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Acute flares of idiopathic pulmonary fibrosis have a mortality rate as high as 90% or more, depending on their severity. But an experimental regimen that includes autoantibody reduction was found to improve survival significantly, as well oxygen levels and walk distances, according to a small preliminary study published in PLOS ONE.

“It’s a preliminary study but it’s very exciting,” Amit Gaggar, MD, buy cephalexin online pharmacy PhD, an endowed professor of medicine at the University of Alabama at Birmingham (UAB), said in an interview. “We don’t really have a treatment for acute exacerbations of pulmonary fibrosis and the mortality is extremely high, so it’s really critical that we start thinking outside the box a little bit for therapeutics.” Gaggar isn’t affiliated with the study.

Study leader Steven R. Duncan, MD, also of UAB, acknowledged that the experimental therapy has its detractors. “There’s been a tremendous bias against the role of immunologic therapy in idiopathic fibrosis, although it seems to be lessening,” he said.

The preliminary study treated 24 patients who had acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) with a 19-day regimen called triple-modality autoantibody reduction. The three contributing modalities are therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin treatments. The standard treatment for AE-IPF consists of antibiotics and corticosteroids.

Duncan led the only other study of autoantibody reduction for AE-IPF, published in PLOS ONE in 2015. The latest preliminary study is a precursor to a National Heart, Lung, and Blood Institute–funded phase 2 randomized clinical trial, called STRIVE-IPF, currently enrolling AE-IPF patients at six sites.

In the preliminary study, 10 patients survived at least a year, an overall survival rate of 42%. Overall survival rates at 1, 3, and 6 months were 67%, 63%, and 46%. The study couldn’t identify characteristics of survivors vs nonsurvivors, although the latter had a trend toward greater initial oxygen requirements. Among the 10 patients who needed <25 L/min supplemental O₂, the survival rate was 57%. In patients who needed more than 25 L/min, the survival rate was 20% (P = .07). Only 1 of 5 patients who needed >40 L/min survived a year (P = .36).

After the 19-day regimen, 15 patients, or 63%, had significant drops in supplemental O₂ requirements, from an average of 15 L/min to 3 L/min (P = .0007). Thirteen (87%) of the patients who were taking an antifibrotic medication (either pirfenidone or nintedanib) at baseline needed less O₂ and/or had increased walking distances compared with five who weren’t prescribed either of the agents (P = .15), although 1-year survival didn’t vary significantly with antifibrotic use.

The mechanism of antibody reduction is to filter out B-cells, infiltrates of which are typically found in lungs of AE-IPF patients, Duncan said. The regimen involves nine TPEs over 15 days, two IV rituximab 1-gm treatments over that course, and IV Ig 0.5-gm/kg treatments daily on days 16 through 19.

“Plasma exchange rapidly gets rid of the antibodies,” Duncan said in an interview. “It’s the basis for a number of autoantibody-mediated diseases, such as myasthenia gravis.”

While the TPE removes the B-cells, they have a proclivity to reemerge, hence the rituximab treatment, he said. IV Ig further inhibits B-cell activity. “The IV Ig probably works in large part by feedback inhibition of the B-cells that have survived the rituximab,” Duncan said.

He added that with the TPE and rituximab patients had “sometimes amazing response,” but then would relapse. “Since we added IV Ig, we see far fewer relapses,” he said. “And interestingly, if they do relapse, we can salvage them by giving them this treatment again.”

The preliminary study doesn’t make clear what patients would benefit most from the triple-modality therapy, but it did provide some clues. “We found that patients who have higher levels of antibodies against epithelial cells tend to do the best, and patients who had less severe disease — that is, less disturbance of gas exchange requiring less O₂ — tend to do better,” Duncan said. The STRIVE trial should serve to identify specific biomarkers, he said.

Gaggar, the UAB professor who’s not affiliated with the study, concurred that it’s “too early to tell” which patients would benefit. “Certainly, these patients that undergo exacerbations would be of high interest,” he said, “but the potential is there that the other chronic lung diseases that have exacerbations may also benefit from this kind of therapy.”

He noted that the preliminary study focused on one type of autoantibody generating from epithelial cells. “In many of these studies where we limit ourselves to a single autoantibody population, we might be at the tip of iceberg,” Gaggar said. “There might be autoantibodies generated from other cells in the lung or the body that might be also pathogenic. This is really powerful because this is a subgroup of autoantibodies, but they still had that kind of impact in this small study.”

The STRIVE study is scheduled for completion in September 2022.

Duncan disclosed relationships with Novartis and Tyr Pharma outside the study subject. Gaggar has no relevant disclosures.

PLoS One. Published online November 23, 2021. Full text

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.

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