Staged multi-target therapy for anti-MDA5-positive dermatomyositis-associated rapidly progressive interstitial lung disease: a case report

Abstract

Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung disease is associated with acute respiratory deterioration and high mortality. A man in his 40s presented with fever, dry cough, progressive dyspnea, mechanic's hand-like lesions and severe hypoxemic respiratory failure. Chest high-resolution computed tomography demonstrated rapidly progressive bilateral ground-glass and reticular opacities. Myositis-specific antibody testing showed strong anti-MDA5 positivity, with concomitant anti-EJ, anti-TIF1γ and anti-Ro52 positivity. Initial intravenous methylprednisolone at 80 mg/day produced limited improvement. Early multi-target escalation included divided-dose methylprednisolone, tofacitinib, short-course intravenous immunoglobulin, Pneumocystis jirovecii prophylaxis and an individualized reduced-dose rituximab regimen consisting of 200 mg followed by three weekly 300-mg infusions. Mycophenolate mofetil was briefly withheld during acute escalation and subsequently resumed for maintenance. Oxygenation improved within 48 h, and serial imaging demonstrated progressive regression of the pulmonary abnormalities. During approximately 6.5 months of follow-up, the patient remained clinically stable without a detected serious opportunistic infection. Because several interventions overlapped and rituximab has a delayed immunological effect, the early response cannot be attributed to rituximab alone. This case illustrates the potential clinical value of staged multi-target treatment adjustment and infection-risk management in severe anti-MDA5-associated rapidly progressive interstitial lung disease.

1. Introduction

Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (MDA5⁺ DM) is a distinct clinical subtype of idiopathic inflammatory myopathy, characterized by mild myositis, typical cutaneous manifestations such as mechanic's hands and skin ulceration, and a high incidence of concomitant interstitial lung disease (ILD) [1,2]. Among these manifestations, rapidly progressive interstitial lung disease (RP-ILD) represents one of the most life-threatening complications, as affected patients may develop respiratory failure within weeks and face an extremely high risk of mortality [3]. For example, in a single-center retrospective study including 40 patients with MDA5⁺ DM-associated ILD, Zhao et al. reported 6-month and 1-year survival rates of only 40% and 35%, respectively [4]. Therefore, how to rapidly control the inflammatory cascade, attenuate pulmonary parenchymal injury, and simultaneously minimize treatment-related infectious risks within a limited therapeutic window remains a critical challenge in clinical management.

Currently, there is no standardized and universally effective treatment strategy for MDA5⁺ DM-associated RP-ILD. Although high-dose glucocorticoids combined with calcineurin inhibitors, such as tacrolimus, or cyclophosphamide are commonly used as initial therapeutic regimens in clinical practice, a considerable proportion of patients show inadequate responses and continue to experience disease progression [5,6]. Moreover, the risks of secondary infections and long-term complications associated with intensive immunosuppressive therapy cannot be overlooked. For example, Mochizuki et al. [7] reported a case in which the underlying disease was controlled after combination therapy with glucocorticoids, tacrolimus, and cyclophosphamide; however, the patient subsequently developed an iatrogenic immunodeficiency-associated lymphoproliferative disorder. This observation suggests that, in selected cases, conventional intensive immunosuppressive strategies may be accompanied by serious immune-related complications.

Against this background, more targeted combination therapeutic strategies have attracted increasing attention. Mechanistic studies have shown that sustained activation of the type I interferon signaling pathway plays a pivotal role in the immunopathogenesis of MDA5⁺ DM [8,9]. Janus kinase (JAK) inhibitors, such as tofacitinib, can suppress interferon-related signaling by blocking the JAK–STAT pathway. Accordingly, they have been considered potential salvage therapeutic options and have shown clinical promise in attenuating inflammatory responses in some refractory cases [10]. On the other hand, rituximab, a CD20-targeted B-cell-depleting agent, has demonstrated efficacy as salvage therapy in various refractory autoimmune diseases [11,12]. Existing theoretical evidence and preliminary clinical observations suggest that JAK inhibitors and B-cell-targeted agents may exert synergistic therapeutic effects when used in combination [13]. However, investigations into such combination strategies remain at an early stage, and most studies have adopted conventional high-dose regimens [14]. For critically ill patients with substantial infectious risk, there is still no clear consensus on how to achieve early and intensive inflammatory control while maintaining an acceptable safety profile.

Notably, several studies have suggested that, in certain autoimmune diseases, low-dose rituximab may achieve clinical remission comparable to that obtained with conventional-dose regimens, while offering potential advantages in terms of safety and health economics [15]. However, whether this experience can be extrapolated to severe MDA5⁺ DM-RP-ILD, particularly in the context of a high infectious risk, remains insufficiently supported by current evidence.

Based on this background, we report a case of severe anti-MDA5 antibody-positive dermatomyositis-associated RP-ILD with an insufficient response to initial glucocorticoid therapy. During the early treatment phase, mycophenolate mofetil was briefly added; however, owing to its relatively delayed onset of action and the rapidly progressive disease course, it was temporarily replaced with low-dose rituximab during acute-phase treatment optimization. The overall regimen was adjusted to an early multi-target escalation strategy centered on optimized glucocorticoid therapy combined with tofacitinib, supplemented by short-course intravenous immunoglobulin and Pneumocystis jirovecii pneumonia prophylaxis. After completion of the low-dose rituximab course and stabilization of the patient's condition, mycophenolate mofetil was resumed as maintenance therapy. This case highlights the clinical feasibility of early multi-target escalation therapy in severe MDA5⁺ DM-RP-ILD and provides a basis for discussing the potential role and limitations of low-dose rituximab in this context.

2. Case report

2.1. Case presentation

A male patient in his 40s, with a height of 165 cm, body weight of 65 kg, and an estimated body surface area of 1.69 m², was admitted to the emergency department in late September 2025 because of “generalized myalgia for 3 months and cough, fever, and progressive dyspnea for 2 weeks.” Approximately 3 months before admission, the patient developed nonspecific generalized myalgia, predominantly involving the lower back, accompanied by pain on the dorsal aspects of both hands. No definite diagnosis was established at an outside hospital, and symptomatic treatment provided limited benefit. Approximately 2 weeks before admission, his symptoms progressed rapidly, with the development of irritating dry cough, exertional dyspnea, and fever, with a maximum body temperature of 38.9°C. High-resolution computed tomography (HRCT) of the chest performed at the outside hospital revealed interstitial lung abnormalities predominantly involving the peripheral zones of both lungs, more pronounced in the lower lobes, presenting as ground-glass opacities and reticular changes (Fig. 1). Concurrent laboratory testing showed positivity for anti-SSA52 antibodies and antinuclear antibodies, with a titer of 1:100 and a nuclear granular/cytoplasmic granular pattern. Despite anti-infective treatment at the outside hospital, his symptoms did not improve, and dyspnea further worsened. He was therefore transferred to our hospital for further evaluation and management.

Fig. 1.

Baseline chest high-resolution computed tomography findings obtained at the outside hospital. The images showed interstitial lung abnormalities predominantly involving the peripheral regions of both lungs, with more pronounced ground-glass opacities and reticular changes in the right lower lobe.

3. Findings on admission

3.1. Physical examination

On admission in late September 2025, the patient had marked dyspnea even at rest, with a respiratory rate of 25 breaths/min. Without supplemental oxygen, peripheral oxygen saturation measured by pulse oximetry was 78%–80%. After oxygen supplementation via nasal cannula at 3 L/min, oxygen saturation was maintained only at 85%–88%, accompanied by obvious cyanosis of the lips. Auscultation revealed dense Velcro-like crackles in both lower lung fields. Typical mechanic's hand-like skin lesions were observed on both hands (Fig. 2).

Fig. 2.

Characteristic mechanic's hand-like skin lesions on both hands of the patient. (a) Punctate hyperpigmentation on the dorsal aspect of the hand. (b, c) Patchy depigmentation on the palmar aspects of the hands. (d) Depigmentation on the palmar aspects of both hands.

3.2. Laboratory findings

Arterial blood gas analysis revealed type I respiratory failure, with a pH of 7.451, PaO₂ of 54.4 mmHg, and PaCO₂ of 38.5 mmHg. Complete blood count showed leukopenia, with a white blood cell count of 3.53 × 10⁹/L, and marked lymphopenia, with a lymphocyte count of 0.27 × 10⁹/L, accounting for 7.5% of total leukocytes. High-sensitivity C-reactive protein was elevated to 6.35 mg/L. Biochemical tests showed mildly elevated aspartate aminotransferase at 46 IU/L, decreased albumin and total protein levels at 32.9 g/L and 57.3 g/L, respectively, elevated lactate dehydrogenase at 479 IU/L, and mildly increased procalcitonin at 0.310 ng/mL (Table 1, Fig. 6).

Table 1.

Dynamic changes in key clinical indicators during treatment and follow-up.

Parameter	Reference range	Baseline	Early reassessment	Pre-3rd RTX	Pre-4th RTX	End-FU	Extended FU	Further extended FU	Final outpatient FU
Lymphocyte count (×109/L)	0.80–4.00	0.27	0.43	0.53	0.56	0.73	1.22	1.30	—
Lymphocyte percentage (%)	20.0–40.0	7.5	8.8	10.4	12.4	17.9	21.2	35.9	—
hs-CRP (mg/L)	0–6.0	6.35	—	—	1.33	5.67	0.350	0.35	—
PCT (ng/mL)	0–0.07	0.310	—	—	0.02	—	0.020	0.020	0.02
Ferritin (μg/L)	21.8–274.7	—	—	—	1625.30	1248.60	1972.9	1049.7	830.584
LDH (IU/L)	120–250	479	—	212	252	288	400	—	—
Albumin (g/L)	40.0–55.0	32.9	—	36.3	42.18	44.5	44.4	44.4	—
Total protein (g/L)	65.0–85.0	57.3	—	58.3	66.4	66.9	67.0	—	—
AST (IU/L)	15–40	46	—	46	40	35	44	—	—

Table note.

Abbreviations: Ref., reference; RTX, rituximab; FU, follow-up; hs-CRP, high-sensitivity C-reactive protein; PCT, procalcitonin; LDH, lactate dehydrogenase; AST, aspartate aminotransferase. “—” indicates not tested at that time point.

Fig. 6.

Dynamic changes in key clinical indicators during treatment and follow-up.; (a) Lymphocyte count (×10⁹/L); (b) Lymphocyte percentage (%); (c) high-sensitivity C-reactive protein (mg/L); (d) procalcitonin (ng/mL); (e) ferritin (μg/L); (f) lactate dehydrogenase (IU/L); (g) albumin (g/L); (h) total protein (g/L); and (i) aspartate aminotransferase (IU/L). The x-axis indicates the following time points: Baseline, Early reassess., Pre-3rd RTX, Pre-4th RTX, End-FU, Extended FU, Further extended FU, and Final outpatient FU. Values are presented only for time points at which the corresponding parameter was assessed.

Myositis-specific autoantibody profiling revealed strong positivity for anti-MDA5 antibodies (+++), along with positivity for anti-Ro-52, anti-TIF1γ, and anti-EJ antibodies. Anti-MDA5 antibodies were assessed using a myositis-associated autoantibody immunoblot/line blot assay, and the laboratory reported the results semi-quantitatively from “+” to “+++“. In this case, the result was “+++“, indicating strong positivity; however, the original laboratory report did not provide quantitative values, such as IU/mL, or specific antibody titers.

3.3. Imaging findings

HRCT performed on the day of admission showed marked short-term progression of bilateral pulmonary lesions compared with the baseline images obtained at the outside hospital. The abnormalities were characterized by diffuse ground-glass opacities, reticular opacities, and interlobular septal thickening, with more prominent involvement of the lower lung fields, consistent with the radiological features of rapidly progressive interstitial lung disease (Fig. 3A–D).

Fig. 3.

Dynamic changes on chest high-resolution computed tomography (HRCT) during treatment and follow-up. (a–d) At admission, diffuse bilateral ground-glass opacities, reticular shadows, and interlobular septal thickening were observed in both lungs, with more prominent involvement of the lower lung fields. (e–h) At the first reassessment after initiation of early multi-target intensified therapy in late September to early October 2025, the bilateral interstitial lung lesions had begun to resolve. (i–l) At the second reassessment in mid-October 2025, the ground-glass opacities and reticular abnormalities showed further resolution, and the newly developed ground-glass nodules had completely disappeared. (m–p) At the third reassessment in late October 2025, the bilateral interstitial lung lesions were further alleviated compared with the previous examination. (q–t) At the end-of-follow-up reassessment in late November 2025, the bilateral interstitial lung abnormalities had almost completely resolved. (u–x) Extended follow-up reassessment in early February 2026 showed that the bilateral interstitial fibrotic changes were slightly reduced compared with those at the end-of-follow-up evaluation, and the overall pulmonary imaging findings remained stably improved.

3.4. Pulmonary function testing

Pulmonary function testing revealed moderate-to-severe restrictive ventilatory impairment and mild diffusion impairment: forced vital capacity (FVC) was 63% of the predicted value (measured value, 2.56 L; predicted value, 4.05 L), forced expiratory volume in 1 s (FEV1) was 59% of the predicted value (measured value, 1.98 L; predicted value, 3.35 L), and diffusing capacity of the lung for carbon monoxide (DLCO) was 67% of the predicted value (measured value, 18.69 mL/min/mmHg; predicted value, 27.56 mL/min/mmHg).

3.5. Bronchoscopy and bronchoalveolar lavage fluid analysis

Electronic bronchoscopy revealed chronic inflammatory changes in the bilateral bronchi. Multiple white nodular protrusions were observed in the trachea, carina, right main bronchus, and bronchus intermedius (Fig. 4). Cytological analysis of bronchoalveolar lavage fluid showed an increased neutrophil proportion of 23.75%, with lymphocytes accounting for 13.25% and macrophages for 62.75%, suggesting neutrophilic alveolitis.

Fig. 4.

Endobronchial findings in the patient. Bronchoscopic examination revealed chronic inflammatory changes in the bilateral bronchi. Multiple diffusely distributed whitish nodular protrusions were observed on the mucosal surfaces of the airways, involving the (a) trachea, (b) carina, (c) right main bronchus, and (d) intermediate bronchus.

3.6. Lymphocyte subset analysis and B-cell-related flow cytometry

Peripheral blood lymphocyte subset analysis showed a markedly reduced proportion of lymphocytes among nucleated cells, at 10.6% (reference range, 20.0%–40.0%), indicating an overall reduction in peripheral lymphocytes. Among T-cell subsets, the proportion of CD3⁺ T cells was increased to 87.3% (reference range, 61.1%–77.0%). The proportions of CD4⁺ and CD8⁺ T cells were 52.1% and 32.8%, respectively, both exceeding the reference ranges, with a CD4/CD8 ratio of 1.5. In contrast, the proportion of NK cells was markedly decreased to 2.7% (reference range, 8.1%–25.6%), and the proportion of NKT cells was also mildly reduced to 1.7% (reference range, 2.0%–13.0%). The proportion of CD19⁺ B cells was 7.6%, close to the lower limit of the reference range.

Further B-cell-related flow cytometric analysis showed that lymphocytes accounted for 7.1% of nucleated cells (reference range, 20.0%–40.0%). CD19⁺ cells, CD20⁺ cells, and CD19⁺CD20⁺ double-positive cells accounted for 11.6%, 11.4%, and 11.4% of lymphocytes, respectively, all within the reference ranges. These findings suggested that, despite an overall reduction in peripheral lymphocytes, the patient retained a measurable proportion of CD20-positive B cells, providing objective evidence to support the subsequent exploratory use of rituximab.

4. Diagnosis

Based on the patient's characteristic cutaneous manifestations, including mechanic's hands, progressively worsening respiratory symptoms, severe hypoxemia, rapidly progressive bilateral interstitial lung abnormalities on HRCT, and strong positivity for anti-MDA5 antibodies, the primary clinical diagnosis was anti-MDA5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung disease (MDA5⁺ DM-RP-ILD) complicated by type I respiratory failure. Given the concomitant positivity for anti-EJ and anti-TIF1γ antibodies, the serological profile in this case was relatively complex, and potential overlap with antisynthetase syndrome as well as malignancy-associated risk required careful consideration. Nevertheless, based on the current clinical phenotype, the anti-MDA5-associated disease spectrum remained the predominant diagnostic consideration. The patient was also diagnosed with a protruding granuloma of the right vocal cord and reflux laryngopharyngitis (Table 2).

Table 2.

Differential diagnostic considerations and supporting evidence.

Diagnostic consideration	Supporting evidence in this patient	Missing or unavailable information
Anti-MDA5-associated disease	Strongly positive anti-MDA5 antibody (+++), rapidly progressive interstitial lung disease (RP-ILD), and cutaneous manifestations	Quantitative anti-MDA5 antibody levels and characteristic dermatomyositis-specific cutaneous findings
Antisynthetase syndrome	Anti-EJ antibody positivity, interstitial lung disease, and mechanic's hands	Arthritis, Raynaud's phenomenon, serum muscle enzyme levels, and confirmatory testing of anti-EJ antibody positivity
Classic dermatomyositis or clinically amyopathic dermatomyositis	Myalgia and cutaneous abnormalities	Objective muscle strength assessment, serum creatine kinase level, electromyography, and muscle magnetic resonance imaging
Malignancy-associated myositis	Anti-TIF1-γ antibody positivity	Comprehensive malignancy screening and long-term oncological surveillance

Abbreviations: MDA5, melanoma differentiation-associated gene 5; RP-ILD, rapidly progressive interstitial lung disease; DM, dermatomyositis; CADM, clinically amyopathic dermatomyositis; CK, creatine kinase; MRI, magnetic resonance imaging; TIF1-γ, transcription intermediary factor 1 gamma.

5. Treatment course and clinical response

Given the primary clinical diagnosis of anti-MDA5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung disease (MDA5⁺ DM-RP-ILD) complicated by type I respiratory failure, together with the critical condition, rapid disease progression, and high short-term mortality risk, the main therapeutic goals were to rapidly control the aberrant immune-inflammatory response, halt the progression of pulmonary injury, improve oxygenation, and ensure prevention and monitoring of opportunistic infections in the context of intensified immunosuppression. According to the adjustments in therapeutic strategy and the patient's clinical course, the treatment process can be summarized into the following four phases. The integrated treatment timeline, clinical course, and dynamic changes in key biomarkers are shown in Fig. 5.

Fig. 5.

Comprehensive treatment timeline, clinical course, and key biomarker trends in a patient with anti-MDA5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung disease.

(A) Treatment timeline. The panel summarizes the major therapeutic milestones and medication adjustments from hospital admission on September 24, 2025, to the final outpatient follow-up on April 8, 2026, including initial treatment, early multi-target salvage therapy, four infusions of low-dose rituximab (RTX), and the maintenance regimen during follow-up.

(B) Clinical and imaging milestones. This panel outlines the major clinical manifestations, improvement in oxygenation, and dynamic changes on chest high-resolution computed tomography (HRCT) across different stages. On admission, the patient presented with fever, cough, severe dyspnea, and marked hypoxemia. Following early combination therapy, dyspnea and oxygenation improved substantially within 48 h, and pulmonary lesions gradually regressed on subsequent imaging. By the end of follow-up, HRCT showed near-complete resolution of bilateral interstitial lung lesions, while extended follow-up demonstrated further reduction of residual abnormalities. No severe infection, hepatitis B virus reactivation, tuberculosis, or invasive fungal infection was observed throughout treatment and follow-up.

(C) Trends in key biomarkers. Dynamic changes in lymphocyte count, lymphocyte percentage, ferritin, lactate dehydrogenase (LDH), and high-sensitivity C-reactive protein (hs-CRP) are shown over the treatment and follow-up course. Overall, lymphocyte-related indices gradually recovered, whereas inflammatory and tissue injury-related markers showed an overall improving trend, suggesting effective control of inflammatory activity, gradual immune reconstitution, and a favorable short-to mid-term clinical outcome. Abbreviations: RTX, rituximab; MMF, mycophenolate mofetil; IVIG, intravenous immunoglobulin; SMZ-TMP, trimethoprim-sulfamethoxazole; hs-CRP, high-sensitivity C-reactive protein; LDH, lactate dehydrogenase; HRCT, high-resolution computed tomography; PFT, pulmonary function test; GGO, ground-glass opacity.

5.1. Phase 1: initial treatment and disease assessment (late September 2025)

After admission, while awaiting the results of myositis-specific antibody testing and further etiological clarification, the possibility of concomitant infection could not be completely excluded because the patient presented with fever, cough, and severe hypoxemia. Therefore, empirical anti-infective therapy with moxifloxacin was initiated, together with intravenous methylprednisolone at 80 mg once daily. As a cornerstone therapy for anti-MDA5 antibody-positive dermatomyositis-associated interstitial lung disease, glucocorticoids may attenuate pulmonary inflammatory exudation and immune-mediated tissue injury by suppressing inflammatory cell activation and cytokine release, thereby providing a therapeutic window for subsequent treatment optimization. After initial treatment, the patient's body temperature decreased to some extent; however, hypoxemia at rest did not improve substantially. SpO₂ remained at 85%–88% despite oxygen supplementation via nasal cannula at 3 L/min, indicating that initial glucocorticoid therapy alone was insufficient to effectively halt disease progression and that further optimization of the therapeutic strategy was urgently required in conjunction with the immunological findings.

5.2. Phase 2: initiation of multi-target combination salvage therapy and early clinical response (late September to early October 2025)

In late September 2025, after strong positivity for anti-MDA5 antibodies was confirmed, the patient was managed according to a treatment pathway for severe MDA5⁺ DM-RP-ILD, based on the characteristic cutaneous manifestations, rapidly progressive respiratory symptoms, severe hypoxemia, and marked short-term radiological deterioration. Subsequently, on the basis of intravenous methylprednisolone sodium succinate at 80 mg once daily, oral mycophenolate mofetil at 750 mg twice daily and oral tofacitinib at 5 mg twice daily were added.

Given the rapid disease progression, limited improvement in oxygenation, and the relatively delayed onset of action of mycophenolate mofetil, which made it unlikely to control the acute progression of RP-ILD within a short period, the therapeutic regimen was further optimized after multidisciplinary discussion. While maintaining the same total daily dose of methylprednisolone, the administration schedule was adjusted to 40 mg intravenously twice daily; oral tofacitinib at 5 mg twice daily was continued; mycophenolate mofetil was temporarily discontinued. Considering the patient's height of 165 cm, body weight of 65 kg, estimated body surface area of approximately 1.69 m², hypoalbuminemia, marked lymphopenia, and high infectious risk, low-dose rituximab was used exploratorily as a temporary substitute, with an initial dose of 200 mg followed by a planned once-weekly regimen for a total of four infusions. When normalized to body surface area, the initial dose was approximately 118 mg/m², and the subsequent 300 mg dose corresponded to approximately 178 mg/m². Both doses were markedly lower than the commonly used 375 mg/m² regimen for lymphoma and also lower than the fixed 500–1000 mg regimens commonly used in some autoimmune diseases. Therefore, this approach represented an empirical, infection-risk-guided individualized dose reduction rather than a standardized low-dose regimen.

Meanwhile, considering that high-dose glucocorticoids combined with multiple immunosuppressive agents could increase the risk of opportunistic infections, intravenous immunoglobulin was administered at 10 g/day for 3 consecutive days to provide adjunctive immunomodulation. Sulfamethoxazole–trimethoprim (SMZ-TMP) was also given for Pneumocystis jirovecii pneumonia prophylaxis. This strategy emphasized active immunological intervention while simultaneously addressing infection prevention and control.

After initiation of combination therapy, the patient's clinical condition improved rapidly. Within 48 h after treatment, dyspnea was markedly relieved, peripheral oxygen saturation could be maintained above 97%, and the patient was gradually weaned from oxygen therapy and became able to perform indoor activities. It should be emphasized that this early improvement more likely reflected the combined effects of multiple interventions, including optimization of the glucocorticoid regimen, tofacitinib, intravenous immunoglobulin, and low-dose rituximab, rather than the effect of any single agent. Early follow-up chest CT from late September to early October 2025 showed initial absorption of bilateral interstitial lung lesions (Fig. 3E–H). Laboratory tests showed that the lymphocyte count increased from 0.27 × 10⁹/L to 0.43 × 10⁹/L, and the lymphocyte percentage increased from 7.5% to 8.8% (Table 1). A second infusion of rituximab was subsequently administered, with the dose adjusted to 300 mg. The patient tolerated the treatment well and was discharged after clinical stabilization.

5.3. Phase 3: Consolidation therapy and sustained clinical improvement (mid-to late October 2025)

In mid-October 2025, to complete the planned rituximab treatment course, the patient subsequently received the third and fourth infusions of low-dose rituximab, each at a dose of 300 mg. Before the third infusion in mid-October 2025, follow-up HRCT showed further absorption of bilateral ground-glass opacities and reticular changes, with complete resolution of newly developed ground-glass nodules (Fig. 3I–L). Meanwhile, laboratory parameters reflecting tissue injury and inflammatory activity continued to improve: lactate dehydrogenase decreased to 212 IU/L, albumin increased to 36.3 g/L, total protein increased to 58.3 g/L, the lymphocyte count increased to 0.53 × 10⁹/L, and the lymphocyte percentage recovered to 10.4% (Table 1, Fig. 6). The parallel improvement in radiological and laboratory findings suggested that the combination therapy had effectively restrained the progression of RP-ILD-associated acute lung injury.

After completion of the fourth low-dose rituximab infusion in late October 2025, repeat HRCT further demonstrated continued attenuation of bilateral interstitial lung lesions compared with previous images (Fig. 3M–P). During the same period, key serological indicators continued to improve: ferritin gradually declined from its peak level of 1625.30 μg/L, lactate dehydrogenase remained at a relatively low level, high-sensitivity C-reactive protein decreased to 1.33 mg/L, albumin increased to 42.18 g/L, total protein increased to 66.4 g/L, aspartate aminotransferase returned to the normal range, procalcitonin decreased to 0.02 ng/mL, the lymphocyte count steadily increased to 0.56 × 10⁹/L, and the lymphocyte percentage rose to 12.4% (Table 1, Fig. 6). These changes indicated sustained control of systemic inflammation and tissue injury, along with gradual recovery of nutritional status and peripheral immune cell levels.

5.4. Phase 4: extended follow-up and safety assessment (late November 2025 to early April 2026)

Subsequent follow-up showed continued improvement in the patient's clinical condition. At the end of the initial follow-up period in late November 2025, repeat HRCT showed near-complete resolution of bilateral interstitial lung lesions (Fig. 3Q–T). Laboratory tests during the same period showed a ferritin level of 1248.60 μg/L, lactate dehydrogenase of 288 IU/L, high-sensitivity C-reactive protein of 5.67 mg/L, albumin of 44.5 g/L, total protein of 66.9 g/L, aspartate aminotransferase of 35 IU/L, a lymphocyte count of 0.73 × 10⁹/L, and a lymphocyte percentage of 17.9%, indicating marked improvement in inflammatory activity, tissue injury, and nutritional status compared with previous findings (Table 1, Fig. 6).

During further extended follow-up in early February 2026, repeat chest CT showed a slight reduction in bilateral interstitial fibrosis compared with the previous follow-up endpoint, with overall radiological findings remaining stably improved (Fig. 3U–X). Laboratory tests during the same period showed a lymphocyte count of 1.22 × 10⁹/L, a lymphocyte percentage of 21.2%, high-sensitivity C-reactive protein of 0.350 mg/L, procalcitonin of 0.020 ng/mL, ferritin of 1972.9 μg/L, lactate dehydrogenase of 400 IU/L, albumin of 44.4 g/L, total protein of 67.0 g/L, and aspartate aminotransferase of 44 IU/L. Repeat pulmonary function testing showed an FVC of 62% predicted, FEV1 of 66% predicted, and DLCO of 74% predicted, suggesting improvement in ventilatory and diffusing capacity compared with previous results. Overall, the patient's oxygenation status and clinical symptoms remained stable, and no serious adverse events, including severe infection, hepatitis B virus reactivation, Mycobacterium tuberculosis infection, or invasive fungal infection, were reported. However, fluctuations in some laboratory parameters persisted, indicating the need for continued dynamic monitoring.

The patient subsequently continued outpatient follow-up. In early March 2026, follow-up testing showed that the lymphocyte count had increased to 1.30 × 10⁹/L and the lymphocyte percentage to 35.9%; high-sensitivity C-reactive protein remained at 0.35 mg/L, procalcitonin remained at 0.020 ng/mL, ferritin further decreased to 1049.7 μg/L, and albumin remained at 44.4 g/L. At the last outpatient follow-up in early April 2026, procalcitonin remained at 0.02 ng/mL, and ferritin further decreased to 830.584 μg/L. Because the patient's clinical symptoms were stable and the previous chest CT had shown sustained overall radiological improvement, repeat chest CT every 2 months was recommended thereafter. Taken together, the extended follow-up findings indicated that the patient's overall clinical condition remained stable in the short-to-intermediate term, with further recovery of some previously abnormal parameters. These findings suggest a favorable overall outcome after early multi-target escalation therapy, although continued dynamic monitoring remains necessary to assess the risk of long-term relapse and laboratory fluctuations.

The post-discharge maintenance regimen included prednisone acetate tablets at 40 mg once daily, with planned gradual tapering according to disease status after subsequent chest CT reassessment; rabeprazole 20 mg once daily; tofacitinib 5 mg twice daily; mycophenolate mofetil 750 mg twice daily; calcium carbonate D3 twice daily; calcitriol 0.25 μg twice daily; and one tablet of sulfamethoxazole–trimethoprim (SMZ-TMP) once daily for Pneumocystis jirovecii pneumonia prophylaxis. Continued outpatient follow-up was planned.

6. Discussion

This case reports a patient with severe anti-MDA5 antibody-positive dermatomyositis-associated rapidly progressive interstitial lung disease (MDA5⁺ DM-RP-ILD), characterized by rapid disease progression and a limited response to initial glucocorticoid therapy. After the patient was managed under a critical-care treatment pathway in late September 2025, he received early multi-target escalation therapy centered on optimization of glucocorticoid administration combined with tofacitinib, with exploratory use of low-dose rituximab. This regimen was supplemented with short-course intravenous immunoglobulin (IVIG) and sulfamethoxazole–trimethoprim (SMZ-TMP) for Pneumocystis jirovecii pneumonia prophylaxis. It should be noted that mycophenolate mofetil was briefly added during the early treatment phase. However, because of its relatively delayed onset of action and the rapidly progressive disease course, it was discontinued during acute-phase treatment optimization and temporarily replaced with low-dose rituximab. After completion of the low-dose rituximab course and stabilization of the patient's condition following discharge, mycophenolate mofetil was resumed as maintenance therapy. Following treatment, the patient's oxygenation status improved rapidly, radiological abnormalities continued to resolve, and laboratory parameters showed an overall favorable trend. During extended follow-up and subsequent outpatient reassessments, the patient's overall clinical condition remained stable, with further recovery of several previously abnormal parameters, although dynamic fluctuations persisted in some indicators. Although multiple autoantibodies, including anti-EJ antibodies, were detected in this case, the acute onset, characteristic cutaneous manifestations such as mechanic's hands, rapidly progressive interstitial lung injury, and strong anti-MDA5 antibody positivity suggest that MDA5⁺ DM remained the central pathological basis underlying this clinical phenotype. The significance of this case does not lie in demonstrating a definitive independent therapeutic effect of any single agent or fixed combination regimen. Rather, it provides clinical practice-based insight into staged, multi-target treatment optimization guided by careful balancing of infectious risk in critically ill patients and generates testable hypotheses for future mechanistic and efficacy-validation studies.

To more accurately understand the clinical significance of the therapeutic pathway used in this case, it is necessary to first consider it within the treatment context and practical challenges associated with the high-mortality clinical setting of MDA5⁺ DM-RP-ILD. MDA5⁺ DM-RP-ILD is one of the most life-threatening clinical phenotypes among inflammatory myopathy-associated interstitial lung diseases. It is characterized by acute onset, rapid progression, and a high short-term mortality risk, with severe cases potentially progressing to respiratory failure within weeks [16]. Previous studies have shown that the development of RP-ILD is one of the key determinants of poor prognosis in patients with anti-MDA5 antibody-positive dermatomyositis. Factors such as fever, elevated inflammatory markers, increased lactate dehydrogenase, hyperferritinemia, severe lymphopenia, and anti-Ro52 antibody positivity are closely associated with disease progression and increased mortality risk [[17], [18], [19]]. Although intensive immunosuppressive strategies, such as high-dose glucocorticoids combined with calcineurin inhibitors or cyclophosphamide, remain commonly used initial treatment approaches in current clinical practice, some patients respond inadequately to conventional regimens. Moreover, intensive immunosuppression itself may impose substantial risks of infection and long-term complications [20,21]. Therefore, for critically ill patients with rapidly progressive disease and prominent infectious risk, the real challenge in clinical management is not whether to initiate immunosuppressive therapy, but how to rapidly control the aberrant immune-inflammatory response, halt the progression of lung injury, and simultaneously keep treatment-related infectious risks within an acceptable range during a limited therapeutic window. This also provides the practical rationale for multi-target combination therapy and dynamic adjustment of therapeutic strategies.

In this therapeutic context, the inclusion of tofacitinib in the regimen was not merely based on empirical combination therapy, but was closely related to the key immunopathological axis of MDA5⁺ DM-RP-ILD. Mechanistic studies have suggested that type I interferon-related signaling pathways play a central role in the immunopathology of MDA5⁺ DM [22]. As a cytoplasmic receptor for viral RNA recognition, aberrant activation of MDA5 can continuously amplify type I interferon responses and further drive inflammatory cytokine release, immune cell dysfunction, and progression of interstitial lung injury [23]. Previous studies have also suggested an association between anti-MDA5 antibody levels and type I interferon signatures, further supporting the pathological relevance of the JAK–STAT pathway in this disease axis [24]. Based on this mechanistic rationale, JAK inhibitors such as tofacitinib have been explored in recent years in selected refractory or rapidly progressive cases of MDA5⁺ DM-associated ILD. Previous case reports and small-scale studies suggest that they may help attenuate inflammatory responses and improve clinical outcomes [25]. Overall, the available evidence more strongly supports its role as an important modulatory component within a combination-treatment framework, rather than providing sufficient justification for its use as monotherapy to rapidly reverse disease progression during the severe acute phase. Nevertheless, the current evidence is still largely derived from case reports and small-scale studies. Moreover, in the acute severe phase, the onset speed and control intensity of tofacitinib monotherapy may not be sufficient to explain the marked improvement in oxygenation observed within 48 h in this case [26]. Therefore, in this case, tofacitinib should be understood as a key component of the early multi-target combination-treatment framework rather than as a single decisive factor.Its clinical significance mainly lies in its intervention in type I interferon-mediated inflammatory amplification and in its integration with optimized glucocorticoid administration, IVIG, and subsequent therapeutic measures to form a comprehensive regulatory strategy targeting immune dysregulation during the acute progressive phase.

Similar to JAK inhibitors, rituximab, a CD20-targeted B-cell-depleting agent, has also been explored in refractory cases of MDA5⁺ DM and its associated interstitial lung disease [27,28]. Current evidence regarding rituximab (RTX) in MDA5⁺ DM-RP-ILD is mainly derived from case reports or small-scale studies, suggesting that it may serve as a salvage therapy in selected patients who respond inadequately to conventional regimens. However, its use has most often been reported in the context of critical illness, rapid disease progression, or previous treatment failure, and it is frequently combined with glucocorticoids, cyclophosphamide, or other immunomodulatory agents [29]. Previous studies have suggested that, in some patients with immune-mediated interstitial lung disease, RTX combined with other immunosuppressive therapies may be associated with improved pulmonary function and reduced glucocorticoid exposure [30]. In addition, in the broader contexts of connective tissue disease-associated interstitial lung disease and antisynthetase syndrome-associated interstitial lung disease, RTX has also been reported to improve pulmonary function and reduce glucocorticoid exposure [31,32]. These findings indirectly support the potential value of B-cell-targeted therapy in immune-mediated lung injury, but they should not be interpreted as definitive evidence of efficacy in MDA5⁺ DM-RP-ILD. Overall, substantial heterogeneity exists in the timing of RTX administration, combination strategies, and dosing regimens reported in the literature, and no consensus has yet been reached. Therefore, the precise role, optimal dose, and most appropriate target population for RTX in MDA5⁺ DM-RP-ILD remain to be further clarified. On this basis, the present case should not be interpreted as supporting RTX as a fully established component of standard therapy. Rather, RTX should be viewed as a salvage intervention that remains under active exploration in high-risk and refractory clinical settings.

Notably, in this case, oxygenation improved markedly within 48 h after the initiation of multi-target combination salvage therapy. Considering the treatment sequence and plausible pharmacological mechanisms, this early response was more likely driven primarily by the cumulative rapid anti-inflammatory and immunomodulatory effects of multiple interventions, rather than being simply attributable to low-dose rituximab itself. First, without increasing the total glucocorticoid dose, changing methylprednisolone from once-daily administration to divided equivalent dosing may have helped maintain more stable plasma drug concentrations, potentially facilitating rapid suppression of the inflammatory cascade [33]. Second, tofacitinib can interfere with type I interferon-mediated inflammatory amplification by inhibiting the JAK–STAT signaling pathway, and previous studies have also suggested that it may exert immunomodulatory effects relatively early during the acute phase of disease [34,35]. In addition, concomitant IVIG may have contributed to clinical improvement through immune neutralization and inflammatory modulation [36]. In contrast, rituximab primarily acts by depleting CD20⁺ B cells and inducing subsequent immune remodeling, effects that generally require a longer time window. Therefore, rituximab alone is unlikely to reasonably explain the marked improvement in oxygenation observed within 48 h [11]. Meanwhile, although mycophenolate mofetil was briefly used during the early treatment phase, its relatively delayed onset of action and rapid temporary replacement by low-dose rituximab during acute-phase treatment optimization suggest that its direct contribution to the rapid improvement in oxygenation within 48 h was also likely limited. Based on these considerations, we do not directly attribute the early therapeutic response in this case to rituximab, but instead emphasize the substantial confounding effects arising from concomitant therapeutic overlap and differences in treatment timing.

Another therapeutic component that requires clarification is the stage-specific role of mycophenolate mofetil (MMF) in this case.MMF has demonstrated certain clinical value in inflammatory myopathy-associated interstitial lung disease and other immune-mediated interstitial lung diseases. Previous studies have suggested that MMF may help improve pulmonary function, reduce glucocorticoid exposure, and has a relatively favorable tolerability profile; therefore, it is commonly used as an important component of combined immunosuppressive therapy or maintenance treatment [37,38]. However, MMF has a relatively delayed onset of action, which may limit its direct effect during the acute progressive phase. In this case, MMF was briefly used in combination during the early treatment phase, which is consistent with the commonly adopted strategy of combined immunosuppression in inflammatory myopathy-associated interstitial lung disease. However, because the patient was in the acute progressive phase with rapidly worsening oxygenation, the more urgent clinical need was to control the aberrant immune-inflammatory response and halt the progression of lung injury within a short period. Therefore, the direct contribution of MMF to the rapid improvement in oxygenation within 48 h after treatment was likely limited. In contrast, resuming MMF after completion of the low-dose rituximab course and clinical stabilization following discharge was more consistent with its clinical role as a component of maintenance therapy.In other words, in this case, MMF was more likely to contribute to subsequent disease stabilization and maintenance therapy rather than serve as a major driver of rapid disease control during the acute phase.

Another important issue in this case is the exploratory use of low-dose rituximab. The dosing regimen used in this case consisted of an initial dose of 200 mg, followed by subsequent maintenance doses of 300 mg, which was substantially lower than the commonly used rituximab regimen of 375 mg/m² for lymphoma and also lower than the fixed-dose regimen of 1000 mg administered twice, on days 1 and 15, commonly used in some autoimmune diseases [39,40]. Given the patient's height of 165 cm, body weight of 65 kg, and estimated body surface area of approximately 1.69 m², the initial 200 mg dose corresponded to approximately 118 mg/m², whereas the subsequent 300 mg doses corresponded to approximately 178 mg/m²; both were markedly lower than standardized regimens. Previous studies in other autoimmune diseases have suggested the potential clinical utility of low-dose rituximab (RTX). For example, Kanagarajan et al. [41] observed in patients with pemphigus vulgaris that a low-dose rituximab regimen of 2 × 500 mg achieved effects comparable to those of the conventional-dose regimen of 2 × 1 g in inducing clinical remission, maintaining durable therapeutic responses, and reducing glucocorticoid exposure, while offering a more favorable cost-effectiveness profile and potentially improved safety characteristics. In patients with chronic inflammatory demyelinating polyneuropathy, low-dose rituximab at 600 mg every 6 months was also associated with clinical improvement, with no serious adverse events reported [42]. These studies provide some external support for the feasibility of dose optimization within a combination-treatment framework. However, it should be specifically noted that the 200–300 mg doses used in this case were even lower than some regimens described as “low-dose” RTX in the literature. Therefore, this approach should be more accurately interpreted as an empirical further dose-reduction attempt in the context of high infectious risk, rather than as a standardized low-dose regimen supported by sufficient evidence. This strategy was selected mainly because the patient had hypoalbuminemia, marked lymphopenia, and a high infectious risk at admission, while B-cell-targeted therapy was still considered potentially valuable as part of treatment optimization during the acute progressive phase. Therefore, a relatively conservative individualized dosing approach was adopted. Meanwhile, considering the potential value of retaining B-cell-targeted intervention during the acute progressive phase, we did not use a higher standard-dose regimen. Instead, we chose a conservative exploratory approach with a lower initial dose and completed short-course maintenance according to tolerability and subsequent clinical evolution. Therefore, the significance of this study does not lie in proving that low-dose RTX has definitive efficacy equivalent to that of conventional-dose regimens in this disease. Rather, it suggests that, in individualized clinical scenarios involving critical illness and high infectious risk, dose reduction may represent a direction worthy of further investigation for balancing potential therapeutic benefit and safety.

Further comparison of this case with the existing literature helps clarify its true clinical value. Previous studies have explored the use of tofacitinib or rituximab in refractory cases of MDA5⁺ DM-related disease. For example, Zhao et al. [43] reported a successful case treated with tofacitinib monotherapy; however, improvement in systemic symptoms generally required 2–4 weeks, suggesting that although tofacitinib may have therapeutic potential, its onset of action as monotherapy may be relatively limited. In the case reported by Mochizuki et al. [7] the patient developed lymphoproliferative disease after receiving rituximab combined with cyclophosphamide and high-dose glucocorticoids, highlighting the potentially high risk of serious complications associated with conventional intensified immunosuppressive strategies. Yen et al. [14] treated MDA5⁺ DM-RP-ILD with prednisone-equivalent glucocorticoids at 0.4 mg/kg/day combined with intravenous rituximab at 1000 mg and pirfenidone. Although clinical benefit was observed, this regimen overall continued the conventional high-intensity immunosuppressive approach and did not involve individualized dose optimization. Compared with these reports, the relative distinction of the present case does not lie in being the first to demonstrate the efficacy of RTX or RTX combined with tofacitinib. Rather, it lies in the use of an early inflammatory-control framework centered on optimization of glucocorticoid administration plus JAK inhibition, supplemented with IVIG and Pneumocystis jirovecii pneumonia prophylaxis. During acute-phase treatment optimization, mycophenolate mofetil, which has a relatively delayed onset of action, was temporarily discontinued and replaced in a phased manner with low-dose rituximab; after completion of the low-dose rituximab course and clinical stabilization, mycophenolate mofetil was resumed as post-discharge maintenance therapy. Subsequent follow-up showed continuous radiological absorption of pulmonary lesions and overall improvement in serological markers related to inflammation and tissue injury. Further outpatient follow-up showed that although some laboratory parameters fluctuated in early February 2026, subsequent reassessments in early March and early April 2026 demonstrated continued recovery of the lymphocyte count and lymphocyte percentage, further decline in ferritin levels, and persistently low levels of inflammation-related markers, suggesting a favorable short-to-intermediate-term overall outcome. Therefore, this case should be interpreted as supporting a staged, multi-target treatment optimization pathway guided by careful balancing of infection risk, rather than as evidence demonstrating a definitive independent causal effect of low-dose RTX on early therapeutic response or long-term outcome. This also suggests that, for similar high-risk patients, future research may need to focus more on the stage-specific synergistic effects of different therapeutic components, rather than solely on whether a single drug is effective. Accordingly, this case is better regarded as a supplementary clinical observation to existing therapeutic experience rather than as evidence supporting a definitive conclusion regarding any specific drug strategy.

Beyond the pharmacological strategy itself, this case also highlights the importance of infection prophylaxis in the management of MDA5⁺ DM-RP-ILD. Patients with this condition are often critically ill and require early intensified immunosuppressive intervention. Although high-dose glucocorticoids combined with one or two immunomodulatory or immunosuppressive agents may improve disease control, such regimens can also increase the risk of opportunistic infections [44]. The potential value of intravenous immunoglobulin (IVIG) in refractory MDA5⁺ DM lies not only in its immunomodulatory effects, but also in the fact that its use in various autoimmune diseases generally does not substantially increase infection risk [45]. In contrast, the use of sulfamethoxazole–trimethoprim (SMZ-TMP) for Pneumocystis jirovecii pneumonia prophylaxis during the initial treatment phase represents an important supportive measure in the setting of intensified immunosuppression [46]. In this case, no severe infection, hepatitis B virus reactivation, Mycobacterium tuberculosis infection, or invasive fungal infection was observed throughout treatment and follow-up. This suggests that implementation of a multi-target combination regimen under close monitoring and infection prophylaxis may have an acceptable short-to intermediate-term safety profile. Nevertheless, this observation is derived from a single case and cannot substitute for systematic safety evaluation.

This study also has several clear limitations. First, as a single-case report, the generalizability of our findings is limited, and the evidence is insufficient to support broadly applicable therapeutic recommendations. Second, although follow-up was extended to early April 2026, the overall observation period remains insufficient to fully assess the risk of long-term relapse, late infectious complications, and potential malignancy. Third, serial dynamic monitoring of peripheral blood CD19/CD20-positive cells and B-cell subsets was not performed, nor were anti-MDA5 antibody levels quantitatively monitored over time. Therefore, we were unable to objectively evaluate the degree of B-cell depletion or its association with clinical outcomes. In addition, several interventions overlapped temporally, including optimization of glucocorticoid administration, tofacitinib, mycophenolate mofetil, which was briefly combined during the early treatment phase and later resumed during maintenance therapy, IVIG, and low-dose rituximab. The combined effects of concomitant therapies and the treatment sequence itself represent substantial confounding factors, which is an inherent limitation of case reports in terms of causal inference. Finally, although the newly added outpatient follow-up data showed that the patient's overall clinical condition remained stable and that several previously abnormal parameters further recovered, longer-term radiological and immunological dynamic data remain unavailable, indicating the need for continued observation.

Despite these limitations, this case suggests that, in the high-mortality clinical context of RP-ILD, a rational multi-target drug combination together with infection-risk-guided individualized dose adjustment may enable rapid control of acute inflammatory responses while maintaining an acceptable safety profile, thereby creating favorable conditions for subsequent disease stabilization. Future studies may focus on several key directions. First, prospective cohort studies are needed to systematically compare the efficacy and safety of such multi-target combination regimens with those of conventional intensive immunosuppressive strategies. Second, biomarkers capable of predicting treatment response and relapse risk should be explored, including baseline interferon signaling intensity, dynamic changes in ferritin levels, and quantitative characteristics of specific autoantibody profiles. Third, serial dynamic monitoring of peripheral blood CD19/CD20-positive cells and B-cell subsets should be incorporated to further clarify the optimal dose, treatment duration, and most appropriate target population for rituximab within combination regimens, with the goal of achieving better long-term outcomes while maximizing patient safety.

7. Conclusion

This case illustrates a staged multi-target treatment approach for severe anti-MDA5-associated rapidly progressive interstitial lung disease in a patient with substantial infectious risk. Clinical and radiological improvement followed early treatment escalation; however, overlapping interventions preclude attribution of the response to reduced-dose rituximab alone. The optimal role and dosing of rituximab in this setting require evaluation in larger studies with serial B-cell and autoantibody monitoring.

CRediT authorship contribution statement

Lvdan Zhang: Conceptualization, Writing – original draft, Writing – review & editing. Mengwen Jiao: Software, Writing – original draft, Writing – review & editing. Yan Hou: Data curation, Funding acquisition. Youchen Jie: Conceptualization, Funding acquisition. Shaokang Mo: Formal analysis, Resources, Visualization. Wei Chen: Methodology, Supervision, Writing – original draft. Qingliang Xue: Supervision, Writing – review & editing. Yongjie Qiao: Conceptualization, Funding acquisition, Resources, Supervision.

Patient consent statement

Written informed consent was obtained from the patient for publication of this case report and the accompanying clinical, radiological, bronchoscopic and cutaneous images. A copy of the written consent is available for review by the Editor-in-Chief upon request.

Generative AI statement

The authors declare that no Generative AI was used in the creation of this manuscript.

Publisher's note

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Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Funding

This work was supported by the following grants: the High-Level Talent Training Program of the 940th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army (Grant No. 2024-G3-5); the Natural Science Foundation of Gansu Province (Grant Nos. 25JRRA812 and 24JRRA007); the Youth Science and Technology Foundation of Gansu Province (Grant No. 25JRRA818); and the Lanzhou Science and Technology Plan Project (Grant No. 2023-ZD-170). These funds were utilized to support the research implementation, manuscript preparation, and publication. The authors hereby declare this financial support.

Declaration of competing interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Appendix A. Supplementary data

The following is the Supplementary data to this article: