**3. Clinical landscape of interstitial lung disease in connective tissue disease**

The connective tissue disease (CTD) is a systemic, inflammatory, autoimmune disorder characterized by immune-mediated multiple organ dysfunction. The category of CTD includes a variety of diseases: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (Scleroderma, SSc), polymyositis/dermatomyositis (PM/DM), and a group of vasculitides. The CTD-related disorders such as Sjögren's syndrome (SS), mixed connective tissue disease (MCTD), etc., are also captured under the extended umbrella of CTD, as they share similar features. Involvement of the respiratory system occurs in those diseases and may be often major contributor to significant morbidity and mortality [5]. The clinical presentation is variable, ranging from cough, dyspnea, pleuritic pain to abnormal diffuse lung shadows on chest X-ray, in addition to clinical features suggestive of rheumatic disorders, i.e., arthralgia, Raynaud's phenomenon, and skin rashes. Some patients may have presentations dominated by pulmonary manifestations over those of autoimmune disease. Thus, it is crucial for physicians to carefully evaluate the evidence of underlying CTDs in all patients who present with ILD.

are SSc, RA, PM/DM, Sjögren's syndrome (SS), mixed connective tissue disease (MCTD), and SLE, according to prevalence [12, 13]. The frequency of ILD in CTDs is presented in **Table 3** [12]. Essentially, as every component of the lungs is a potential target for CTDs, there is a wide

Interstitial Pneumonia Associated with Connective Tissue Disease: A Comprehensive…

http://dx.doi.org/10.5772/intechopen.70864

151

Though the prevalence of ILD in CTDs varies based on patient selection and methods used for detection, the percentage appears to be higher than previously regarded. ILD may precede the extrapulmonary manifestations of CTD as a *forme fruste* of systemic disease, in some patients by years, while the rheumatic symptoms predate ILD in others [14–16]. Sometimes, it makes the distinction between idiopathic pulmonary fibrosis (IPF) and CTD-related ILD difficult [11, 16]. Despite similarities in clinical and pathologic presentation, the prognosis and treatment of CTD-associated ILD can differ greatly from that of other forms of ILD such as IPF [13, 16, 17]. Therefore, early detection of pulmonary involvement and early accurate diagnosis of CTDs are both important for initiating appropriate intervention. The multidisciplinary diagnostic team (MDD team), including a pulmonologist, a pathologist, and a rheumatologist, can contribute to it; a report indicates that 50% of patients referred with an initial concern for IPF had their diagnosis changed to a CTD-ILD after combined evaluation

The evaluation of ILD in patients with CTD is complex due to the heterogeneity of CTDs, the varied types and severity of ILD, and also the fact that ILD may be identified at any point in time in these patients. Fischer, et al. emphasize the importance of cross-disciplinary collaboration and thorough evaluations, which are needed either when CTD patients develop ILD or when encountering ILD patients with possible occult CTD [18]. The detection of occult CTD in patients with "idiopathic" ILD requires careful attention to historical clues, subtle physical examination findings, and autoantibody profiles, as well as radiologic and histopathological features. Such evaluation can be optimized by a multidisciplinary approach in collaboration with specialists including radiologists, pathologists, and rheumatologists. The standard clinical approach for evaluating patients with ILD for CTDs is well summarized by

variety of pulmonary manifestations associated with the diseases [13].

**3.2. Multidisciplinary diagnostic approach**

by the specialists [12].

Vij R and Strek ME in their review [5].

Modified from Castelino et al. [12].

**Table 3.** Features of ILD associated with CTD.

**Connective tissue disease Frequency of ILD Patterns**

Polymyositis/dermatomyositis 30–70% NSIP, OP, UIP, DAD Sjögren's syndrome Up to 25% NSIP, OP, UIP, LIP Systemic lupus erythematosus 2–8% NSIP, OP, UIP, DAD Mixed connective tissue disease 20–60% NSIP, OP, UIP, DAD

Systemic sclerosis 45% (clinically significant) NSIP 80–90%, UIP 10–20%, OP, DAD

Rheumatoid arthritis 5–58% UIP 50–60%, NSIP 30–60%, OP, LIP, DAD, DIP

#### **3.1. Prevalence of ILD**

**Pattern Histology CT features** UIP Subpleural and peripheral fibrosis. Temporal and spatial heterogeneity. Scattered *fibroblastic foci* and honeycombing are key features Basal, subpleural reticulation and honeycombing; traction bronchiectasis; little, if any, ground-glass attenuation NSIP Uniform interstitial involvement by variable degrees of degrees of fibrosis and inflammation. Honeycombing is rare Bilateral patchy ground-glass opacities admixed with reticulation and traction bronchiectasis/ bronchiolectasis. Little or no honeycombing. Usually, predominantly basal OP Connective tissue plugs within small airways and air spaces (Masson bodies). In its "pure" form, little or no inflammation or fibrosis in the surrounding interstitium Airspace consolidation, with a predominantly basal/peripheral or peribronchovascular distribution. Bands with air bronchograms and a perilobular pattern can also be seen DIP Extensive macrophage accumulation within the distal air spaces. Mild interstitisal involvement Patchy ground-glass opacities. Microcystic change can be seen within the ground-glass, Basal, peripheral distribution frequent LIP Bronchiolocentric lymphoid tissue hyperplasia Ground-glass attenuation is the predominant finding, with thin-walled cysts frequently present. Lung nodules and septal thickening may also be seen RB-ILD Bronchiolocentric macrophage accumulation. Mild bronchiolar fibrosis Centrilobular nodules, ground glass opacities. Diffuse or upper lung distribution DAD In the acute phase: hyaline membrane, edema. In the organizing phase: airspace and interstitial organization Acute phase: diffuse ground-glass opacities and consolidation in dependent areas. Organizing phase: reticular pattern, traction bronchiectasis

ILD, especially IP, is one of the most common and clinically important complications of the various CTDs and the CTD-related disorders of which the most often implicated disorders

Abbreviation: DIP, desquamative interstitial pneumonia; NSIP, non-specific interstitial pneumonia; UIP, usual interstitial pneumonia; OP, organizing pneumonia; DAD, diffuse alveolar damage; RB-ILD, respiratory bronchiolitis interstitial lung disease; LIP, lymphocytic interstitial pneumonia. Adapted from de Lauretis et al. [11].

and architectural distortion

**Table 2.** Classification of histological and radiological patterns for IP.

are SSc, RA, PM/DM, Sjögren's syndrome (SS), mixed connective tissue disease (MCTD), and SLE, according to prevalence [12, 13]. The frequency of ILD in CTDs is presented in **Table 3** [12]. Essentially, as every component of the lungs is a potential target for CTDs, there is a wide variety of pulmonary manifestations associated with the diseases [13].

#### **3.2. Multidisciplinary diagnostic approach**

variety of diseases: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (Scleroderma, SSc), polymyositis/dermatomyositis (PM/DM), and a group of vasculitides. The CTD-related disorders such as Sjögren's syndrome (SS), mixed connective tissue disease (MCTD), etc., are also captured under the extended umbrella of CTD, as they share similar features. Involvement of the respiratory system occurs in those diseases and may be often major contributor to significant morbidity and mortality [5]. The clinical presentation is variable, ranging from cough, dyspnea, pleuritic pain to abnormal diffuse lung shadows on chest X-ray, in addition to clinical features suggestive of rheumatic disorders, i.e., arthralgia, Raynaud's phenomenon, and skin rashes. Some patients may have presentations dominated by pulmonary manifestations over those of autoimmune disease. Thus, it is crucial for physicians to carefully evaluate the evidence of underlying CTDs in all patients who present with ILD.

ILD, especially IP, is one of the most common and clinically important complications of the various CTDs and the CTD-related disorders of which the most often implicated disorders

LIP Bronchiolocentric lymphoid tissue hyperplasia Ground-glass attenuation is the predominant

Abbreviation: DIP, desquamative interstitial pneumonia; NSIP, non-specific interstitial pneumonia; UIP, usual interstitial pneumonia; OP, organizing pneumonia; DAD, diffuse alveolar damage; RB-ILD, respiratory bronchiolitis

attenuation

seen

Basal, subpleural reticulation and honeycombing; traction bronchiectasis; little, if any, ground-glass

Bilateral patchy ground-glass opacities admixed with reticulation and traction bronchiectasis/ bronchiolectasis. Little or no honeycombing.

Airspace consolidation, with a predominantly basal/peripheral or peribronchovascular distribution. Bands with air bronchograms and a

Patchy ground-glass opacities. Microcystic change can be seen within the ground-glass, Basal, peripheral distribution frequent

finding, with thin-walled cysts frequently present. Lung nodules and septal thickening may also be

Centrilobular nodules, ground glass opacities.

Acute phase: diffuse ground-glass opacities and consolidation in dependent areas. Organizing phase: reticular pattern, traction bronchiectasis

Diffuse or upper lung distribution

and architectural distortion

Usually, predominantly basal

perilobular pattern can also be seen

**Pattern Histology CT features**

spatial heterogeneity. Scattered *fibroblastic foci* and

degrees of degrees of fibrosis and inflammation.

air spaces (Masson bodies). In its "pure" form, little or no inflammation or fibrosis in the surrounding

UIP Subpleural and peripheral fibrosis. Temporal and

OP Connective tissue plugs within small airways and

DIP Extensive macrophage accumulation within the distal air spaces. Mild interstitisal involvement

RB-ILD Bronchiolocentric macrophage accumulation. Mild

interstitial lung disease; LIP, lymphocytic interstitial pneumonia.

**Table 2.** Classification of histological and radiological patterns for IP.

In the organizing phase: airspace and interstitial

DAD In the acute phase: hyaline membrane, edema.

honeycombing are key features

NSIP Uniform interstitial involvement by variable

Honeycombing is rare

interstitium

bronchiolar fibrosis

organization

Adapted from de Lauretis et al. [11].

**3.1. Prevalence of ILD**

150 Contemporary Topics of Pneumonia

Though the prevalence of ILD in CTDs varies based on patient selection and methods used for detection, the percentage appears to be higher than previously regarded. ILD may precede the extrapulmonary manifestations of CTD as a *forme fruste* of systemic disease, in some patients by years, while the rheumatic symptoms predate ILD in others [14–16]. Sometimes, it makes the distinction between idiopathic pulmonary fibrosis (IPF) and CTD-related ILD difficult [11, 16]. Despite similarities in clinical and pathologic presentation, the prognosis and treatment of CTD-associated ILD can differ greatly from that of other forms of ILD such as IPF [13, 16, 17]. Therefore, early detection of pulmonary involvement and early accurate diagnosis of CTDs are both important for initiating appropriate intervention. The multidisciplinary diagnostic team (MDD team), including a pulmonologist, a pathologist, and a rheumatologist, can contribute to it; a report indicates that 50% of patients referred with an initial concern for IPF had their diagnosis changed to a CTD-ILD after combined evaluation by the specialists [12].

The evaluation of ILD in patients with CTD is complex due to the heterogeneity of CTDs, the varied types and severity of ILD, and also the fact that ILD may be identified at any point in time in these patients. Fischer, et al. emphasize the importance of cross-disciplinary collaboration and thorough evaluations, which are needed either when CTD patients develop ILD or when encountering ILD patients with possible occult CTD [18]. The detection of occult CTD in patients with "idiopathic" ILD requires careful attention to historical clues, subtle physical examination findings, and autoantibody profiles, as well as radiologic and histopathological features. Such evaluation can be optimized by a multidisciplinary approach in collaboration with specialists including radiologists, pathologists, and rheumatologists. The standard clinical approach for evaluating patients with ILD for CTDs is well summarized by Vij R and Strek ME in their review [5].


**Table 3.** Features of ILD associated with CTD.
