Idiopathic Pulmonary Fibrosis: Novel Treatment Promising

Lara C. Pullen, PhD

July 11, 2015

Severely ill patients with acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) may benefit from treatments that reduce autoantibodies, according to a pilot trial. Specifically, therapeutic plasma exchange (TPE) and rituximab rapidly reduced circulating autoantibodies in quickly progressing patients. The investigators argue that the findings justify clinical trials of autoantibody-targeted therapies in this patient population.

Michael Donohoe, MD, from the University of Pittsburgh in Pennsylvania, and colleagues published the results of their pilot trial of 11 critically ill patients online June 17 in PLoS One.

"Idiopathic pulmonary fibrosis is an almost invariably fatal disease with a median survival of ≤ 3 years. IPF patients typically experience slowly progressive, if somewhat episodic, lung function deterioration," the researchers write. "Nonetheless, a sizeable proportion of these patients, variously estimated as 10-to-50% or more, develop acute exacerbations that can result in respiratory failure and death within days. No medical treatment has been shown to benefit AE-IPF patients."

The first group of patients received five treatments of TPE plus rituximab. The last cohort of four patients received intravenous immunoglobulin as well as nine treatments of TPE plus rituximab.

The trial was open-label and involved an unprecedented treatment for a highly lethal disease. The investigators compared experimental outcomes with outcomes from 20 historical control subjects treated with conventional glucocorticoid therapy.

After treatment, 82% (n = 9) of patients had improvements in pulmonary gas exchange compared with only 5% (n = 1) in the historical control. Of the nine patients who had improvement with the treatment, three relapsed; two of those improved with additional TPE and one failed to respond to additional TPE. One-year survival was 46% ± 15% in the experimental group vs 0% in historical controls. The clinical response to TPE correlated with a decrease in pretreatment autoantibody titers.

The results suggest that what was once considered an untreatable syndrome may respond to specific autoantibody-targeted therapies.

"Given many parallels between classical autoimmune syndromes and IPF, we hypothesized specific treatments that reduce autoantibodies might also benefit AE-IPF patients. No inference can yet be drawn as to whether or not autoimmunity, defined by the presence of autoantibodies and autoreactive T-cells, is a primary cause of the IPF, or is instead a 'secondary' response that develops subsequent to a distinct initial injury or other dysfunctional consequence of aging (e.g., immunosenescence)," the authors write.

"Nonetheless, the favorable effects of focused autoantibody-reduction therapies in many of the trial subjects here are at least an indication that autoantibodies might play a role in AE-IPF."

They go on to explain that the autoreactive B-cell clones continued to produce antibodies, and therefore the benefit from each TPE treatment was ultimately limited. Rituximab was thus used to kill the B cells.

"These are intriguing data," stated Paul W. Noble, MD, from Cedars-Sinai in Los Angeles, California, in an interview with Medscape Medical News. "I am very glad to see it published, and I think it is something that should be considered for a given patient."

The authors also note that the findings have implications with regard to the mechanisms of IPF progression. They go on to suggest that these implications be further investigated via clinical trials, using concurrent, conventionally treated randomized control subjects.

One coauthor reported receiving an honorarium from Genentech. The authors and Dr Noble have disclosed no other relevant financial relationships.

PLoS One. Published online June 17, 2015. Full text

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