Search

Background Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease that may progress towards pulmonary fibrosis. Data about fibrosis prevalence and risk factors are lacking. Methods In this retrospective multicentre nationwide cohort, we included patients newly diagnosed with aPAP between 2008 and 2018 in France and Belgium. Data were collected from medical records using a standardised questionnaire. Results 61 patients were included in the final analysis. We identified 5 patients (8%) with fibrosis on initial computed tomography (CT) and 16 patients (26%) with fibrosis on final CT after a median time of 3.6 years. Dust exposure was associated with pulmonary fibrosis occurrence (OR 4.3; p=0.038). aPAP patients treated with whole-lung lavage, rituximab or granulocyte–monocyte colony-stimulating factor therapy did not have more fibrotic evolution than patients who did not receive these treatments (n=25 out of 45, 57% versus n=10 out of 16, 62%; p=0.69). All-cause mortality was significantly higher in fibrotic than in nonfibrotic cases (n=4 out of 16, 25% versus n=2 out of 45, 4.4%; p=0.036, respectively). Conclusion In our population, a quarter of aPAP patients progressed towards pulmonary fibrosis. Dust exposure seems to be an important factor associated with this complication. More studies are needed to analyse precisely the impact of dust exposure impact, especially silica, in patients with aPAP.

Abstract Background Whole lung lavage is the current standard therapy for pulmonary alveolar proteinosis (PAP) that is characterized by the alveolar accumulation of surfactant. Rituximab showed promising results in auto-immune PAP (aPAP) related to anti-GM-CSF antibody. Methods We aimed to assess efficacy of rituximab in aPAP in real life and all patients with aPAP in France that received rituximab were retrospectively analyzed. Results Thirteen patients were included. No patients showed improvement 6 months after treatment, but, 4 patients (30%) presented a significant decrease of alveolar-arterial difference in oxygen after 1 year. One patient received lung transplantation and one patient was lost of follow-up within one year. Although a spontaneous improvement cannot be excluded in these 4 patients, improvement was more frequent in patients naïve to prior specific therapy and with higher level of anti-GM-CSF antibodies evaluated by ELISA. No serious adverse event was evidenced. Conclusions These data do not support rituximab as a second line therapy for patients with refractory aPAP.

Obinutuzumab (OBZ) shows stronger antibody-dependent cell cytotoxicity (ADCC) compared to rituximab and improved clinical activity for treating certain CD20+ neoplasia. However, the efficacy of monoclonal antibody (mAb) as a monotherapy is limited. Natural Killer (NK) cells are mediators of ADCC. Hematological cancer patients possess antitumor NK cells that are unable to control disease, possibly because they are dysfunctional. The immunomodulatory drug lenalidomide (LEN) could be a treatment to restore exhausted NK cell cytotoxic functions. The clinical trial GALEN is a Phase Ib/II study of OBZ combined with LEN for the treatment of relapsed/refractory follicular and aggressive (DLBCL and MCL) B-cell Lymphoma. During treatment, we analyzed specific aspects of NK cell biology. Treatment reversed the immature NK phenotype of patients and increased expression of NK activating receptors. Inhibitory receptors were either unchanged or decreased. There was a strong NK response at the end of the 1st cycle: NK number and intracellular granzyme B (GrzB) expression decreased, degranulation increased and NK responded better to allogeneic target challenge. Moreover, the interaction of NK cells with B cell targets, measured by trogocytosis, decreased during treatment. At the end of treatment, when target cells had been wiped out, the proportion of reactive NK cells (CD69+, CD45RARO+, CD107a+, CD19+) strongly decreased. Because all patients received LEN and OBZ, it was uncertain which drug was responsible of our observations, or even if a combination of both products was necessary for the described effects on this lymphocyte lineage.