**5. Characteristic of interstitial lung disease in major connective tissue disease**

#### **5.1. Interstitial lung disease in systemic sclerosis**

SSc is recognized as the CTD with the highest prevalence of ILD, ranging from 40 to 80%, depending on the modalities used for ascertainment [63]. The frequency of ILD varies according to patient selection, subsets of skin disease extent and ethnicity. In a large autopsy study, ILD was the most common pulmonary lesion in SSc, being found in >70% of the cases, and arteriolar thickening, described as medial hypertrophy or concentric intimal proliferation, was the most specific lesion in the lungs suggestive of pulmonary hypertension, being noted in 29% of the patients [64]. SSc, classically "scleroderma," is defined by the presence of major criteria; i.e., skin thickening proximal to metacarpo-phalangeal joints and minor criteria; i.e., sclerodactyly, esophageal involvement, and lung fibrosis [65]. It is subdivided into a limited cutaneous form, including CREST (Calcinosis, Raynaud's syndrome, Esophageal dysmotility, Sclerodactyly, Telangiectasia) syndrome and a diffuse cutaneous form (diffuse SSc has skin sclerosis proximal to elbows and knees), with varying degrees of skin, esophageal, lung, cardiac, and vascular involvement. Both forms can be progressive in nature.

As mentioned above, pulmonary manifestations in SSc include ILD and vascular disorder manifesting as pulmonary arterial hypertension (PAH). Today, both pulmonary complications are the leading cause of morbidity and mortality in patients with SSc. In line with SSc as the vasculature disorder, ranging from Raynaud' s phenomenon to PAH and renal crisis, nailfold capillary microscopy is now a well-established measure to evaluate capillary damage or abnormality [66]. The capillary changes observed in digits can be a predictor of severe vascular complications, being helpful in recognizing early disease [67].

ILD affects men twice as commonly as women. The prevalence of ILD ranges widely from 5 to 58% in various reports [78–80]. It is difficult to confirm the exact prevalence because it depends on modalities of ascertainment and patient selection such as autopsy, hospital, and community-based studies. In a study of 36 patients with new onset RA, abnormalities consistent with ILD were found in 58% of patients; physiology 22%, chest X ray 6%, HRCT 33%, BAL 52%, and 99mTc-DTPA radionuclide scan 15% [81]. Smoking is a significant risk factor for ILD; an odds ratio of 3.8 for ILD was observed in RA patients with a smoking history >25 pack years [82]. In the context of histological patterns, the predominant ILD histology in RA patients is NSIP (cellular or, more commonly, fibrotic NSIP), followed closely by UIP, accounting for 30–67% and 13–57% of RA-associated ILD, respectively [42, 44, 59, 83–85]. Some studies have noted greater incidence of UIP histology in RA-ILD found in up to 56% of patients in a series [42]. These NSIP and UIP patterns are followed by organizing pneumonia (OP). There is evidence suggesting that a UIP pattern may be associated with a worse survival than fibrotic NSIP in cases of RA, in contrast with the other CTDs. A pattern of DAD/acute interstitial pneumonia (AIP) is infrequent but may occur as fulminant ILD manifestation of RA, which can develop in a previously normal lung or as the presenting pattern of a previously undiagnosed ILD. The characteristic CT pattern of DAD includes widespread ground glass with/without areas of dependent consolidation, although a similar pattern could represent opportunistic or viral infection and acute heart failure.

Interstitial Pneumonia Associated with Connective Tissue Disease: A Comprehensive…

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

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Idiopathic inflammatory myopathy (IIM), a group of systemic autoimmune disorders that affect skeletal muscles and other organs, comprises three major categories: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). PM and DM are sometimes recognized together as they share similar clinical signs and symptoms with exception of cutaneous manifestations such as "heliotrope rash" on the upper eyelids, "mechanic's hands" on the fingers, and "Gottron papules" on the dorsal surface of the hands seen in DM. Pathologically, however, these are distinct entities; PM is T cell-mediated diseases, where CD8-positive cytotoxic T cells invade muscle fibers expressing MHC class I antigens, whereas DM is character-

The diagnosis of PM/DM is made on the basis of clinical features and examinations, which include symmetrical proximal muscle weakness, elevated serum muscle enzymes, characteristic electromyographic alterations, muscle biopsy histopathology consistent with myositis, and for DM, typical cutaneous manifestations mentioned above and less-specific skin rashes. Moreover, muscle magnetic resonance imaging (MRI) and ultrasound (US) have been also introduced in the diagnostic work up of patients with inflammatory myopathies. Classification criteria for PM/DM date back to initial publications by Medsger et al. [89]. Since, in 1975, Bohan and Peter classified myositis, their criteria have been widely used [90, 91]. However, it demonstrated poor specificity and cannot distinguish PM from IBM or some forms of dystrophies for instance. Thus, several diagnostic criteria for inflammatory myopathies have been proposed with little acceptance, including recent muscle-biopsy-based diagnostic criteria [92]. Further prospective studies are required to develop improved and

**5.3. Interstitial lung disease in polymyositis/dermatomyositis**

ized by a complement-mediated microangiopathy [86–88].

universal classification criteria.

In the context of autoantibodies, anti-nuclear antibodies (ANA) are found in the majority of SSc patients although not in every case. In 2013, the novel classification criteria of American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) collaborative initiative for SSc incorporated three major autoantibodies [68]. These antibodies with high specificity for SSc are against topoisomerase (ATA or anti Scl-70), anticentromere antibodies (ACA), and anti-RNA polymerase III (ARA). They are closely related to distinct disease patterns; anti-topoisomerase antibodies are strongly associated with ILD, whereas anticentromere antibodies are highly predictive of the absence of significant lung fibrosis but associated with development of pulmonary hypertension [69]. Anticentromere antibodies, which are frequently found among Caucasians (20–35%), are strongly indicative of a limited form disease referred as CREST syndrome [69]. The other major autoantibody, anti-RNA polymerase III, is linked to diffuse skin disease and renal crisis, with less significant lung fibrosis. This antibody has another aspect that may herald paraneoplastic SSc [70]. While almost all patients with anti-topoisomerase antibodies have some extent of ILD, more than half of the SSc patients with ILD are negative for this antibody.

The most common pattern of ILD in SSc is fibrotic NSIP which manifests as dense, paucicellular interstitial fibrosis that maintains the underlying architecture [60, 71, 72]. As the lung disease progresses, the areas of fibrosis may become confluent and appear as honeycomb. SSc patients may also present with typical UIP pattern with temporal and special heterogeneity, in contrast to the diffuse and uniform fibrosis of NSIP. In most SSc patients, ILD remains stable without treatment despite having some degree of lung fibrosis. However, some proportions of the SSc patients develop significant and progressive ILD. In SSc-associated ILD, placebocontrolled randomized trials, named the Scleroderma Lung Study (SLS) and the fibrosing alveolitis scleroderma trial (FAST), have been performed, suggesting certain effectiveness of immunosuppressive therapy in preventing further decline in patients with progressive ILD to be mentioned later [73, 74].

#### **5.2. Interstitial lung disease in rheumatoid arthritis**

RA is the most common CTD, occurring in 1–2% of the population, more frequently in women. Although RA is primarily characterized by synovial inflammation which leads an erosive inflammatory polyarthropathy, predominantly affecting the distal joints, extra-articular manifestations are seen in approximately half of patients with RA. Extra-articular manifestations include subcutaneous nodules, skin ulceration, scleritis/episcleritis, pericarditis, splenomegaly, and a variety of pleuro-pulmonary abnormalities.

Lung disease accounts for 10–20% of mortality in RA, second only to cardiac disease [75–77]. Airway, pleural, vascular, and parenchymal involvement can occur in RA patients, as well as pulmonary disorders indirectly associated with RA such as opportunistic infections and druginduced lung disease. All pleuro-pulmonary manifestations in RA are more common in males; ILD affects men twice as commonly as women. The prevalence of ILD ranges widely from 5 to 58% in various reports [78–80]. It is difficult to confirm the exact prevalence because it depends on modalities of ascertainment and patient selection such as autopsy, hospital, and community-based studies. In a study of 36 patients with new onset RA, abnormalities consistent with ILD were found in 58% of patients; physiology 22%, chest X ray 6%, HRCT 33%, BAL 52%, and 99mTc-DTPA radionuclide scan 15% [81]. Smoking is a significant risk factor for ILD; an odds ratio of 3.8 for ILD was observed in RA patients with a smoking history >25 pack years [82].

In the context of histological patterns, the predominant ILD histology in RA patients is NSIP (cellular or, more commonly, fibrotic NSIP), followed closely by UIP, accounting for 30–67% and 13–57% of RA-associated ILD, respectively [42, 44, 59, 83–85]. Some studies have noted greater incidence of UIP histology in RA-ILD found in up to 56% of patients in a series [42]. These NSIP and UIP patterns are followed by organizing pneumonia (OP). There is evidence suggesting that a UIP pattern may be associated with a worse survival than fibrotic NSIP in cases of RA, in contrast with the other CTDs. A pattern of DAD/acute interstitial pneumonia (AIP) is infrequent but may occur as fulminant ILD manifestation of RA, which can develop in a previously normal lung or as the presenting pattern of a previously undiagnosed ILD. The characteristic CT pattern of DAD includes widespread ground glass with/without areas of dependent consolidation, although a similar pattern could represent opportunistic or viral infection and acute heart failure.
