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Long-Term Inhaled Granulocyte Macrophage–Colony-Stimulating Factor in Autoimmune Pulmonary Alveolar Proteinosis: Effectiveness, Safety, and Lowest Effective Dose

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Abstract

Background and Objectives

Granulocyte macrophage–colony-stimulating factor (GM-CSF) causes variable improvement in autoimmune pulmonary alveolar proteinosis (aPAP). Upon response to short-term treatment, patients are divided into responders and non-responders. The aim of this study was to test the hypothesis that long-term inhaled GM-CSF (iGM-CSF) is effective in all patients and that attainment of remission permits gradual de-escalation of the dose to the lowest effective safe dose.

Methods

Patients were treated with iGM-CSF 250 μg once a day given 4 days on and 4 days off for as long as necessary (the “as far as it takes” protocol). Upon remission, defined as absence of symptoms, oxygen desaturation <4 % at the walking test, and significant radiographic reduction of the infiltrates, or at least two of the above, the iGM-CSF dose was de-escalated. In the case of relapse, the patient was repositioned at the previous effective dose. Patients were investigated at 6-month intervals. To detect hematopoietic effects, blood cell counts, CD34+ cells, granulocyte macrophage progenitor colony-forming-units, and burst-forming-unit erythroid were measured.

Results

Six (five female) patients 43.8 ± 15.7 years of age were treated for 14–65 months and all responded to treatment. Remission was achieved after 25.6 ± 10 months. Three patients maintained remission at their lowest effective dose. Two patients relapsed at de-escalating doses. One patient remains on full-dose treatment. iGM-CSF had no impact on any of the hematological parameters tested.

Conclusions

In aPAP, long-term adherence to the dose schedule permitted remission in all patients. Long-term treatment with iGM-CSF also permitted the definition of lower effective doses, minimizing disease burden and treatment costs safely, since no stimulating activity on hematopoiesis was observed, a fact that is of paramount importance for those aPAP patients needing lifelong treatment.

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Acknowledgments

This study is dedicated to the National Health System (ΕΣΥ) and to the people of Greece who, despite a quite catastrophic economic crisis, still support patients with severe and rare diseases to live. We thank Mrs. Andrea Schams for her help with determination of the GM-CSF autoantibodies. This work was supported in part by the German Federal Ministry of Education and Research (EuPAPNet project inside ERARE, Number 01GM1011A). We sincerely thank Mr. A. Analitis for statistical assistance.

Conflict of interest statement

Matthias Griese was supported in part by the German Ministry of Education and Research (EuPAPNet project inside ERARE, Number 01GM1011A). Spyros A. Papiris, Panagiotis Tsirigotis, Likurgos Kolilekas, Georgia Papadaki, Andriana I. Papaioannou, Christina Triantafillidou, Anastasia Papaporfyriou, Anna Karakatsani, Konstantinos Kagouridis, and Effrosyni D. Manali have no conflict of interest related to this work.

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Authors and Affiliations

  1. 2nd Pulmonary Medicine Department, “Attikon” University Hospital, Athens Medical School, National and Kapodistrian University of Athens, 1 Rimini Street, 12462, Haidari, Greece

    Spyros A. Papiris, Georgia Papadaki, Andriana I. Papaioannou, Anna Karakatsani, Konstantinos Kagouridis & Effrosyni D. Manali

  2. 2nd Department of Internal Medicine, “Attikon” General University Hospital, Medical School, University of Athens, Athens, Greece

    Panagiotis Tsirigotis

  3. 7th Pulmonary Department and Asthma Center, Athens Chest Hospital, Athens, Greece

    Likurgos Kolilekas

  4. 6th Pulmonary Department, Athens Chest Hospital, Athens, Greece

    Christina Triantafillidou

  5. 1st Pulmonary Department, Athens Chest Hospital, Athens Medical School, National and Kapodistrian University of Athens, Haidari, Greece

    Anastasia Papaporfyriou

  6. Hauner Children’s Hospital, Ludwig-Maximilians-University, Member of the German Center for Lung Research (DZL), Munich, Germany

    Matthias Griese

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  1. Spyros A. Papiris
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Corresponding author

Correspondence to Effrosyni D. Manali.

Additional information

L. Kolilekas, G. Papadaki and A.I. Papaioannou contributed equally to this article.

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Papiris, S.A., Tsirigotis, P., Kolilekas, L. et al. Long-Term Inhaled Granulocyte Macrophage–Colony-Stimulating Factor in Autoimmune Pulmonary Alveolar Proteinosis: Effectiveness, Safety, and Lowest Effective Dose. Clin Drug Investig 34, 553–564 (2014). https://doi.org/10.1007/s40261-014-0208-z

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