Although a number of the combined immunosuppressive regimen have been used for anti-MDA5-positive DM-ILD, the efficacy of such pharmacological treatments have not been confirmed in large prospective studies. This study evaluated the associations of 6-month survival with CS alone or use of immunomodulatory therapy (tacrolimus/cyclosporine, IVCY), which are administered in combination with CS in Chinese anti-MDA5-positive DM-ILD patients. The present study clearly indicated that early combined immunosuppressive regimen was better than CS alone for improving 6-month survival of anti-MDA5-positive DM-ILD patients. This finding was consistent with the prior report that in DM-ILD patients, the early combination of CS with immunosuppressants obtained better outcome, compared the other patients who were administered with CS alone [20, 21]. In this study, the patients treated with CS alone - which was correlated with a higher CYFRA21-1 level - leaded to worse prognosis.
It is well known that DM associated ILD can be divided into RPILD and Non-RPILD based on its pathological progression [22, 23]. The prognosis of a subset of patients with RPILD complicating anti-MDA5-positive DM, is extremely poor, compared with Non-RPILD [24–27]. In clinical practice, intensified immunomodulators including CS pulsed doses in combination with tacrolimus/cyclosporine and/or IVCY, are sometimes used in DM-ILD patients, especially in RPILD [28, 29].
Tacrolimus/cyclosporine as calcineurin inhibitor suppresses expression of interleukin (IL)-2 to reduce the activation of T cells . T cells and alveolar macrophages play an important role in anti-MDA5-positive DM-ILD pathogenesis [10, 31]. CTX mainly suppresses the function of B cells for treatment of DM-ILD . Thus, a combined therapy of various immunomodulators can significantly increase the risk of infection. Although intensified immunosuppressive therapy is considered as necessary for RPILD complicating DM, the evidence of benefit is not conclusive. A previous study showed that early commencement of a regimen therapy including CS, cyclosporine and IVCY may be more efficacious for those patients with RPILD . Early treatment of cyclosporine should be effective to control disease progression of HRCT and improve the survival in DM-ILD . A previous study demonstrated that intensified immunosuppressive treatment with CS, tacrolimus, and IVCY improve survival of anti-MDA5-positive DM/CADM-ILD patients with well-tolerated adverse events . However, our results indicated that anti-MDA5-positive DM-RPILD patients couldn’t obtain better efficacious with a combined regimen (CS, tacrolimus/cyclosporine and IVCY). There was no difference at 6-month survival between treatment with tacrolimus/cyclosporine and combination therapy with tacrolimus/cyclosporine and IVCY in anti-MDA5-positive DM-RPILD patients. In contrast, combination therapy with tacrolimus/cyclosporine and CS was shown to be superior to the combination of tacrolimus/cyclosporine, IVCY and CS in Non-RPILD patients. Non-RPILD patients administered with tacrolimus/cyclosporine, which was associated with a significantly lower ESR and CYFRA21-1 levels, -had better prognosis. Furthermore, such patients using single agent such as tacrolimus or cyclosporine, in addition CS, could reduce long-term adverse reactions and obtained better outcome. Thus triple intensive immunosuppressive therapy was not necessary in anti-MDA5-positive DM Non-RPILD in our study.
Overall, we assessed the relationship between intensive immunosuppressive regimen and 6-months survival in anti-MDA5 positive DM-ILD patients. However, there were several limitations in our study. First, other therapies such as plasmapheresis could not be applied generally in subjects due to rarity of plasma. Second, our ability to perform serial analysis of immunosuppressive regimen was limited due to the small study cohort, which was understandable in view of the rarity of anti-MDA5 positive DM-ILD. Third, this was a retrospective single-center study, so it was uncertain whether or not our results could be generalised to the entire population of patients with anti-MDA5 positive DM-ILD. A large-scale prospective trial would be helpful to confirm our results.
Summary, we showed the early administration of immunosuppressants was important in anti-MDA5 positive DM-ILD. The triple regimen (CS, tacrolimus/ cyclosporine and CTX) were not necessary in Chinese anti-MDA5-positive DM Non-RPILD patients. Further investigations were needed to find an additional effective and safe therapy.