A 36-year-old man with inverse Gottron's sign was admitted for clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD). Early addition of plasma exchange (PE) to triple therapy improved severe respiratory failure and transiently decreased serum ferritin levels and anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) titers. Furthermore, switching from tacrolimus to tofacitinib resulted in disease remission. Recognition of the inverse Gottron's sign may allow for the earlier diagnosis of anti-MDA5 Ab-positive dermatomyositis, and early addition of PE to triple therapy and administration of tofacitinib in refractory cases may be effective for anti-MDA5 Ab-positive CADM with RP-ILD under life-threatening conditions.