A New Era in the Treatment of Autoimmune Pulmonary Alveolar Proteinosis

In 1999, Nakata et al. identified increased production of granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies as a causative factor for idiopathic pulmonary alveolar proteinosis (PAP), which later came to be called autoimmune PAP (aPAP). GM-CSF therapy has been studied as a novel treatment for aPAP over the past quarter-century, initially via subcutaneous injection [1-4] and later as inhalation therapy [5-10]. Pilot studies in the 2000s were followed by a multicentre phase II study [8], the PAGE randomised control trial in Japan [9], and the IMPALA international clinical trial [10]. Based on the results of the PAGE trial, in 2024, a recombinant human (rh)GM-CSF was approved as a treatment for aPAP in Japan, ahead of the rest of the world. Due to the rarity of aPAP and the high cost of rhGM-CSF agents, only a few treated case series and clinical trials with small groups of participants have been published. Since the incidence of APAP is 1.65 per million, even when conducting a placebo-controlled randomised trial, it can only be a trial of one dose of GM-CSF. Therefore, while the efficacy of inhaled GM-CSF can be verified, the optimal dose and optimal treatment duration have not been established. Since the 2024 regulatory approval, more than 100 patients have undergone inhalation therapy in Japan under public health insurance coverage. It is expected that new clinical trials will be conducted to determine the optimal dosage, and the optimal treatment period will be clarified through post-marketing surveillance. A major challenge not yet addressed is whether every other week or everyday inhalation of GM-CSF is better for inducing remission. The PAGE trial demonstrated significant efficacy with intermittent administration, whereas the IMPALA trial demonstrated efficacy with daily administration. The results of the PAGE study also indicated that a longer treatment duration might be advantageous for achieving a better therapeutic effect [9]. The results of the IMPALA trial showed a significant difference in effectiveness between the placebo inhalation group and the daily inhalation group, but no significant difference was found between the intermittent inhalation group and the daily inhalation group [10]. As the IMPALA-2 study only evaluates the daily inhalation group and the placebo group, the matter seems to remain unresolved. Regarding the effects of long-term rhGM-CSF inhalation on the living body, there is a non-clinical study conducted before the PAGE trial. Repeated long-term administration of rhGM-CSF (every other week for 26 weeks) was performed in cynomolgus macaques by inhalation through a face mask connected to a nebulizer [11]. The administered rhGM-CSF was immunohistochemically confirmed in bronchus-associated lymphoid tissue (BALT) follicles formed around the alveoli. The macaques that received the drug produced GM-CSF antibodies, starting 2 weeks after administration. Residual rhGM-CSF in BALT may be associated with GM-CSF antibody production as an antidrug antibody. Of course, GM-CSF inhalation in patients with aPAP may differ from that in individuals without anti-GM-CSF antibodies in terms of the response to exogenous GM-CSF and the production of anti-drug antibodies. These points warrant further investigation. Another challenge is determining the type of nebulizer that is best suited for rhGM-CSF inhalation. For efficient inhalation, nebulizers are required to generate aerosols that can reach the lower airways. The jet nebulizer used in the PAGE trial generates a drug mist by injecting air from the nozzle at the apex of a conical structure, utilising Bernoulli's principle. It is a robust product that can be easily managed at home and has been widely used in rhGM-CSF inhalation trials. A single inhalation in the PAGE trial took approximately 10 min. The mesh nebulizer used in the IMPALA trial generates a drug mist by electrically vibrating a resonant membrane with several micrometre-sized holes, producing a denser drug mist than the jet nebulizer, and inhalation takes a few minutes. Significant therapeutic effects of rhGM-CSF inhalation were observed in both trials using the jet and mesh nebulizers, although no studies have compared nebulizer efficacy directly. The Japanese regulatory authority has not specified the inhalation device of choice for the recently approved rhGM-CSF. Further comparative studies may lead to clarity regarding optimal nebulizer type. Whether the current rhGM-CSF inhalation therapy regimen (250 μg/day inhalation for 7 days every other week for 24 weeks) can be extended for up to 48 weeks remains to be assessed. Presently for maintenance, 125 μg of rhGM-CSF is administered 1–2 times a day twice every fortnight [12]. It is not yet clear if the dosage and duration of inhalation should be shortened for maintenance post-remission of symptoms or be maintained. Further studies are thus required to identify maintenance therapy endpoints and expected duration for improving the treatment algorithm (Figure 1). We also need to consider a combination therapy with whole-lung lavage (WLL), which is the conventional treatment for aPAP, and rhGM-CSF inhalation. In rhGM-CSF inhalation therapy for aPAP, insoluble substances formed in the airways may block access of inhaled rhGM-CSF to the alveoli. A recent study suggests better therapeutic effects of rhGM-CSF inhalation therapy after WLL [13]. Campo et al. reported that a group receiving repeated cycles of rhGM-CSF inhalation after WLL had better outcomes than a group that was observed after WLL [14]. This requires further investigation and can benefit especially in severe patients with vital capacity below 80%, who might need additional treatment after initial GM-CSF inhalation [15]. Last but not least, to administer GM-CSF inhalation therapy, patients must be diagnosed with aPAP, but this serodiagnosis has not necessarily been widespread. GM-CSF antibodies are measured using standard antibodies in an ELISA method. Recently, a measurement kit for GM-CSF antibodies using immunochromatography was developed in Japan and approved by the Japanese Pharmaceuticals and Medical Devices Agency. This kit allows for the detection of the autoantibodies within 15 min by applying 5 μL of serum to the assay system and adding 100 μL of developing solution dropwise into the window of the assay kit. The detection sensitivity is equivalent to the cutoff value used in conventional ELISA methods. This novel measurement kit may also allow rapid diagnosis of aPAP in clinical settings. Ryushi Tazawa received a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, and honoraria for lectures from Nobelpharma Co. Ltd. Koh Nakata received consulting fees from Nobelpharma Co. Ltd.