and A.T.F.; supervision, I.A., S.I. result, despite high mortality, diagnosis is often delayed, necessitating increased awareness of this possible condition. Despite a severe course of lung disease and an increased mortality rate, there is currently no standard treatment. Recent insights based on observational studies and case reports support combined therapy with immunosuppressive drugs and corticotherapy, as soon as the symptoms appear. The aim of this paper is to describe anti-MDA5 DM, focusing on the recent literature about the unique clinical manifestations and therapeutic options, starting from a severe clinical case diagnosed in our Rheumatology Department. 0.0001) [43]. A recent systematic review suggested that combination therapy should be the first option in patients with DM-related ILD with MDA5 seropositivity. The usual approach includes glucocorticoids (GC) and calcineurin inhibitors (Cyclosporine A, Tacrolimus) or, alternatively, triple therapy, adding to the previous scheme, intravenous Cyclophosphamide (CYC), or Mycophenolate Mofetil (MM) if CYC is not feasible [44]. GC can be administered orally (Prednisone or Prednisolone) or intravenous (Methylprednisolone) with tapering dosages over several months, dependent on the clinical response [1]. Regarding the calcineurin inhibitors, Cyclosporine A and Tacrolimus showed similar efficacy [32]. In the absence of a response to treatment with GC plus Ki8751 calcineurin inhibitors, adding CYC, MM, Rituximab, Basilixumab or Tofacitinib should be considered [44]. Special attention should be given to CYCs toxicity and adverse effects. It is known to be teratogenic, embryotoxic and can cause infertility, therefore, if possible, should be Ki8751 avoided in women of childbearing age [45]. In a study that examined 65 patients with rheumatic diseases who were treated with intravenous CYC, the adverse effects reported, in descending order, were: infections, nausea, vomiting, abdominal pain and pancytopenia [46]. Several studies showed the efficacy of Tofacitinib in myositis-associated ILD, concomitantly emphasizing the major risk of viral infections, especially of cytomegalovirus infection (up to 100% of patients) and varicella-zoster virus reactivation (in up to 80% of cases) [47,48]. Numerous studies support the efficacy of Rituximab in anti-MDA5 antibody positive ILD, many patients achieving remission or improvement in pulmonary function and imaging after 3 years of follow-up [35,48,49]. An association between Rituximab and an increased risk of severe COVID-19 was observed [50]. Jyssum et al. analyzed the serological response after two vaccine doses in patients treated with Rituximab in comparison to the general population. A total of 62.1% of those included in the Rituximab group produced no antibodies against SARS-CoV-2, compared to 0.4% of controls. They recommend carefully assessing the riskCbenefit ratio and changing the treatment, when possible [51,52]. In the context of a higher risk of severe COVID-19 [53] and lower titers of antibodies against SARS-CoV-2 after vaccination, seen in the patients CD48 treated with Rituximab, the European League Against Rheumatism (EULAR) recommends postponing the next cycle of treatment or replacing it, when possible, if the patient contacts the infection [11]. Regarding the COVID-19 vaccine, EULAR suggests initiating it 4 weeks before a new cycle, and to delay Rituximab 2 to 4 weeks after the vaccination [54]. With reference to Anakinra, an interleukin-1 inhibitor, data about its efficacy in myositis related ILD are scarce. Chiapparoli et al. conducted a study that included 15 patients with refractory myositis who were treated with Anakinra for 12 months. Muscle biopsies were performed before and after the treatment. A total of seven patients showed significant clinical response, at the same time, three worsened. The comparative biopsies revealed no differences at the end of the study. In terms of adverse events, the most frequent were infections and rashes at the injection site. Further studies on more patients are required [55,56]. Regarding COVID-19 respiratory syndrome and Anakinra, various studies confirmed its benefits. The inflammatory response to lung injury in SARS-CoV-2 is centrally mediated by IL-1 [57]. An increase in IL-1 concentrations was seen in patients with acute respiratory distress syndrome [58]. Marco Franzetti et al. compared 56 patients with moderateCsevere Ki8751 COVID-19, who were treated with Anakinra, to 56 controls. They observed that the 28-day survival rate was higher in the Anakinra group versus those receiving the.