**4. Treatment of IP**

Therapy with massive doses of corticosteroids is used in the treatment of DM/PMcomplicated IP. Although it is often effective in PM, IP associated with DM, especially in the initial treatment of RPIP, is often refractory to corticosteroid therapy . Nawata et al. reported on the prognosis of the treatment of IP in 31 cases of DM/PM using corticosteroid drugs along with pulse therapy (Nawata, 1999). The first-year survival rate after beginning the treatment was 50% in 20 patients with DM and 90% in 11 patients with PM. In addition, in all patients who died, death occurred within 12 weeks and was due to an exacerbation of IP or infection. Fujisawa et al. reported initial survival rates in 12 patients with DM and 16 patients with PM of 58% and 81%, respectively, when combining corticosteroids with an immunosuppressive agent such as cyclophosphamide (Fujisawa, 2005).

The combination of corticosteroids with immunosuppressive agents is currently the preferred method of treatment of DM/PM-complicated IP, especially in the early treatment of RPIP. Nagasawa et al. surveyed 32 facilities nationwide that specialize in the treatment of connective tissue diseases. The group analyzed clinical data from 38 patients with acute IP in DM/PM who were treated for 2 or more weeks with cyclosporine (Nagasawa, 2003). Among 25 patients who were initially treated for 2 weeks or longer using only corticosteroids following the addition of cyclosporine, the 2-year survival rate was 32%. Among the other13 patients who were treated with cyclosporine within 2 weeks of starting corticosteroid treatment, the average survival rate 2 years later was 69%. Takada et al. reported that when comparing the results from 20 active cases of DM/PM-complicated IP, in which only additional immunosuppressive agents were added if corticosteroid alone did not result in a favorable response, with 14 additional cases in which immunosuppressive agents were combined with corticosteroids, the combination therapy led to a higher survival rate (Takada, 2007). Other clinical trials reported similar results (Yamasaki, 2007, Kotani, 2008). These reports indicate that early combined therapy is more effective than combining additional agents at a later time; as a result, this maximizes the effectiveness of the immunosuppressant.

#### **4.1 Immunosuppressants available for DM/PM-complicated IP**

Currently, positive clinical trials are going forward for the following immunosuppressive drugs used in the treatment of DM/PM-complicated IP: cyclophosphamide, cyclosporine, and tacrolimus, amongst others. It is important to introduce treatment with the immunosuppressive agent at an early stage before remodeling the lung tissues, and the dosage and the mode of administration can also greatly influence the therapeutic effect. In addition, because of possible side effects, it is necessary to monitor renal function and carefully consider the dosages and effects of possible drug combinations. Specifically, 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 to prevent *Pneumocystis jiroveci*.

#### **4.2 Cyclosporine**

146 Neuromuscular Disorders

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

Therapy with massive doses of corticosteroids is used in the treatment of DM/PMcomplicated IP. Although it is often effective in PM, IP associated with DM, especially in the initial treatment of RPIP, is often refractory to corticosteroid therapy . Nawata et al. reported on the prognosis of the treatment of IP in 31 cases of DM/PM using corticosteroid drugs along with pulse therapy (Nawata, 1999). The first-year survival rate after beginning the treatment was 50% in 20 patients with DM and 90% in 11 patients with PM. In addition, in all patients who died, death occurred within 12 weeks and was due to an exacerbation of IP or infection. Fujisawa et al. reported initial survival rates in 12 patients with DM and 16 patients with PM of 58% and 81%, respectively, when combining corticosteroids with an

The combination of corticosteroids with immunosuppressive agents is currently the preferred method of treatment of DM/PM-complicated IP, especially in the early treatment of RPIP. Nagasawa et al. surveyed 32 facilities nationwide that specialize in the treatment of connective tissue diseases. The group analyzed clinical data from 38 patients with acute IP in DM/PM who were treated for 2 or more weeks with cyclosporine (Nagasawa, 2003). Among 25 patients who were initially treated for 2 weeks or longer using only corticosteroids following the addition of cyclosporine, the 2-year survival rate was 32%. Among the other13 patients who were treated with cyclosporine within 2 weeks of starting corticosteroid treatment, the average survival rate 2 years later was 69%. Takada et al. reported that when comparing the results from 20 active cases of DM/PM-complicated IP, in which only additional immunosuppressive agents were added if corticosteroid alone did not result in a favorable response, with 14 additional cases in which immunosuppressive agents were combined with corticosteroids, the combination therapy led to a higher survival rate (Takada, 2007). Other clinical trials reported similar results (Yamasaki, 2007, Kotani, 2008). These reports indicate that early combined therapy is more effective than combining additional agents at a later time; as a result, this maximizes the effectiveness of the

Currently, positive clinical trials are going forward for the following immunosuppressive drugs used in the treatment of DM/PM-complicated IP: cyclophosphamide, cyclosporine, and tacrolimus, amongst others. It is important to introduce treatment with the immunosuppressive agent at an early stage before remodeling the lung tissues, and the dosage and the mode of administration can also greatly influence the therapeutic effect. In addition, because of possible side effects, it is necessary to monitor renal function and carefully consider the dosages and effects of possible drug combinations. Specifically,

immunosuppressive agent such as cyclophosphamide (Fujisawa, 2005).

**4.1 Immunosuppressants available for DM/PM-complicated IP** 

activation of alveolar macrophages.

**4. Treatment of IP** 

immunosuppressant.

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

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 guidelines.

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 reported.

Interstitial Pneumonia in Dermatomyositis 149

It has been reported that the immunosuppressive effect of cyclosporine reaches its maximum effects if the C2 exceeds 1000 ng/mL. The ideal dose of cyclosporine in the treatment of DM/PM-complicated IP has not been established yet. The dose is reported to be variable, which may affect its therapeutic effect. In the future, it will be necessary to evaluate not only dosage and C0 but also C2. Recently, Kotani et al. reported that the C2 of cyclosporine correlated with the HRCT findings and improvement of respiratory function

Tacrolimus is a metabolic product of an actinobacteria, *Streptomyces tsukubaensis*, and has a macrolide skeleton. When it is incorporated into T-lymphocytes, it forms a complex with the FK506-binding protein. As a cyclosporine, this complex shows immunosuppressive effects by inhibiting the activity of calcineurin. The activity of tacrolimus is 30- to 100-times higher than that of cyclosporine *in vitro,* and it inhibits mixed lymphocyte culture reaction, production of IL-2, expression of IL-2 receptor, and production of IFN-γ. Clinically, tacrolimus is used for inhibition of rejection after transplantation of kidneys, liver, heart, lung and pancreas and in rheumatic diseases such as systemic lupus erythematosus,

Oddis et al. reported the utility of tacrolimus in 8 patients with refractory PM associated with IP (Oddis, 1999). When tacrolimus was orally administered to maintain the C0 at 5 to 20 ng/mL, recovery of muscle strength was observed in all 8 patients, and among 5 patients complicated with IP, 3 showed improvement, and 1 was stabilized. Thereafter, Wilkes et al. reported 13 patients with anti-tRNA synthase antibody-positive refractory DM/PM who were treated with tacrolimus (Wilkes, 2005). It was possible to rescue all the patients, to improve respiratory function, and to reduce the dose of corticosteroids administered. Takada et al. retrospectively examined the clinical effects of tacrolimus in 5 IP patients complicated with refractory DM/PM (Takada, 2005). As a result, they reported that all 5 patients could be rescued and that in 4 patients who could be evaluated by PFT before and

The treatment of DM/PM-complicated IP is conducted at a tacrolimus dose of 4 to 6 mg/day and a C0 of 5 to 10 ng/mL. Tacrolimus is also likely to be affected by food, and it is known that the AUC and the maximum blood concentration (Cmax) decrease with postprandial administration. For cyclosporine, C2 monitoring is required to evaluate immunosuppressive effects, but for tacrolimus, since both the blood concentrations before and at 0 to 7 hours after administration correlate well with the AUC, it is better to monitor

The adverse events of tacrolimus are infection as well as renal disorders, hypertension, diabetes mellitus, and hyperkalemia. The onset of adverse events depends on the concentration, and if the C0 is as high as 20 ng/mL for a long time, adverse reactions increase. Similar to cyclosporine, because tacrolimus is metabolized at CYP3A4, it is necessary to pay attention to concomitant drug use. Moreover, because hyperkalemia can be observed, attention must be paid to administration of potassium-conserving diuretics such

rheumatoid arthritis, Behçet's disease, and myasthenia gravis.

after treatment, the PFT values were improved.

instead of C0 (Kotani, 2011).

**4.3 Tacrolimus** 

C0 only. (Figure 4)

as spironolactone and eplerenone.

Fig. 2. Correlation of AUC0-6 with C0, C2 and C4 of cyclosporine. C0 presents the serum trough concentration. C2 and C4 present the blood concentration at 2 and 4 hours after administration, respectively. *Closed* and *Open circles* represent patients with preprandial and postprandial administration, respectively. Reproduced with permission from Nagai K, et al., Therapeutic drug monitoring of cyclosporine microemulsion in interstitial pneumonia with dermatomyositis. *Mod Rheumatol*, 2010 (21): 32-36.

Fig. 3. Comparison of blood cyclosporine level between postprandial daily administration in two doses and preprandial, once daily administration; *Pre* preprandial, once daily before breakfast in a single dose; *Post* postprandial, twice daily in a divided dose. Reproduced with permission from Nagai K, et al., Therapeutic drug monitoring of cyclosporine microemulsion in interstitial pneumonia with dermatomyositis. *Mod Rheumatol*, 2010 (21): 32-36.

Adverse events to cyclosporine include infection as well as renal disorders, hypertension, diabetes mellitus, and hepatic disorders. Because the onset of adverse events is concentration-dependent, the dose is adjusted so that the C0 is 200 ng/mL or less, but it may be impossible to reduce the dose because of the high activity of IP. Nagai et al. reported that when the C2 was 1222.6±523.8 ng/mL, the C0 was 157.3±41.4 ng/mL (Nagai, 2010), so cyclosporine can be used relatively safely if the C2 is maintained at about 1200 ng/mL. If cyclosporine is used for a long time, however, the serum creatinine value gradually increases. Thus, monitoring of both C2 and C0 are required for the assessment of immunosuppressive effects and adverse events. Moreover, because cyclosporine is metabolized at cytochrome P450 (CYP) 3A4, concomitant use with tacrolimus, bosentan, pitavastatin, and rosuvastatin is contraindicated, and it is also necessary to pay attention to concomitant use with aminoglycoside antibiotics and amphotericin B, which have been known to induce renal disorders.

It has been reported that the immunosuppressive effect of cyclosporine reaches its maximum effects if the C2 exceeds 1000 ng/mL. The ideal dose of cyclosporine in the treatment of DM/PM-complicated IP has not been established yet. The dose is reported to be variable, which may affect its therapeutic effect. In the future, it will be necessary to evaluate not only dosage and C0 but also C2. Recently, Kotani et al. reported that the C2 of cyclosporine correlated with the HRCT findings and improvement of respiratory function instead of C0 (Kotani, 2011).
