RARE DISEASE
Autoimmune pulmonary alveolar proteinosis
Autoimmune pulmonary alveolar proteinosis
Autoimmune pulmonary alveolar proteinosis
Synonyms: Autoimmune PAP, aPAP
Synonyms: Autoimmune PAP, aPAP
Synonyms: Autoimmune PAP, aPAP
Drug discovery
5
drugs
With orphan designations
Overview
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare interstitial lung disease caused by neutralizing autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), leading to impaired surfactant clearance and progressive respiratory insufficiency. Diagnosis relies on high-resolution CT findings, bronchoalveolar lavage with PAS-positive material, and serum GM-CSF autoantibody detection [1][5][6]. Clinical presentation typically includes insidious dyspnea, cough, and fatigue, with variable progression from spontaneous remission to respiratory failure [7][12]. Current management includes whole-lung lavage, inhaled GM-CSF therapy, and emerging biologic therapies [3][8][13].
Categories: rare respiratory diseases, rare transplant-related disorders
Research Papers
227 drug discovery papers about Autoimmune pulmonary alveolar proteinosis, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
227 drug discovery papers about Autoimmune pulmonary alveolar proteinosis, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-02 | Progressive Fibrosing Lung Disease Treated With Nintedanib in a Patient With Long-Standing Autoimmune Pulmonary Alveolar Proteinosis: A Case Report.
Autoimmune pulmonary alveolar proteinosis (APAP) is caused by impaired surfactant clearance due to neutralizing autoantibodies against granulocyte-macrophage colony-stimulating factor. Although whole-lung lavage and inhaled granulocyte-macrophage colony-stimulating factor therapy are established treatment options, pulmonary fibrosis is increasingly recognized as a clinically relevant complication in a subset of patients with APAP. However, the clinical behavior of APAP-associated fibrosing lung disease and the role of antifibrotic therapy remain unclear. A 54-year-old man with a 15-year history of APAP was referred to our institution. High-resolution computed tomography images obtained before referral showed slow progression of reticulation and traction bronchiectasis, suggesting fibrotic progression rather than recurrence of APAP. At presentation, forced vital capacity (FVC) was 3.31 L (80.0% predicted), and diffusion capacity for carbon monoxide (DLCO) was preserved. During 6 months of observation, FVC declined to 3.03 L (73.5% predicted), accompanied by worsening dry cough and exertional dyspnea. Nintedanib was initiated for a progressive fibrosing phenotype in the context of APAP. Thereafter, FVC remained relatively stable for 2 years, whereas DLCO declined during follow-up. APAP-associated fibrosing lung disease may present with a progressive fibrosing phenotype, but its diagnosis and management remain challenging. This case highlights the importance of distinguishing fibrotic progression from recurrence of intra-alveolar proteinosis.
2026-05-01 | A93-08 Human Bone Marrow-derived Mesenchymal Stem Cell Therapy For Autoimmune Pulmonary Alveolar Proteinosis: A First-in-human Phase Iia Clinical Trial
Abstract Rationale Autoimmune pulmonary alveolar proteinosis (aPAP) is characterized by impaired alveolar macrophage function and elevated anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. Previous studies demonstrated that human bone marrow-derived mesenchymal stem cells (hBMMSCs) can remodel the alveolar immune microenvironment and enhance macrophage phagocytic function. We conducted the first clinical study of hBMMSC therapy for aPAP to evaluate its safety and preliminary efficacy. Methods This phase IIa, open-label, single-arm clinical trial enrolled 10 aPAP patients, assigned to three groups: low-dose (1 × 106 cells/kg, single infusion), high-dose (2 × 106 cells/kg, single infusion), and high-dose repeated (2 × 106 cells/kg, two infusions two weeks apart), all via intravenous infusion. The primary endpoint was change in alveolar-arterial oxygen gradient (A-aDO2) from baseline to 24 weeks. Safety and tolerability were assessed by incidence of serious adverse events (SAEs). Results Of 10 subjects enrolled, 3 withdrew and 7 completed 24-week evaluation. No treatment-related SAEs occurred. In 7 evaluable subjects, A-aDO2 and oxygenation index (P/F ratio) improved significantly at 24 weeks compared with baseline (both p < 0.05). Repeated high-dose infusion produced greater A-aDO2 improvement than single-dose groups. Conclusion This first clinical trial of hBMMSC therapy for aPAP demonstrates that the treatment is safe, well tolerated, and improves A-aDO2 and P/F ratio. Repeated dosing appears more effective than a single infusion, providing initial real-world clinical evidence supporting potential therapeutic application. This abstract is funded by: Jiuzhitang Maker(Beijing) Cell Technology Co.Ltd
2026-02-20 | A Case of Autoimmune Pulmonary Alveolar Proteinosis.
Chemotherapeutic agents or regular doses of Rituximab may represent a potential therapeutic option for refractory cases of autoimmune pulmonary alveolar proteinosis.
2026-02-19 | Significant but Temporary Efficacy of Statin for a Patient With Severe Autoimmune Pulmonary Alveolar Proteinosis: A Case Report.
Autoimmune pulmonary alveolar proteinosis (APAP) is a rare autoimmune lung disorder characterised by the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies. Whole-lung lavage (WLL) therapy remains the standard treatment for severe cases. Recently, inhaled GM-CSF therapy has been approved in Japan; however, the cost of the treatment remains a limiting factor. Several reports have suggested that oral statin therapy may be a promising therapeutic option for APAP. Herein, we report a case of severe APAP that underwent WLL therapy twice and achieved an excellent response and remarkable clinical resolution of respiratory failure after the initiation of oral statin therapy. Remarkable improvements in oxygen saturation, blood gas analysis, serum biomarker levels and pulmonary function test results were observed after statin administration. However, the efficacy was temporary, and respiratory failure relapsed 2 years after the initiation of statin therapy. Statin therapy for APAP was deemed effective but potentially temporary.
2026-02-01 | Extracellular DNA in bronchoalveolar lavage fluid as a candidate biomarker of disease severity in autoimmune pulmonary alveolar proteinosis.
Autoimmune pulmonary alveolar proteinosis (aPAP) results from the neutralization of autoantibodies against granulocyte-macrophage colony-stimulating factor, which leads to alveolar macrophage (AM) dysfunction and surfactant accumulation. However, disease progression cannot be solely explained by surfactant overload. This study aimed to investigate whether defective efferocytosis in aPAP contributes to persistent apoptotic debris and accumulation of extracellular double-stranded DNA (dsDNA), which is a candidate biomarker of disease severity. We analyzed bronchoalveolar lavage fluid (BALF) samples obtained from 13 patients with aPAP and 13 patients with other interstitial lung diseases (controls). Apoptotic debris was assessed cytologically, extracellular dsDNA was quantified fluorometrically with urea correction, and efferocytosis was evaluated using flow cytometry. Additionally, we analyzed correlations between BALF dsDNA levels and clinical indices. BALF samples from patients with aPAP contained abundant apoptotic debris and significantly higher dsDNA levels than those from controls. Further, AMs from patients with aPAP showed s markedly reduced uptake apoptotic cells, indicating altered efferocytosis-related processes. Corrected BALF dsDNA levels were negatively correlated with the arterial oxygen pressure to inspired oxygen fraction ratio and percent predicted diffusing capacity of the lung for carbon monoxide. Altered efferocytosis-related processes in patients with aPAP may promote the accumulation of apoptotic debris and extracellular DNA in the alveolar space. Further, dsDNA levels in BALF strongly reflect impaired gas exchange and provide a biomarker of disease severity. These findings further elucidate the pathogenesis of aPAP and establish extracellular DNA as a promising tool for disease monitoring and therapeutic evaluation.
2026-08-02 | Progressive Fibrosing Lung Disease Treated With Nintedanib in a Patient With Long-Standing Autoimmune Pulmonary Alveolar Proteinosis: A Case Report.
Autoimmune pulmonary alveolar proteinosis (APAP) is caused by impaired surfactant clearance due to neutralizing autoantibodies against granulocyte-macrophage colony-stimulating factor. Although whole-lung lavage and inhaled granulocyte-macrophage colony-stimulating factor therapy are established treatment options, pulmonary fibrosis is increasingly recognized as a clinically relevant complication in a subset of patients with APAP. However, the clinical behavior of APAP-associated fibrosing lung disease and the role of antifibrotic therapy remain unclear. A 54-year-old man with a 15-year history of APAP was referred to our institution. High-resolution computed tomography images obtained before referral showed slow progression of reticulation and traction bronchiectasis, suggesting fibrotic progression rather than recurrence of APAP. At presentation, forced vital capacity (FVC) was 3.31 L (80.0% predicted), and diffusion capacity for carbon monoxide (DLCO) was preserved. During 6 months of observation, FVC declined to 3.03 L (73.5% predicted), accompanied by worsening dry cough and exertional dyspnea. Nintedanib was initiated for a progressive fibrosing phenotype in the context of APAP. Thereafter, FVC remained relatively stable for 2 years, whereas DLCO declined during follow-up. APAP-associated fibrosing lung disease may present with a progressive fibrosing phenotype, but its diagnosis and management remain challenging. This case highlights the importance of distinguishing fibrotic progression from recurrence of intra-alveolar proteinosis.
2026-05-01 | A93-08 Human Bone Marrow-derived Mesenchymal Stem Cell Therapy For Autoimmune Pulmonary Alveolar Proteinosis: A First-in-human Phase Iia Clinical Trial
Abstract Rationale Autoimmune pulmonary alveolar proteinosis (aPAP) is characterized by impaired alveolar macrophage function and elevated anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. Previous studies demonstrated that human bone marrow-derived mesenchymal stem cells (hBMMSCs) can remodel the alveolar immune microenvironment and enhance macrophage phagocytic function. We conducted the first clinical study of hBMMSC therapy for aPAP to evaluate its safety and preliminary efficacy. Methods This phase IIa, open-label, single-arm clinical trial enrolled 10 aPAP patients, assigned to three groups: low-dose (1 × 106 cells/kg, single infusion), high-dose (2 × 106 cells/kg, single infusion), and high-dose repeated (2 × 106 cells/kg, two infusions two weeks apart), all via intravenous infusion. The primary endpoint was change in alveolar-arterial oxygen gradient (A-aDO2) from baseline to 24 weeks. Safety and tolerability were assessed by incidence of serious adverse events (SAEs). Results Of 10 subjects enrolled, 3 withdrew and 7 completed 24-week evaluation. No treatment-related SAEs occurred. In 7 evaluable subjects, A-aDO2 and oxygenation index (P/F ratio) improved significantly at 24 weeks compared with baseline (both p < 0.05). Repeated high-dose infusion produced greater A-aDO2 improvement than single-dose groups. Conclusion This first clinical trial of hBMMSC therapy for aPAP demonstrates that the treatment is safe, well tolerated, and improves A-aDO2 and P/F ratio. Repeated dosing appears more effective than a single infusion, providing initial real-world clinical evidence supporting potential therapeutic application. This abstract is funded by: Jiuzhitang Maker(Beijing) Cell Technology Co.Ltd
2026-02-20 | A Case of Autoimmune Pulmonary Alveolar Proteinosis.
Chemotherapeutic agents or regular doses of Rituximab may represent a potential therapeutic option for refractory cases of autoimmune pulmonary alveolar proteinosis.
2026-02-19 | Significant but Temporary Efficacy of Statin for a Patient With Severe Autoimmune Pulmonary Alveolar Proteinosis: A Case Report.
Autoimmune pulmonary alveolar proteinosis (APAP) is a rare autoimmune lung disorder characterised by the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies. Whole-lung lavage (WLL) therapy remains the standard treatment for severe cases. Recently, inhaled GM-CSF therapy has been approved in Japan; however, the cost of the treatment remains a limiting factor. Several reports have suggested that oral statin therapy may be a promising therapeutic option for APAP. Herein, we report a case of severe APAP that underwent WLL therapy twice and achieved an excellent response and remarkable clinical resolution of respiratory failure after the initiation of oral statin therapy. Remarkable improvements in oxygen saturation, blood gas analysis, serum biomarker levels and pulmonary function test results were observed after statin administration. However, the efficacy was temporary, and respiratory failure relapsed 2 years after the initiation of statin therapy. Statin therapy for APAP was deemed effective but potentially temporary.
2026-02-01 | Extracellular DNA in bronchoalveolar lavage fluid as a candidate biomarker of disease severity in autoimmune pulmonary alveolar proteinosis.
Autoimmune pulmonary alveolar proteinosis (aPAP) results from the neutralization of autoantibodies against granulocyte-macrophage colony-stimulating factor, which leads to alveolar macrophage (AM) dysfunction and surfactant accumulation. However, disease progression cannot be solely explained by surfactant overload. This study aimed to investigate whether defective efferocytosis in aPAP contributes to persistent apoptotic debris and accumulation of extracellular double-stranded DNA (dsDNA), which is a candidate biomarker of disease severity. We analyzed bronchoalveolar lavage fluid (BALF) samples obtained from 13 patients with aPAP and 13 patients with other interstitial lung diseases (controls). Apoptotic debris was assessed cytologically, extracellular dsDNA was quantified fluorometrically with urea correction, and efferocytosis was evaluated using flow cytometry. Additionally, we analyzed correlations between BALF dsDNA levels and clinical indices. BALF samples from patients with aPAP contained abundant apoptotic debris and significantly higher dsDNA levels than those from controls. Further, AMs from patients with aPAP showed s markedly reduced uptake apoptotic cells, indicating altered efferocytosis-related processes. Corrected BALF dsDNA levels were negatively correlated with the arterial oxygen pressure to inspired oxygen fraction ratio and percent predicted diffusing capacity of the lung for carbon monoxide. Altered efferocytosis-related processes in patients with aPAP may promote the accumulation of apoptotic debris and extracellular DNA in the alveolar space. Further, dsDNA levels in BALF strongly reflect impaired gas exchange and provide a biomarker of disease severity. These findings further elucidate the pathogenesis of aPAP and establish extracellular DNA as a promising tool for disease monitoring and therapeutic evaluation.
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Drug Discovery Landscape
5 orphan drug designations for Autoimmune pulmonary alveolar proteinosis.
5 orphan drug designations for Autoimmune pulmonary alveolar proteinosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
L-methionine | other | EMA | 2024-06-28 | — | Imagine Institut Des Maladies Genetiques Necker Enfants Malades |
Sargramostim | proteins | EMA | 2024-06-28 | — | CATS Consultants GmbH |
sargramostim | proteins | FDA | 2018-10-22 | — | Partner Therapeutics, Inc. |
Granulocyte macrophage colony stimulating factor | proteins | EMA | 2013-07-17 | — | Savara ApS |
recombinant human GM-CSF, molgramostim | proteins | FDA | 2012-10-31 | — | Savara Inc. |
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