Multicenter Prospective Study of the Efficacy and Safety of Combined Immunosuppressive Therapy With High‐Dose Glucocorticoid, Tacrolimus, and Cyclophosphamide in Interstitial Lung Diseases Accompanied by Anti–Melanoma Differentiation–Associated Gene 5–Positive Dermatomyositis

Abstract

Objective Interstitial lung disease (ILD) accompanied by anti–melanoma differentiation–associated gene 5 (anti–MDA‐5)–positive dermatomyositis (DM) is often rapidly progressive and associated with poor prognosis. Because there is no established treatment, we undertook this study to prospectively evaluate the efficacy and safety of a combined immunosuppressive regimen for anti–MDA‐5–positive DM patients with ILD. Methods Adult Japanese patients with new‐onset anti–MDA‐5–positive DM with ILD (n = 29) were enrolled at multiple study centers from 2014 to 2017. They were treated with a regimen of high‐dose glucocorticoids (GCs), tacrolimus, and intravenous cyclophosphamide (IV CYC). Plasmapheresis was used if a patient's condition worsened after the regimen started. The primary end point was 6‐month survival, which was compared between this group of patients and a historical control group (n = 15) consisting of anti–MDA‐5–positive DM patients with ILD who received step‐up treatment (high‐dose GC and stepwise addition of immunosuppressant). Secondary end points were 12‐month survival rate, adverse events, and changes in laboratory data. Results The combined immunosuppressive regimen group showed significantly higher 6‐month survival rates than the step‐up treatment group (89% versus 33%; P < 0.0001). Over a period of 52 weeks, improvements in anti–MDA‐5 titers, serum ferritin levels, vital capacity, and chest high‐resolution computed tomography scores were observed. The combined immunosuppressive regimen group received IV CYC nearly 20 days earlier with shorter intervals and tended to receive plasmapheresis more often than patients undergoing step‐up treatment. Cytomegalovirus reactivation was frequently observed over 52 weeks. Conclusion A combined immunosuppressive regimen is effective for anti–MDA‐5–positive DM patients with ILD. Plasmapheresis can be used for additional effect in intractable disease. Patients should be carefully monitored for opportunistic infections during treatment.

Anti‐MDA5‐associated dermatomyositis

“…More importantly, the prognosis can be extremely poor due to high incidence of rapidly progressive interstitial disease (RP‐ILD) in these patients. The condition requires prompt diagnosis and early initiation of aggressive immunosuppressive therapy to improve prognosis . We report two interesting patients of Polynesian descent, presenting with MDA5‐associated DM, with fatal outcome in one.…”

“…Anti‐melanoma differentiation‐associated gene 5 antibody‐associated dermatomyositis (MDA5‐associated DM) is a rare subgroup of idiopathic inflammatory myositis, presenting with cutaneous features of classical dermatomyositis (DM), but no or minimal involvement of the proximal muscles. Numerous cases of DM associated with MDA5 antibodies have been described in the literature, emphasising the need for early diagnosis in this rare entity which may be overlooked due to substantially different clinical presentations . More importantly, the prognosis can be extremely poor due to high incidence of rapidly progressive interstitial disease (RP‐ILD) in these patients.…”

Acral Cutaneous Ulcerations and Livedo Reticularis with Rapidly Progressive Interstitial Lung Disease in Anti-MDA5 Antibody-Positive Classical Dermatomyositis

“…Typically, RP-ILD requires initial high-dose glucocorticoid combined with other immunosuppressive agents such as cyclophosphamide, rituximab, and calcineurin inhibitors (including cyclosporin A and tacrolimus) [16,17]. A recent multicenter prospective study demonstrated that a combination of immunosuppressive drugs, consisting of high-dose glucocorticoid, tacrolimus, and intravenous cyclophosphamide, was significantly more effective in patients with anti-MDA5-positive DM with ILD than step-up treatment (high-dose glucocorticoid and stepwise addition of immunosuppressive drugs) [18]. Although our patient received a combination of high-dose intravenous corticosteroids and immunoglobulin, his condition worsened, and he passed away due to respiratory failure.…”

Elevated serum B‐cell activating factor levels in patients with dermatomyositis: Association with interstitial lung disease

“…Currently, anti‐MDA5‐Ab‐positive DM patients with RP‐ILD are treated with intensive immunosuppressive therapy as induction therapy that includes high‐dose prednisone, tacrolimus and IVCY. These intensive immunosuppressive therapies increaseed the survival rate of these patients . After induction therapy, DM patients with anti‐MDA5‐Ab are treated with low‐dose prednisone and tacrolimus as maintenance therapy; however, some patients may show flare‐up with an increase in anti‐MDA5‐Ab level during maintenance therapy.…”

“…These intensive immunosuppressive therapies increaseed the survival rate of these patients. 33 After induction therapy, DM patients with anti-MDA5-Ab are treated with low-dose prednisone and tacrolimus as maintenance therapy; however, some patients may show flare-up with an increase in anti-MDA5-Ab level during maintenance therapy. Thus, adding BAFF inhibition therapy may be an ideal treatment strategy for maintenance therapy in these patients.…”