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

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

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

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

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,

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;

vascular complications, being helpful in recognizing early disease [67].

with ILD are negative for this antibody.

158 Contemporary Topics of Pneumonia

to be mentioned later [73, 74].

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

splenomegaly, and a variety of pleuro-pulmonary abnormalities.

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

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 universal classification criteria.

Several neuromuscular diseases which may mimic PM/DM and should be considered in the differential diagnosis include drug or toxic myopathies (alcohol, colchicine, statins, etc.), endocrine myopathies (hyper-hypothyroidism), metabolic myopathies, mitochondrial myopathies, muscular dystrophies, infectious myositis, neuropathies, paraneoplastic syndromes, other connective tissue disorders, amyloidosis, and sarcoidosis [93]. Muscular dystrophies, where an increase of creatine kinase (CK), electrodiagnostic, and bioptic abnormalities similar to PM/DM may be present, can be distinguished from DM/PM by the positive family history, the relatively early insidious onset, and slow progression. Iatrogenic myopathy is secondary to corticosteroids use, where CK is normal and the histological examination shows atrophic changes of muscle fibers. Other diseases to consider in the differential diagnosis are endocrine or dysionemia-induced myopathies. Rheumatic polymyalgia (polymyalgia rheumatica) is characterized by normal CK and histological absence of inflammatory abnormalities. Infectious myositis especially viral and parasitic myositis are characterized by a diffuse muscular involvement and a subacute or chronic course. Bacterial myositis is localized and acute. Among other rare inflammatory myopathies, nodular focal myositis is considered as a variant of PM/DM and may present at onset (As localized, a differential diagnosis with muscular cancers and/or thrombophlebitis must be considered). Eosinophilic myositis, characterized by muscle eosinophil infiltrate, may be part of a hypereosinophilic syndrome (pneumonia, endocardial and myocardial fibrosis, and peripheral neuropathy, etc.) or be associated with eosinophilic fasciitis. Granulomatous myositis can be isolated or in the context of granulomatous syndromes, such as sarcoidosis or Crohn's disease; the main histological finding is the presence of granulomatous lesions which may contain epithelioid cells, histiocyte, and Langerhans giant cells. In the differential diagnoses of IBM, polyneuropathy and amyotrophic lateral sclerosis have also to be considered [93, 94].

**5.4. Amyopathic dermatomyositis**

ated with particularly poor clinical outcomes.

**5.5. Anti-synthetase syndrome (ASS)**

Clinically amyopathic dermatomyositis (CADM), which is characterized by the cutaneous findings of DM with no muscle involvement or only minimal weakness, affects approximately 20% of patients with DM [109, 110]. Patients with CADM have a greater risk of developing ILD, especially prone to rapidly progressive lung disease corresponding to DAD [111, 112]. Anti-melanoma differentiation-associated gene 5 (MDA5) antibodies (also referred to as anti-CADM-140 antibodies) were identified in the serum from patients with CADM by firstly immunoprecipitation assays [113]. The presence of anti-MDA5 antibodies is strongly associated with DM, especially with CADM, and rapidly progressive ILD, which are thus associ-

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A subset of patients may manifest a clinical syndrome known as "anti-synthetase syndrome (ASS)," which is characterized by the presence of one of the anti-aminoacyl-t-RNA synthetase (ARS) antibodies such as anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, and anti-KS, together with stigmata of PM/DM including myositis, ILD, polyarthritis, fever, Raynaud's phenomenon, and mechanic's hand [114, 115]. Anti-Jo-1, the first anti-ARS antibody, is the best understood of the anti-synthetase antibodies, with a strong correlation with ILD in

Circulating autoantibodies directed against nuclear or cellular components are frequently detected in patients with PM or DM. These antibodies are categorized into two groups; one is specific to PM/DM, whereas the other is found in overlap syndrome with myositis. Targoff et al. designated these two categories of autoantibodies as "myositis-specific antibodies; MSAs" and "myositis-associated antibodies; MAAs," respectively [114]. Classical autoantibodies such as anti-aminoacyl transfer RNA synthetases (ARS) antibodies, anti-signal recognition particle (SRP) antibodies [118, 119], and Mi-2 antibodies are classified as MSAs, where especially anti-Mi-2 antibodies are DM specific [120]. Later, the new DM specific antibodies have been disclosed. These include the antibodies directed against melanoma differentiation– associated gene5 (MDA5) (anti-CADM-140 antibody, mentioned above) [113, 121, 122], transcriptional intermediary factor-1-gamma (anti-p155 antibody) [123, 124], NXP-2 (anti-NMP-2 antibody) [125, 126], and small ubiquitin-like modifier activating enzyme (anti-SAE antibody)

Because of their strong associations with a pattern of clinical features, such as myopathy, skin lesions, and ILD, these novel autoantibodies are useful biomarkers for classifying disease subgroups, predicting future organ involvement, and forecasting the prognosis of patients with PM/DM [114, 128–131]. The autoantibodies are detectable in PM/DM; both MSA and MAA are listed and summarized in **Table 4** [102]. The pathogenetic mechanisms of expression of

patients with PM/DM; the incidence of ILD approaches 90% [116, 117].

**5.6. Myositis-specific autoantibodies and myositis-associated autoantibodies**

[127]. Usually, MSAs are distinct, and their presence is mutually exclusive.

such autoantibodies are still awaited to be illuminated.

Concerning extra-muscular involvement, respiratory disease is a major cause of morbidity and mortality in PM/DM [53, 95–100]. PM/DM-associated pulmonary disorders may manifest as ILD and as a consequence of respiratory muscle weakness leading to hypoventilation or aspiration pneumonia. ILD is the most common extra-muscular complication in PM/DM and have been recognized in 30–70% of the patients [100–102]. The reported prevalence varies depending on the modalities or tests for detection and patient selections. Since Tazelaar et al. reported a histopathological study of lung biopsy specimens in patients with PM/DM in terms of treatment responses and survivals, histopathology fairly serves relevant clinical decisions [53]. As for the prevalence of the different histopathologic patterns, NSIP is by far the most frequent finding, followed by DAD, UIP, and OP [54, 103–107]. Our study with HRCT scans of 14 cases of histologically proven NSIP associated with PM/DM showed that the predominant features were of reticular and/or ground-glass opacities with or without consolidation. Reticular and ground-glass opacities predominated in the lower zone of each lung, and consolidation predominated at the lung periphery [108].

In the context of subtypes of PM/DM, the following concepts of amyopathic dermatomyositis and anti-synthetase syndrome warrant particular attentions.
