronchitis or bronchiolitis (FB) is characterized by prominent peribronchial or peribronchiolar lymphoid follicles, with a minor interstitial inflammatory component. Compression of the airway lumina can lead to obstruction and intraluminal acute inflammatory cell infiltrate, plus pneumonia in some cases. FB is part of the spectrum of pulmonary lymphoid hyperplasia, with FB peribronchiolar in localization at one end and lymphocytic interstitial pneumonia (LIP) showing interstitial predominance at the other end. Both FB and LIP are rarely found in an idiopathic setting, and their recognition should always prompt investigation for an underlying CTD.
Obliterative bronchiolitis (OB) is thought to begin with damage of the respiratory epithelium of terminal bronchioles, leading to the formation of chronic inflammatory granulation tissue, often laid down in a circumferential pattern causing narrowing of the airways. Disease progression leads to obliteration of terminal bronchioles by dense fibrous tissue, with sparing of the respiratory bronchioles and alveoli (Figure 53-1).
Organizing pneumonia (OP) is one of the seven entities that constitute IP and has been confused with OB because of the previous term “bronchiolitis obliterans organizing pneumonia” (BOOP). In cryptogenic OP, patchy filling of alveoli with buds of granulation tissue may extend into respiratory bronchioles, but not terminal bronchioles.
Interstitial pneumonia is now used as a term to indicate the presence of diffuse inflammatory and/or fibrosing lung disease, either idiopathic or in the context of CTDs. In the past the term “fibrosing alveolitis” was often used for this condition. The past decade has seen considerable refinement in the recognition of pathologic IP patterns. For idiopathic IPs, there are presently seven histologic patterns: usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP; with a cellular and fibrotic subgroup), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP; with diffuse alveolar damage [DAD]), lymphocytic interstitial pneumonia (LIP), desquamative interstitial pneumonia (DIP), and respiratory bronchiolitis interstitial lung disease (RBILD). Use of this classification seems consistent and reliable and provides prognostic information for idiopathic disease.
In patients with UIP on lung biopsy and HRCT characteristics compatible with UIP, and with no known cause or association, the diagnosis of idiopathic UIP, idiopathic pulmonary fibrosis, is justified and carries a poor prognosis, especially compared with idiopathic NSIP. However, this prognostic difference between idiopathic UIP and NSIP is not necessarily the case in patients with CTD. Those with a UIP pattern on biopsy have a better chance of response to treatment and better prognosis than their counterparts with idiopathic disease.
Both DIP and RBILD are strongly associated with smoking and might not belong in the “idiopathic” IP classification system. Moreover, only small numbers of patients with histologic patterns of DIP and RBILD have been reported in series relating to CTDs, and many of these were smokers. Therefore, these two IP entities are unlikely to be causally related to CTD. Table 53-2 summarizes the histopathologic characteristics of the IPs typically seen in CTDs.
|Usual interstitial pneumonia (UIP)
|Fibrosis with honeycombing, fibroblast foci; anatomic destruction; little inflammatory cell infiltrate; normal/near-normal intervening lung parenchyma (temporal heterogeneity)
|Nonspecific interstitial pneumonia (NSIP)
|Variable interstitial inflammation and fibrosis; fibroblastic foci absent or scarce; uniformity of changes within biopsy specimen
|Organizing pneumonia (OP; or cryptogenic OP)
|Patchy filling of alveoli by buds of granulation tissue that may extend into bronchioles (Masson bodies); preservation of lung architecture
|Lymphocytic interstitial pneumonia (LIP)
|Extensive lymphocytic infiltration in the interstitium often associated with peribronchiolar lymphoid follicles (follicular bronchiolitis)
|Diffuse alveolar damage (DAD)*
|Diffuse alveolar septal thickening by inflammatory cell infiltrate, hyperplastic pneumocytes, hyaline membranes, air space organization
Other parenchymal disorders that can sometimes be found in CTDs include diffuse alveolar hemorrhage, amyloidosis, eosinophilic pneumonia, and alveolar proteinosis. In alveolar hemorrhage, biopsy shows a combination of intraalveolar hemorrhage and hemosiderosis. The hemosiderin, which provides evidence of previous bleeding, is largely contained within alveolar macrophages but may also impregnate elastin in a blood vessel. Alveolar hemorrhage is usually caused by small-vessel vasculitis of the lung, which is a rare pulmonary manifestation of CTDs, especially in SLE.
Amyloidosis is characterized by extracellular deposition of a proteinaceous substance that can be visualized under polarized light after Congo red staining. Amyloidosis is seen most often in relation to SS, with lymphoid hyperplasia and causing cystic changes.
Eosinophilic pneumonia is characterized by the expansion of alveoli by eosinophils, macrophages, and fibrinous debris, often with eosinophils involving the interstitium, as well as focal intraalveolar organization. This condition is often related to drug exposure in patients with CTD, but has also been attributed to RA itself.
The histologic features in CTD-associated pulmonary hypertension vary in relation to the degree of raised pulmonary artery pressure. In mild pulmonary hypertension, the histologic features are typically those of medial hypertrophy. With progression of the disease, marked intimal fibrous thickening and eventually plexiform lesions can be found. These histologic changes are essentially the same as those in idiopathic pulmonary hypertension. Early changes need to be distinguished from secondary changes related to an associated IP.
There is an increased risk for lung cancer in CTDs, especially in patients with lung fibrosis who also smoke. The most common neoplasm in SSc is adenocarcinoma, in some cases with a bronchoalveolar pattern. Patients with Sjögren syndrome have an increased risk of pulmonary lymphoma. This is usually a marginal zone, non-Hodgkin lymphoma of mucosa-associated lymphoid tissue (MALT). Preexisting follicular bronchiolitis or LIP is a risk factor (±5% may develop lymphoma).
The clinical hallmark of RA is an inflammatory erosive arthritis of small and large joints. Although rheumatoid factor (RF) has a reasonable sensitivity (60%), its specificity is often low (90%). Recently, anticyclic citrullinated peptide (CCP) antibodies have been identified that combine a high sensitivity (75%) with an excellent specificity (97%) for the diagnosis of RA. Extraarticular manifestations of RA are associated with RF, but interestingly not with anti-CCP antibodies. RA can involve any part of the respiratory tract, including the cricoarytenoid joint, airways, parenchyma, and pleura. Usually, only one of these disorders is predominant in a single individual, although parenchymal changes are often associated with airway disease (on HRCT).
Rheumatoid arthritis–associated pleural disease can be asymptomatic, although presenting symptoms and signs can include fever, pleuritic chest pain, and shortness of breath. Pleural effusions are generally small and unilateral, but rarely may occur in large volume or bilaterally. The fluid is exudative, with high protein and lactate dehydrogenase levels and low glucose concentration. Rheumatoid effusions usually have a low pH (<7.2) and are often paucicellular (<10,000/mL), with lymphocytic or polymorphonuclear predominance. Cytologic examination may reveal lipid droplets in the cytoplasm of neutrophils, similar to the phagocytes seen in the joint fluid of arthritic patients and known as RA cells, but these may occur in other conditions. Immunocytochemistry may reveal IgM (RF) and phagocytosed immune complexes in granulocytes and histiocytes. Thoracoscopy may reveal a fine granular appearance to the pleural wall. Histopathologic examination of these micronodules may show a linear granulomatous reaction with the mesothelium replaced by palisading histiocytes. Histologic examination can also show fibrosis with often prominent chronic inflammation, including hyperplastic lymphoid follicles. In general, however, pleural biopsy is especially helpful for exclusion of other causes of pleural disease.
Obliterative bronchiolitis is a serious complication of RA, and seems to be more common in women. OB usually occurs in patients who are RF positive and have well-established joint disease. In the past, penicillamine, which is rarely used now, was associated with development of OB in patients with RA. Also, a relationship with gold therapy has been suggested. Patients most often are initially seen with dyspnea and a nonproductive cough, which can worsen rapidly. The chest radiograph is usually normal but may show signs of hyperinflation (Figure 53-2) and in later stages fibrobullous degeneration (Figure 53-3). The diagnosis of OB should be considered in any patient with RA with progressive dyspnea and cough who has rapidly progressive airflow obstruction. Characteristic HRCT findings of OB consist of areas of decreased attenuation and vascularity with blood flow redistribution, resulting in areas of increased lung attenuation and vascularity (“mosaic perfusion” pattern), which is accentuated on expiratory scans (Figure 53-4). The prognosis is poor in RA patients with OB.
Figure 53-4 Characteristic findings on high-resolution computed tomography (HRCT) in 36-year-old woman with rheumatoid arthritis and severe constrictive bronchiolitis (FEV1 of 35% predicted). A, Inspiratory HRCT scan shows geographic pattern, with areas of increased (normal) and decreased (air trapping) attenuation. B, This pattern is accentuated on the expiratory scan.
The prevalence of clinically significant IP in patients with RA is estimated at 5%. IP is seen more often in men than in women, especially in the context of a high RF titer and severe articular disease. The pathologic patterns are diverse, but in contrast to other CTDs, a UIP pattern is relatively common (Figure 53-5). Symptoms are nonspecific and include progressive dyspnea and nonproductive cough. Dyspnea may appear late because of physical inactivity secondary to polyarthritis. Most patients have fine bibasilar crackles, but digital clubbing is less common than in patients with idiopathic pulmonary fibrosis (IPF). Lung function tests usually reveal a restrictive defect with normal airflow and reduced diffusion capacity (DLCO). HRCT is the most appropriate investigation to detect IP and is also useful in follow-up. UIP patterns on HRCT appear similar in RA and IPF, but coexisting pleural effusion or (necrobiotic) nodules may help in the differential diagnosis. In general, UIP associated with RA tends to follow a more benign course than the idiopathic form, but patients may develop end-stage respiratory failure (Figure 53-6).