Polymyositis/dermatomyositis and interstitial lung disease: A new therapeutic approach with T-cell-specific immunosuppressants

Abstract

Interstitial lung disease (ILD) is a common complication of polymyositis (PM) and dermatomyositis (DM), and accounts for a significant proportion of their morbidity and mortality because of the resistance to therapeutic agents including corticosteroids. Its pathogenic mechanism is not known, but several studies have provided findings implicating that T-cells, especially activated CD8+ cells, may play essential roles, and thus could be therapeutic targets in this disease. To test this hypothesis, we began clinical investigation of the efficacy of T-cell-specific immunosuppressants, cyclosporine (CsA) and FK506, in PM/DM patients with ILD. In our retrospective nationwide multi-center study compiling a total of 53 patients, a combination of CsA and corticosteroids resulted in favorable early and long-term outcome in the majority of patients except for DM patients with acute ILD. In this subset, those who received the combination as an initial therapy had better survival than those who initially received corticosteroids alone. FK506 has a similar mode of action but is up to 100-fold more potent than CsA in vitro, and has been used in more refractory ILD cases. We next reviewed 5 PM/DM patients with ILD who failed on various immunosuppressants including CsA and were subsequently treated with FK506 in our hospital, and found that 3 improved promptly, 1 gradually and steadily, and another case responded slowly after prednisolone dose was increased. None developed adverse effects. In summary, these T-cell targeted therapies have a potential to be the cornerstone of the treatment for ILD in PM/DM patients. The combination therapy with CsA and corticosteroids may be efficacious especially when used early. FK506 may be advantageous even in refractory cases to CsA. These findings indicate that further investigation is warranted. Currently, prospective investigation of FK506 is underway.

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

“…37 Activated T cells, especially CD8 þ T cells, are proven to have essential roles in ILD in PM/DM patients. 38 In the presence of ILD, bronchoalveolar lavages consistently revealed lymphocytosis with a marked predominance of CD8 þ T cells, which was associated with anti-Jo-1 autoantibodies. 39 Recently, CX3CL1 and its receptor CX3CR1 might contribute to the inflammatory cell infiltration into the affected muscle and lung with ILD in PM/DM patients, among which CX3CR1 was expressed on a majority of CD8 þ T cells, most macrophages, and some CD4 þ T cells in the lung.…”

A case of primary Sjögren’s syndrome complicated with inflammatory myopathy and interstitial lung disease

“…ILD complicated in DM / PM is often refractory to glucocorticoids [12]; however, ILD of the present case showed favorable response to prednisolone of 30 mg / day. This clinical outcome also agrees with the report that the prognosis of ILD is less severe in pSS than in overlap syndrome [2].…”

A Case of Relapsing Polychondritis Successfully Treated with Combination of a Glucocorticoid and Cyclosporine

“…The patient has maintained a remission state by these combination treatments. Cyclosporine reportedly inhibits the function of helper T cells and production of pro-inflammatory cytokines [17]. Better effects against RP with combination treatment suggest that glucocorticoids and cyclosporine might have additive effects.…”