**5.4. Amyopathic dermatomyositis**

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

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

In the context of subtypes of PM/DM, the following concepts of amyopathic dermatomyositis

and anti-synthetase syndrome warrant particular attentions.

considered [93, 94].

160 Contemporary Topics of Pneumonia

at the lung periphery [108].

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 associated with particularly poor clinical outcomes.

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

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

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

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

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 such autoantibodies are still awaited to be illuminated.


**Autoantibodies**

**Other MSA**

Anti-SRP Anti-HMGR(200-100)

Anti-SAE

3-hydroxy-3-methylglu tarylcoenzyme A reductase

Small ubiquitin-like modifier

<1/5–10/1–9

DM

Unknown

activating enzymes

**Myositis associated autoantibodies**

Anti-RO/SSA

Anti-U1RNP

RNP complexes with small

12/13/0

cytoplasmic RNAs(hy-RNA)

70 KDa,A and C polypeptides of U1

5/6/6

7

DM, fever, RP, sclerodactyly

snRNP

Anti-PM/Scl(75 and

PM/Scl complex encompassing

6/9/4

38

Fever, RP, sclerodactyly

C1D,PM-SCl-100 and PM-SCl-75

proteins of the human exosome

80 and 70 KDa DNA binding dimeric

2/1/0

27 ADM: adult dermatomyositis; JDM: juvenile dermatomyositis; ILD: interstitial lung disease; SRP: signal recognition particle; ARS: aminoacyl-t-RNA synthetase; RP:

Raynaud's phenomenon; DM: dermatomyositis specific rash; RP-ILP: rapidly progressive ILD; JPM: juvenile poly myositis

Adapted from Lega et al. [120].

**Table 4.** Autoantibodies in polymyositis/dermatomyositis.

Fever, RP, sclerodactyly

Interstitial Pneumonia Associated with Connective Tissue Disease: A Comprehensive…

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

163

protein

100 Kda)

Anti-Ku

Signal recognition particle

5/1/<3 10/<1/unknown

Unknown

15/0

Necrotising myopathy

Necrotising myopathy

 Unknown

Severe JPM

**Antibody target**

**Frequency in** 

**Frequency of ILD** 

**Clinical spectrum**

**In adulthood**

**In childhood**

**in adult /juvenile** 

**myositis %**

**polymyositis/ADM/**

**JDM %**


**Autoantibodies**

**Myositis- specific autoantibodies (MSA**)

*Anti-t-RNA synthetase*

Anti-Jo1 (PL1)

Anti- PL7 Anti- PL12

Anti-KS Anti-OJ

Anti-EJ Anti-SC

Anti-JS Anti-YRS(Ha)

Anti-Zo

Tyrosyl-ARS Phenylalanyl-ARS

**Dermatomyositis Specific autoantibodies**

Anti-Mi2

Nucleosome remodeling deacetylase

1/9/4–10

4/0

Classical DM without

Mild or moderate JDM

extramuscular involvement

DM without extramuscular

Mild or moderate JDM

involvement, calcinosis

complex

Anti-NXP2(MJ,p140)

Anti-

MDA5(CADM-140)

Anti-TIF1γ(p1555/140)

Transcriptional intermediary factor 1γ

<1/10–30/14–29

<10/3

Melanoma differentiation-associated gene encoding RNA helicase

<1/14–46/7

Europe:60; Asia:90/

Europe:19; Asia:53

progressive ILD

Cancer associated DM in

78% of cases

Amyopathic DM, severe cutaneous ulcers, rapidly

Severe cutaneous ulcers,

RP-ILP, mediastinal

emphysema

Mild or moderate JDM

Nuclear matrix protein 2

10/0–3/12–25

 0/25

Histidyl-ARS Threonyl-ARS

Alanyl-ARS Asparaginyl-ARS

Isoleucyl-ARS

Glycyl-ARS

Lysyl-ARS Glutaminyl-ARS

**Antibody target**

**Frequency in** 

**Frequency of ILD** 

**Clinical spectrum**

**In adulthood**

**In childhood**

**in adult /juvenile** 

**myositis %**

**polymyositis/ADM/**

**JDM %**

29/20/5

21/11/<3

5/2/<1 2/3/<1

<1

<1

<1

<1

<1

<1 <1

<1

84/63

66/63

Arthralgia, fever, RP,

Arthralgia, fever, RP,

162 Contemporary Topics of Pneumonia

mechanic's hand,

sclerodactyly

mechanic's hand, puffy

finger

ADM: adult dermatomyositis; JDM: juvenile dermatomyositis; ILD: interstitial lung disease; SRP: signal recognition particle; ARS: aminoacyl-t-RNA synthetase; RP: Raynaud's phenomenon; DM: dermatomyositis specific rash; RP-ILP: rapidly progressive ILD; JPM: juvenile poly myositis Adapted from Lega et al. [120].

**Table 4.** Autoantibodies in polymyositis/dermatomyositis.
