Exogenous GM-CSF therapy for autoimmune pulmonary alveolar proteinosis: a systematic literature review

Abstract

Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy is an important treatment for autoimmune pulmonary alveolar proteinosis (aPAP). Exogenous GM-CSF treatment can be administered either through subcutaneous injection or nebulized inhalation. However, data on the effectiveness and safety of these two approaches are lacking.

Method: We conducted a systematic literature review of different methods, including subcutaneous injection and nebulized inhalation of GM-CSF, for the treatment of aPAP patients. Patients were divided into a subcutaneous injection group (SIG) and a nebulized inhalation group (NIG) according to the route of administration. Treatment efficacy and safety, including adverse events, were statistically assessed. We analyzed different GM-CSF treatment cycles with different time intervals. The analyses were performed using chi-square tests, unpaired t-tests, and Kruskal-Wallis H-tests.

Results: A total of 304 aPAP patients were treated with GM-CSF, including 66 (21.7%) in the SIG and 238 (78.3%) in the NIG. In total, we identified 220 (72.37%) patients whose treatment was effective and 84 (27.63%) patients whose treatment was ineffective. Efficacy was achieved in 54.55% (36/66) of the SIG patients and 77.31% (184/238) of the NIG patients (P < 0.001). More metrics were changed than in the NIG than SIG, suggesting the superior effectiveness of nebulized inhalation. The nebulized inhalation of GM-CSF was more effective (P < 0.001) and caused fewer adverse events than its subcutaneous injection. A significant difference in the NIG was noted across treatment durations, with an efficacy rate of 88% for those treated for over 24 weeks, compared with 48% in the SIG (P < 0.001). Among the NIG patients, the optimal efficacy was found to be at a dosage of 300-400 μg/d, with diminishing efficacy at higher doses (P < 0.036).

Conclusion: Nebulized inhalation is a more effective and safer route of GM-CSF administration than subcutaneous injection is, with a potential optimal dosage of 300-400 μg/day, and the duration of GM-CSF treatment via nebulized inhalation with the greatest efficacy is >24 weeks.

Keywords: GM-CSF; aPAP; inhalation; subcutaneous injection; treatment dosage and duration.

Figure 1

Flowchart of the collection process.

Figure 2

Statistics on the concomitant toxic effects of treatment. Symptoms with * are those where there is a significant difference in toxicity between the two treatment methods (P < 0.005).

Figure 3

Comparison of the efficacy rates across treatment cycles for different GM-CSF delivery methods. Treatment cycles with * are defined as significantly different between the efficacy rates of the two GM-CSF treatments (P < 0.005).

Figure 4

Effects of GM-CSF and anti-GM-CSF autoantibodies on the body and PAP formation. Anti-GM-CSF autoantibodies negatively affect alveolar macrophages, which in turn affects their ability to catabolize alveolar surface-active substances and protect the host from infectious diseases, which in turn leads to an accumulation of alveolar surface-active substances and PAP. The Janus kinase (JAK)2/STAT5, Ras-Raf-neutral gene-activated protein kinase (MAPK), nuclear factor (NF)-kB, and phosphatidylinositol 3-kinase (PI3K)-Akt pathways are implicated in GM-CSF receptor activation, and together, they regulate the immune effects of GM-CSF. GM-CSF activates macrophages and dendritic cells, which produce IL-23, IL-1, and IL-6 that drive Th17 and Th1 cell differentiation, thus creating a positive feedback loop in addition to the expression of GM-CSF by Th1 cells. PAP, pulmonary alveolar proteinosis; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-1, interleukin-1; IL-6, interleukin-6; IL-23, interleukin-23; Th1, T helper 1; Th17, T helper 17; (JAK) 2/STAT5 pathway, Janus kinase 2/signal transducer and activator of transcription 5; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol-3-kinase; NF-kB2, nuclear factor kappa-B.