**3.3 Biomarkers of IP**

Autoantibodies to various cell components are detected in 50 to 80% of PM/DM patients (Reichlin & Arnett, 1984, Love 1991). Myositis-specific autoantibodies such as anti-aminoacyl transfer RNA synthetase (ARS) antibody and anti-signal recognition particle (SRP) antibody are specifically detected in PM/DM, and myositis-related antigens, such as anti-Ku antibody and anti-U1-RNP antibody, are also detected in connective tissue diseases other

Nagai, 2000). It often evolves into corticosteroid-resistant RPIP, often progressing to acute or subacute disease in several weeks or months, and many patients die in spite of strong immunosuppressive therapies. There are many unclear points as to how certain cases evolve into RPIP. Some cases that were identified histologically as NSIP change to DAD. In addition, pathological findings can be mixed within the same patient, and the histological

Pulmonary function tests (PFT) provide objective evaluation of respiratory symptoms and are important in determining the disease activity and therapeutic effects. However, in patients with severe respiratory failure such as that in RPIP, the tests cannot be performed or the results are not determined. Typically, a restrictive ventilatory impairment is present, and total lung capacity (TLC), vital capacity (VC), forced vital capacity (FVC), and the diffusing capacity for carbon monoxide (DLco) are decreased (Fathi, 2008). A decrease in DLco is one of the most sensitive indices showing a decrease in gas exchange. These abnormalities are improved by treatment. In cases without IP but with decreased FVC, it is

For imaging assessment of IP, the sensitivity of the chest X-ray is lower than that of highresolution CT (HRCT) using less than 3-mm slices (Figure 1). When PM/DM or IP associated with PM/DM is suspected, the lung should be assessed by HRCT. However, because the chest X-ray is easy to use and radiation exposure is low, it is useful for following

HRCT findings observed in PM/DM are diverse. The most frequently observed findings are reticular opacity or ground-glass opacity with subpleural curvilinear shadow that is predominantly distributed just below the bilateral dorsal regions of the lungs, and the findings sometimes accompany consolidation (Mino, 1997, Douglas, 2001, Arakawa, 2003, Bonnefoy, 2004, Hayashi, 2008). Ground-glass opacity and consolidation are improved by treatment. The decreased lung volume and traction bronchiectasis (TBE) are sometimes observed, but patients with honeycomb lung are rare. It is difficult to predict the prognosis of IP associated with DM/PM and to select treatment based only on HRCT findings. However, HRCT are useful for the assessment of disease activity and therapeutic effect. IP that is distributed through a wide area of the lungs and accompanies TBE at the early onset

Autoantibodies to various cell components are detected in 50 to 80% of PM/DM patients (Reichlin & Arnett, 1984, Love 1991). Myositis-specific autoantibodies such as anti-aminoacyl transfer RNA synthetase (ARS) antibody and anti-signal recognition particle (SRP) antibody are specifically detected in PM/DM, and myositis-related antigens, such as anti-Ku antibody and anti-U1-RNP antibody, are also detected in connective tissue diseases other

picture may vary according to the site of tissue sampling.

necessary to also consider a decrease in ventilatory muscle strength.

the course of the disease and for diagnosing complications such as infection.

**3. Laboratory findings** 

**3.2 Diagnostic Imaging** 

or exacerbation has a poor prognosis.

**3.3 Biomarkers of IP** 

**3.1 Pulmonary function tests** 

Fig. 1. Chest HRCT of IP associated with DM. (A) ground-glass opacity (open arrow) and consolidation (arrow); (B) subpleural curvilinear shadow (arrow); (C) Traction bronchiectasis.

than PM/DM. Patients from whom these autoantibodies are detected have respective clinical characteristics. Anti-ARS antibodies are detected in 25 to 30% of PM/DM patients, and of these anti-ARS antibodies, anti-Jo-1 antibody is most frequently detected and is closely related with myositis. Antibodies related to IP include anti-PL-12 antibody and anti-KS antibody (Friedman, 1996, Hirakata, 2007). Patients who test positive for anti-SRP antibody are considered to have fewer complications from IP (Targoff, 1990). Patients with CADM frequently complicate RPIP with poor prognosis and have been found to frequently test negative for antinuclear antibody. Recently, anti-CADM-140 (mda-5) antibody has been detected in the serum of patients with CADM (Sato, 2005). In the future, if a relation between this antibody and pathogenesis/clinical presentation is revealed, selection of treatment and prognosis are expected to improve.

Krebs von den Lungen-6 (KL-6) and surfactant D (SpD), which are produced and secreted on the epithelial surface by alveolar type II cells and bronchial epithelial cells, are useful markers for IP. These makers increase in the serum of patients with IP associated with PM/DM. The levels of these markers are inversely correlated with DLco and are useful in judging therapeutic effect (Kubo, 2000, Bandoh, 2000, Ihn, 2002). Not all patients with IP associated with PM/DM show increases in KL-6 and SpD, and there are patients without increased levels of KL-6 and SpD, especially in the acute phase.

Interstitial Pneumonia in Dermatomyositis 147

infectious diseases are a critical side effect of each type of medicine. As reported by Kameda et al. and Kotani et al., through careful monitoring and early detection of infection, preventative treatments can be administered at an early stage leading to a decreased number of deaths due to infectious diseases (Kamdeda 2006, Kotani, 2008). In our facility, factors such as leukocyte count (lymphocyte count), CRP, IgG, β-D-glucan, CMV-C7-HRP, procalcitonin, are regularly measured, and Trimethoprim-sulfamethoxazole is administered

Cyclosporine is a metabolic product of fungi and a hydrophobic cyclic polypeptide. When it is incorporated into T-lymphocytes, it binds to cyclophilin to form a complex, and when this complex inhibits the activity of calcineurin, expression of cytokine genes such as IL-2 and early activation genes is down-regulated. In DM/PM-complicated IP, because involvement of T-lymphocytes has been suggested from the lung biopsy and lymphocyte subset analysis of bronchoalveolar lavage fluid, concomitant therapy with steroids and cyclosporine has been conducted and has been shown to be efficacious (Nawata, 1999, Nagasawa, 2003, Kameda, 2005, Kotani, 2008). However, these various reports indicate variability in

Cyclosporine is likely to be affected by food and the amount of bile acid secreted, and the absorbed amount of cyclosporine varies within and between individuals. Because the therapeutic efficacy of cyclosporine depends on the concentration of the drug in the body and not on the dose, therapeutic drug monitoring (TDM) to determine the method of administration based on the concentration of the drug in the blood of individual patients has been recommended. In the treatment of DM/PM-complicated IP, cyclosporine has been administered at doses between 100 and 300 g/day (3 to 5 mg/kg/day) and at a serum trough concentration (C0) between 150 and 250 ng/mL, but there are no specific

Recently, Nagai et al. conducted and reported on TDM in 15 IP patients complicated with DM to determine the optimal method of cyclosporine administration (Nagai, 2010). It is known from organ transplantation that the immunosuppressive effect of cyclosporine correlates best with the area under the blood concentration curve (AUC), but this is not so suitable for use in daily management because frequent blood sampling is required. Therefore, the concentration of cyclosporine in the blood was determined before and after administration to determine which concentration correlates best with the AUC. As a result, the blood concentration at 2 hours after administration (C2) was the highest among all the patients, correlated best with AUC, and was considered to be an index of immunosuppressive effect (Figure 2). However, C0 did not correlate with the AUC. Moreover, when comparing between two postprandial doses and one preprandial dose, there was no difference in C2, but C0 was significantly lower when cyclosporine was administered once daily breakfast (Figure 3). Because the incidence of adverse events with cyclosporine increases when cyclosporine is used for a long time at a C0 of 200 ng/mL or higher (Min, 1998), the utility of the administration of one preprandial dose has been

therapeutic effect as the reported survival rates range from 42 to 78%.

to prevent *Pneumocystis jiroveci*.

**4.2 Cyclosporine** 

guidelines.

reported.

Ferritin is the major molecule of iron storage, and it was reported that serum ferritin level increases in A/SIP associated with DM (Gono, 2010). Serum ferritin level is also useful as a predictive factor for onset of A/SIP and is related to its prognosis. Although it is not altogether clear why serum ferritin increases in A/SIP, it is considered to be related to activation of alveolar macrophages.
