Connective Tissue Diseases

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).


Specific CTDs include the following:

Other CTDs include relapsing polychondritis and ankylosing spondylitis.


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.


Interstitial Fibrosis

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.

Lung Pathology

Airway Pathology

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.

Parenchymal Pathology

Alveolar parenchymal disease in CTDs usually involves the IPs and sometimes other rare conditions such as alveolar hemorrhage and amyloidosis.

Interstitial Pneumonias

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.

Table 53-2 Interstitial Pneumonias in Connective Tissue Disease: Major Histopathologic Characteristics

Type Histopathologic Characteristics
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

* In acute interstitial pneumonia (AIP).

Clinical Features

Rheumatoid Arthritis

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).

Airways Disease

Bronchiectasis is a frequent finding on HRCT in patients with RA (up to 70%), but in most patients, it is asymptomatic.

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 53-3 Chest radiograph of same patient as in Figure 53-2 a few years later, showing evolution toward fibrosis and bullous degeneration.

Interstitial Pneumonias

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).

Jun 12, 2016 | Posted by in RESPIRATORY | Comments Off on Connective Tissue Diseases

Full access? Get Clinical Tree

Get Clinical Tree app for offline access