Acute outbreaks of idiopathic pulmonary fibrosis have a death rate of up to 90% or more, depending on their severity. But an experimental diet that included a reduction in autoantibodies was found to dramatically improve survival, as well as oxygen levels and walking distances, according to a small preliminary study published in PLOS ONE.
“It’s a preliminary study but it’s very exciting,” said Amit Gaggar, MD, PhD, an endowed professor of medicine at the University of Alabama at Birmingham (UAB), 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 essential that we start to think outside the box for therapeutics.” Gaggar is not affiliated with the study.
Study leader Steven R. Duncan, MD, also of UAB, acknowledged that experimental therapy has its critics. “There has been a huge prejudice against the role of immunologic therapy in idiopathic fibrosis, although it appears to be diminishing,” 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 therapy. The standard treatment for AE-IPF consists of antibiotics and corticosteroids.
Duncan led the only other autoantibody reduction study for AE-IPF, published in PLOS ONE in 2015. The latest preliminary study is a precursor to a Phase 2 randomized clinical trial funded by the National Heart, Lung, and Blood Institute called STRIVE-IPF, which is currently recruiting AE-IPF patients at six sites.
In the preliminary study, 10 patients survived at least one year, for an overall survival rate of 42%. The overall survival rates at 1, 3 and 6 months were 67%, 63% and 46%. The study could not identify the characteristics of survivors compared to non-survivors, although the latter tended to have higher initial oxygen requirements. Among the 10 patients who required less than 25 L / min of additional O2, the survival rate was 57%. In patients who required more than 25 L / min, the survival rate was 20% (P = .07). Only 1 in 5 patients who required> 40 L / min survived one year (P = .36).
After the 19-day regimen, 15 patients, or 63%, experienced significant reductions in additional O2 needs, from an average of 15 L / min to 3 L / min (P = .0007). Thirteen (87%) of patients who were taking an antifibrotic drug (pirfenidone or nintedanib) at baseline needed less O2 and / or had increased walking distances compared to five who did not receive any of the agents (P = 0.15), although the 1-year survival does not vary significantly with the use of antifibrotics.
The mechanism for reducing antibodies is to filter out B cells, whose infiltrates are usually found in the lungs of patients with AE-IPF, Duncan said. The regimen includes nine TPEs over 15 days, two IV treatments of 1g rituximab during this period, and IV treatments of 0.5g / kg Ig per day on days 16-19.
“Plasma exchange quickly removes antibodies,” Duncan said in an interview. “It is the basis for a number of autoantibody mediated diseases, such as myasthenia gravis.”
While TPE eliminates B cells, they have a propensity to reappear, hence the rituximab treatment, he said. IV Ig further inhibits B-cell activity. “IV Ig probably works largely by feedback inhibition of B cells that have survived rituximab,” Duncan said.
He added that with ETP and rituximab, patients had “a sometimes amazing response”, but then relapsed. “Since we added IV Ig, we are seeing a lot less relapses,” he said. “And interestingly, if they do relapse, we can save them by giving them this treatment again.”
The preliminary study does not specify which patients would benefit the most from the three-modality therapy, but it did provide some clues. “We have found that patients who have higher levels of antibodies to epithelial cells tend to do better, and patients who have less severe disease – that is, less gas exchange disturbances. requiring less O2 – tend to do better, ”Duncan said. The STRIVE trial should be used to identify specific biomarkers, he said.
Gaggar, the UAB professor who is not affiliated with the study, agreed it was “too early to say” which patients would benefit. “Certainly, those patients who experience exacerbations would be of great interest,” he said, “but it is possible that other chronic lung diseases that have exacerbations could also benefit from this type of therapy.”
He noted that the preliminary study focused on a type of autoantibody generated from epithelial cells. “In many of these studies where we limit ourselves to a single autoantibody population, we might be the tip of the iceberg,” Gaggar said. “There could be autoantibodies generated from other cells in the lungs or body that could also be pathogenic. It’s really potent because it’s a subgroup of autoantibodies, but they still had that kind of impact in this little study. “
The STRIVE study is expected to be completed in September 2022.
Duncan disclosed relationships with Novartis and Tyr Pharma outside of the subject of the study. Gaggar does not have any relevant disclosure.
PLoS A. Published online 23 November 2021. Full text
Richard Mark Kirkner is a medical journalist based in the Philadelphia area.
For more news, follow Medscape on Facebook, Twitter, Instagram and YouTube.