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case_images: Comprehensive Assessment of clinical findings while the patient was receiving Tofacitinib treatment. (A, B) showcases chest imaging findings throughout entire treatment, including before and after Tofacitinib administration. (A) panel presents CT scans of the chest (lung window) before Tofacitinib treatment captured at three critical stages: initially upon admission to the Rheumatology Department, marking the onset of the disease, and again 20 days after the commencement of a step-up treatment regimen. (B) panel shows plain X-rays of the lungs after Tofacitinib treatment, captured at admission to the ICU, and one week and three weeks after the administration of tofacitinib, providing a temporal view of chest imaging findings from disease onset to the end of treatment. (C) presents a series of respiratory mechanics measurements conducted during the period of mechanical ventilation, specifically while the patient was receiving Tofacitinib at a dose of 5 mg twice daily for 20 days. (D) illustrates the serum levels of several key biomarkers throughout the treatment period, including peripheral blood lymphocytes, ferritin, and Krebs von den Lungen-6 (KL-6). (E) Decreased static lung compliance (CstatL) and pulse oximetry-measured oxygen saturation index (SpO2/FiO2) demonstrated the aggravation of interstitial lung injury.
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case_images: Chest high-resolution Computed Tomography (HRCT) demonstrated interlobular septal thickening and subpleural ground-glass opacities ( Figure 1A ). A step-up treatment regimen was initiated immediately for the rapid progressive interstitial lung disease (RP-ILD) ( Figure 1A ), with a combination of high-dose methylprednisolone equivalent of 2 mg/kg/day (1000mg/day) for 3days, intravenous immunoglobulin 20 g/d for 5 days, intravenous cyclophosphamide at a dosage of 0.4 grams once weekly (QW), and oral tacrolimus 2mg/day. However, chest HRCT showed a rapid progression of interstitial lesions ( Figure 1A ), and she required invasive ventilation for worsening hypoxemia after transferred to intensive care unit (ICU). ICU, multiple indicators were conducted at the start of treatment and subsequently tested every 3-5 days. In the initial stage of tofacitinib therapy, a transient improvement in lung parenchymal translucency was observed on chest radiograph ( Figure 1B ). The improvement in respiratory effort markers, including plateau pressure (Pplat), peak inspiratory pressure (Ppeak), and driving pressure, occured simultaneously ( Figure 1C ). Both chest radiograph and above respiratory parameters underwent deterioration ( Figures 1B, C ), accompanied by a series of changes in laboratory indicators. Increasement of serum ferritin levels and Krebs von den Lungen-6 (KL-6) levels, as well as a marked decrease in peripheral blood lymphocyte count ( Figure 1D ), were parallelled with the aggravation of interstitial lung injury. In line with these deterioration, decreased static lung compliance (CstatL) and pulse oximetry-measured oxygen saturation index (SpO2/FiO2) were accompanied during the treatment period ( Figure 1E ).
case_images: Treatment strategies for five enrolled MDA5-DM with rapidly progressive ILD patients. IVIG, intravenous immunoglobulin; CTX, cyclophosphamide.
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case_images: The patient was received high-dose intravenous methylprednisolone (160 mg/d for 2 weeks) in the following 20days of treatment ( Figure 2 ). After all above triple combination therapy, JAK inhibition of oral tofacitinib(at a dose of 5 mg twice daily) were all administrated in these four refractory MDA5-DM patients ( Figure 2 ).
case_images: Analysis of Myeloid Cells and Cytokine/Chemokine Levels in bronchoalveolar lavage fluids (BALFs) during Tofacitinib treatment. (A) presents an analysis of myeloid cells in BALFs across intubation time points at day 1, day 7, day 15, and day 20. Monocyte was defined as CD45+CD16+(a), and macrophage was defined as CD45+CD206+ lymphocytes by flow cytometry analysis (B). Changes of IFN signaling related cytokines (C) and cytokines/chemokines (D) in supernatants of BALFs were measured by cytometric bead array at the same time points.
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case_images: In the initial period of tofacitinib therapy, we observed percentages of CD45+CD16+ monocyte and CD45+CD206+ macrophage subsets(methods seen in Supplementary) maintaining stability in BALF ( Figure 3A ). However, as dyspnea progression, their accumulation accelerated ( Figure 3B ). As we expected, secretions of IFN-gamma and IFN-alpha in BLAF reduced in the initial period of tofacitinib therapy, subsequently increased as interstitial lung disease progressed to uncontrollable levels afterwards ( Figure 3C ). These immune biomarkers, which are associated with macrophage activity, demonstrated an initial transient decrease followed by a subsequent increase, similar with the accumulation of alveolar myeloid cells ( Figure 3D ). The comprehensive deep-immune atlas of RP-ILD suggest that pronounced myeloid-driven immune process and increased immune mediators are predominant immunological hallmarks of critical MDA5-DM patients.
case_images: Changes in four MDA5-DM patients before and after treatment with tofacitinib. Interstitial lung injury demonstrated by static lung compliance (CstatL) and pulse oximetry-measured oxygen saturation index (SpO2/FiO2) (A), with the serum levels of key biomarkers for ferritin, and Krebs von den Lungen-6 (KL-6) (B). Changes of IFN signaling related cytokines (C) in peripheral blood were measured by cytometric bead array at the same time points.
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case_images: After approximate 20 days of treatment, case2 and case 3 patients achieved clinically significant improvement accompanied with increase in the absolute peripheral lymphocyte number and SpO2/FiO2 ( Figure 4A ). Biomarkers for lung damage, including ferritin and Krebs von den Lungen-6 (KL-6), also decreased during disease remission ( Figure 4B ). However, case 5 patient showed major improvement after 6 months of oral triple combination therapy ( Figures 4A, B ). Case 3 patient showed significant decrease in the absolute peripheral lymphocyte number and SpO2/FiO2, with elevation levels of serum ferritin KL-6 ( Figures 4A, B ).Eventually, her family gave up on treatment and discharged from hospital. The serum interferon(IFN) signaling pathways related cytokines, IFN-gamma and IFN-alpha, at the baseline were higher in case 3 than those three alive patients ( Figure 4C ). The changes in IFN-gamma and IFN-alpha were parallel to the deterioration of peripheral lymphocyte count, oxygen index and biomarkers in case 3 patient ( Figures 4A-C ).