The purpose of the study is to evaluate the efficacy and safety of the combination treatment of tacrolimus and corticosteroid in polymyositis/dermatomyositis patients with interstitial pneumonitis with comparison against corticosteroid-treated historical controls.

Interstitial pneumonia (IP) is a common complication of and has a significant impact on the prognosis of patients with polymyositis (PM) and dermatomyositis (DM). Reported prevalence of IP in PM/DM patients varies between 23 to 65% depending on criteria applied as well as on clinical settings of studied cohorts, and an earlier overview and a later study reported its high short-term mortality.

However, treatment for this grave complication has not yet been either established or even been prospectively investigated. Glucocorticoids, while long been considered as the first-line drugs, is effective in less than 50% of patients. Furthermore, the mortality of these glucocorticoids-resistant patients does not improve even if immunosuppressive drugs are later added.

Recently, we and others reported retrospective data which suggest that either an early addition of immunosuppressive drugs to glucocorticoids or the combined use of glucocorticoids and immunosuppressive drugs from the initial treatment may improve the survival of PM/DM patients. To save lives of PM/DM-IP patients, desperate treating physicians have started using this approach, strongly urging the conduct of prospective studies to investigate the superiority of this approach over glucocorticoids alone. At the same time, it was considered not ethically appropriate to conduct a prospective study with a concurrent controlled group receiving glucocorticoids alone given the presence of the PM/DM-IP subtype with rapidly progressive course and high short-term mortality if treated with glucocorticoids alone and the absence of useful demographic or bio-markers which could distinguish patients with this subtype early. Among immunosuppressive drugs used in the treatment of PM/DM-IP, tacrolimus has recently been suggested to be effective even for those patients who are resistant to cyclosporine or cyclosphosphamide.

To investigate whether the combined initial treatment of glucocorticoids and tacrolimus is superior to glucocorticoids alone in PM/DM-IP patients, we conducted a multicenter clinical trial to evaluate the efficacy and safety of a combination treatment of glucocorticoids and tacrolimus for 1 year in patients with newly developed active PM/DM-IP or its relapse by comparing against clinical outcome of historical control patients who were treated with glucocorticoid alone as an initial treatment.

Inclusion Criteria:

Experimental treatment group

1. Diagnosis of definite or probable polymyositis or dermatomyositis by criteria of Bohan et al, or of clinically-amyopathic dermatomyositis by the definition proposed by Sontheimer et al

2. High-resolution CT findings consistent with interstitial pneumonitis, confirmed by a radiologist. If consolidation is the only abnormal findings, the patient must have pathologically documented evidence of interstitial pneumonitis of other histological type than cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia (the patient could have more than one histological type including cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia)

3. Meet two or more of the following criteria (must include 1) 1. Serum KL-6 above the upper normal limit 2. Presence of dyspnea on exertion (grade 2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index 3. PaO2 of less than 80 mmHg while breathing ambient air at rest, not accompanied by abnormal increase of PaCO2 4. Vital capacity < 80% predicted, or diffusing capacity for carbon monoxide < 65% predicted 5. Meet at least one of the following condition over the 12-week period (84 days) prior to the initiation of the study drug

   • Decrease in either % forced vital capacity or % diffusing capacity for carbon monoxide of 10% or more
   • Worsening of interstitial pneumonitis findings by chest CT, confirmed by a radiologist

4. 16 to 74 years of age

Historical control group

1. Diagnosis of definite or probable polymyositis or dermatomyositis by criteria of Bohan et al, or of clinically-amyopathic dermatomyositis by the definition proposed by Sontheimer et al

2. High-resolution CT findings consistent with interstitial pneumonitis, confirmed by a radiologist. If consolidation is the only abnormal findings, the patient must have pathologically documented evidence of interstitial pneumonitis of other histological type than cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia (the patient could have more than one histological type including cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia)

3. Meet two or more of the following criteria (must include 1) 1. Serum KL-6 above the upper normal limit 2. Presence of dyspnea on exertion (grade 2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index 3. PaO2 of less than 80 mmHg while breathing ambient air at rest, not accompanied by abnormal increase of PaCO2 4. Vital capacity < 80% predicted, or diffusing capacity for carbon monoxide < 65% predicted 5. Meet at least one of the following condition over the 12-week period (84 days) prior to the initiation of the study drug

   • Decrease in either % forced vital capacity or % diffusing capacity for carbon monoxide of 10% or more
   • Worsening of interstitial pneumonitis findings by chest CT, confirmed by a radiologist

4. Use of corticosteroids at doses equivalent to between 0.6 to 1.0mg/kg/day of prednisolone for 14 days or longer to treat interstitial pneumonitis on or after the day when the inclusion criteria (3) was met (up to two courses of pulse IV corticosteroid therapy within the first 28 days are allowed)

5. 16 to 74 years of age

Exclusion Criteria:

Experimental treatment group

1. Use of corticosteroids at doses equivalent to or higher than prednisolone 0.6mg/kg/day within 4 weeks (28 days) prior to the initiation of the study drug
2. Use of immunosuppressive agents other than corticosteroids within 12 weeks (84 days) prior to the initiation of the study drug
3. Could not exclude the following conditions on clinical ground: drug-induced pneumonitis, occupational lung disease, hypersensitivity pneumonitis, radiation-induced lung injury
4. Presence of end-stage interstitial pneumonitis as identified on the basis of a vital capacity < 45% predicted, diffusing capacity for carbon monoxide < 30% predicted, or lung CT with predominantly honeycombing appearance
5. Presence of pancreatitis
6. Presence of diabetes mellitus with the exception of glucocorticoid-induced one that is well-controlled (HbA1c < 6.5%)
7. Serum creatinine of 1.5 mg/dL or above
8. Presence of liver dysfunction (AST(GOT) or ALT (GPT) greater than 2.5 times the upper limit of normal) with the exception of the one that is considered to be due to myositis and is accompanied by the elevation of muscle enzymes above the upper limit of normal
9. Serum potassium above the upper limit of normal
10. Presence of ischemic heart disease, arrhythmia requiring treatment, congestive heart failure, or pulmonary hypertension requiring treatment
11. Presence or history of malignancy with the exception of those without relapse off treatment for 5 years or longer
12. Presence of serious active infection
13. Presence of active hepatitis B, hepatitis C, or HIV infection
14. History of severe drug hypersensitivity reaction
15. Patients who are pregnant or breast-feeding, or patients who intend to or whose spouses intend to conceive during the course of the study, including the follow-up period
16. Participation in another clinical trial or post-marketing clinical study within 26 weeks (182 days) prior to screening
17. Other medical condition which, in the investigator's judgment, may be associated with increased risk to the subject or may interfere with study assessments or outcomes

Historical control group

1. Use of immunosuppressive agents other than corticosteroids within 12 weeks (84 days) prior to or 2 weeks (14 days) after the corticosteroid treatment as defined by the inclusion criteria (4) is initiated
2. Could not exclude the following conditions on clinical ground: drug-induced pneumonitis, occupational lung disease, hypersensitivity pneumonitis, radiation-induced lung injury
3. Presence of end-stage interstitial pneumonitis as identified on the basis of a vital capacity < 45% predicted, diffusing capacity for carbon monoxide < 30% predicted, or lung CT with predominantly honeycombing appearance
4. Presence of pancreatitis
5. Presence of diabetes mellitus with the exception of glucocorticoid-induced one that is well-controlled (HbA1c < 6.5%)
6. Serum creatinine of 1.5 mg/dL or above
7. Presence of liver dysfunction (AST(GOT) or ALT (GPT) greater than 2.5 times the upper limit of normal) with the exception of the one that is considered to be due to myositis and is accompanied by the elevation of muscle enzymes above the upper limit of normal
8. Serum potassium above the upper limit of normal
9. Presence of ischemic heart disease, arrhythmia requiring treatment, congestive heart failure, or pulmonary hypertension requiring treatment
10. Presence or history of malignancy with the exception of those without relapse off treatment for 5 years or longer
11. Presence of serious active infection including active hepatitis B, hepatitis C, or HIV infection
12. Other medical condition which, in the investigator's judgment, may be associated with increased risk to the subject or may interfere with study assessments or outcomes

All adverse events observed between the first dose and 28 days after the last dose of tacrolimus.

Testing for safety was performed at set intervals and consisted of vital signs and physical examinations, laboratory testing, and evaluation for adverse events and serious adverse events.

Conclusion is not based on meaningful statistical comparison, will not apply to asymptomatic or subclinical IP, or to the exacerbation of IP, or will not separately provide the efficacy of the treatment in the anti-MDA-5 positive subgroup.