Study ‘provides some reassurance’ on use of tacrolimus.

The addition of tacrolimus (Prograf) to conventional immunosuppressive therapy improved survival among patients with the inflammatory myopathies complicated by interstitial lung disease, a small, retrospective study found.

During a median follow-up of 25.7 months, event-free survival was significantly longer among patients who received tacrolimus, with a weighted hazard ratio of 0.32 (95% CI 0.14-0.75, P=0.008), according to Shinsuke Yasuda, MD, and colleagues from Hokkaido University in Sapporo, Japan.

Interstitial lung disease develops in up to half of patients with polymyositis or dermatomyositis (PM/DM), and is a frequent cause of morbidity and mortality.

High-dose steroids are the first-line treatment for this pulmonary complication in PM/DM, but many patients require additional immunosuppression. In one previous study, 50% of patients were refractory to prednisone alone and the mortality rate of these patients was 50%.

The optimal second-line approach has not been determined, however. Conventional choices have been cyclosporin A and cyclophosphamide.

Tacrolimus has effects similar to those of cyclosporin in its suppression of interleukin-2 production by T cells, but the inhibition is approximately 100-fold higher, and it has been shown to be more effective as a post-transplantation treatment.

“Activated pulmonary T cells play an important role in the development of corticosteroid-resistant PM/DM-related interstitial lung disease. Thus, these activated pulmonary T cells in patients with PM/DM-related interstitial lung disease would be ideal treatment targets,” the authors explained.

“Therefore, we hypothesized that tacrolimus is more effective than cyclosporin for the treatment of severe autoimmune conditions, including PM/DM-related interstitial lung disease,” Yasuda and colleagues wrote.

Accordingly, they conducted a retrospective study of 49 patients seen in their center between 2000 and 2013, adjusting the data with inverse probability of treatment weighting statistical methods to limit the influence of bias.

All patients received 0.8 to 1 mg/kg/day of oral prednisone. If additional immune suppression was needed, they were given intravenous methylprednisolone pulse therapy, cyclosporin in dosages of 2 to 3 mg/kg/day, intravenous cyclophosphamide, 500 mg/m²/month, or tacrolimus beginning in oral dosages of 1 to 3 mg/day.

Relapse was defined as worsening of symptoms, radiologic progression of the interstitial lung disease, and the need for increased treatment.

A total of 32 of the patients had dermatomyositis and 17 had polymyositis. Two-thirds were men, and mean age at onset was 52.

Tacrolimus was given as part of the regimen for 25 patients. Among the tacrolimus group, 18 also received steroid pulses, and nine were given cyclophosphamide. None of the tacrolimus patients received cyclosporin.

Among the conventional therapy group, 10 had steroid pulses, seven received cyclosporin, and two were given cyclophosphamide.

Relapses were seen in five patients in both the conventional therapy and tacrolimus groups. One patient receiving tacrolimus died from respiratory disease, as did five in the conventional group. Other serious adverse events were reported in one patient in the tacrolimus group (liver cirrhosis) and in two of the conventional therapy group (malignancies).

Other events included a case of cytomegalovirus and two cases of herpes zoster in the tacrolimus group, and kidney dysfunction in two patients in the conventional therapy group.

In both groups, there were improvements in muscle strength and spirometry tests by 1 year, but no between-group differences were seen.

“To the best of our knowledge, this retrospective study is the first report statistically demonstrating that the addition of tacrolimus significantly improves the event-free and disease-free survival of patients with PM/DM-related interstitial lung disease,” the researchers noted.

Limitations of the study included its retrospective design and the use of varying combinations in treatment. It also was not randomized, but the authors pointed out that because the condition is life-threatening, randomized trials are difficult.

“Therefore, it is meaningful that we have shown the efficacy of tacrolimus as an additional treatment of PM/DM-related interstitial lung disease using systematic statistical methods,” they wrote.

In an accompanying editorial, Patrick Gordon, PhD, and Bibek Gooptu, MD, of King’s College in London, agreed that the the study design had limitations and called for further research.

“Given the paucity of data in this area, [the study] represents an important addition to the current literature. It provides some reassurance for the use of tacrolimus in moderate to severe idiopathic inflammatory myopathy-associated interstitial lung disease and sets the scene for future prospective studies,” Gordon and Gooptu observed.