Autoantibody-Targeted Treatments for Acute Exacerbations of Idiopathic Pulmonary Fibrosis

<div><p>Background</p><p>Severe acute exacerbations (AE) of idiopathic pulmonary fibrosis (IPF) are medically untreatable and often fatal within days. Recent evidence suggests autoantibodies may be involved in IPF progression. Autoantibody-mediated lung diseases are typically refractory to glucocorticoids and nonspecific medications, but frequently respond to focused autoantibody reduction treatments. We conducted a pilot trial to test the hypothesis that autoantibody-targeted therapies may also benefit AE-IPF patients.</p><p>Methods</p><p>Eleven (11) critically-ill AE-IPF patients with no evidence of conventional autoimmune diseases were treated with therapeutic plasma exchanges (TPE) and rituximab, supplemented in later cases with intravenous immunoglobulin (IVIG). Plasma anti-epithelial (HEp-2) autoantibodies and matrix metalloproteinase-7 (MMP7) were evaluated by indirect immunofluorescence and ELISA, respectively. Outcomes among the trial subjects were compared to those of 20 historical control AE-IPF patients treated with conventional glucocorticoid therapy prior to this experimental trial.</p><p>Results</p><p>Nine (9) trial subjects (82%) had improvements of pulmonary gas exchange after treatment, compared to one (5%) historical control. Two of the three trial subjects who relapsed after only five TPE responded again with additional TPE. The three latest subjects who responded to an augmented regimen of nine TPE plus rituximab plus IVIG have had sustained responses without relapses after 96-to-237 days. Anti-HEp-2 autoantibodies were present in trial subjects prior to therapy, and were reduced by TPE among those who responded to treatment. Conversely, plasma MMP7 levels were not systematically affected by therapy nor correlated with clinical responses. One-year survival of trial subjects was 46+15% vs. 0% among historical controls. No serious adverse events were attributable to the experimental medications.</p><p>Conclusion</p><p>This pilot trial indicates specific treatments that reduce autoantibodies might benefit some severely-ill AE-IPF patients. These findings have potential implications regarding mechanisms of IPF progression, and justify considerations for incremental trials of autoantibody-targeted therapies in AE-IPF patients.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/results?term=NCT01266317" target="_blank">NCT01266317</a></p></div

Survival Comparisons.

<p>A.) Survival in the aggregate trial subject population (n = 11) was greater than among historical control AE-IPF patients (n = 20). Cross hatches and numbers in parentheses denote censored observations. Lung transplantation censoring is denoted with “T”. B.) Clinical responses may be more durable and survival may be further enhanced among the later trial subjects (n = 4) treated with a more aggressive regimen of autoantibody-targeted modalities (9 initial TPE + rituximab + IVIG).</p

Individual Treatment Outcomes.

<p>Pre and Post are relative to experimental treatment courses (Rx); O₂ requirements denoted as that necessary to maintain resting arterial oxygen saturations at ≥93%; MI = myocardial infarction; FM = face mask; NC = nasal cannula; NC_oxi = nasal cannula with “oxymizer” reservoir; CMO = comfort measures only; MS gtts = morphine sulfate infusion; TPE = therapeutic plasma exchange; SNF = skilled nursing facility.</p><p>Individual Treatment Outcomes.</p

Matrix Metalloproteinase 7 (MMP7).

<p>Plasma MMP7 levels did not appear to consistently decrease with TPE, nor correlate with clinical responses. In particular, three subjects (#3,4,7, open circles, dotted lines) had increases or no changes of MMP7 levels from pretreatment values despite having prolonged clinical remissions.</p

Flowchart of subject recruitments for these experimental trials.

<p>Original Regimen denotes the first series of subjects who were treated with the initial, relatively more conservative regimen (#1–7). Augmented Regimen denotes the most recent four subjects (#8–11) who received a more aggressive therapeutic course, based on interval results in the first cohort (see text for details). TPE = therapeutic plasma exchange; IVIG = intravenous immunoglobulin; * denotes oral consent of patients, under auspices of innovative clinical practice, that were given by these patients after being fully informed of potential risks and yet-unproven efficiencies of the novel treatments.</p

Radiographic Changes with Experimental Treatment.

<p>In addition to better lung function and gas exchange, experimental treatments frequently improved the chest radiographs (CXR) of these subjects. a) Pretreatment CXR of Subject #5 during relapse shows diffuse infiltrates; b.) Radiographic improvement (and extubation) of this subject to 2^nd TPE series. c.) CXR of Subject #7 immediately prior to treatment and d.) after first three TPE. These (and other) radiographic and clinical improvements in the subject population were not attributable to changes in intravascular volume status or infection.</p

Demographic Characteristics and Prior Histories of Trial Subjects.

<p>Age denoted in years. IPF Dx denotes when the original IPF diagnosis was established in these subjects, prior to their admission for acute exacerbations. AE = acute exacerbation; UIP = usual interstitial pneumonia.[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127771#pone.0127771.ref001" target="_blank">1</a>] Subjects were not listed for lung transplantation due to advanced age (Subjects #1,2,4–6,8,11), irreparable coronary artery disease (#3), or being too acutely ill to undergo the extensive necessary pre-transplantation evaluations (#7,#9). The AE-IPF in all subjects was rapidly progressive, with daily or near daily increases of hypoxemia and dyspnea. None had infections, congestive heart failure, or other causes of pulmonary dysfunction aside from the AE-IPF (2).</p><p>Demographic Characteristics and Prior Histories of Trial Subjects.</p

Cytokine elaborations by autologous CD4 subpopulations of IPF patients.

<p>Initial (left) data point in each series represents control unstimulated (basal) condition, while second (right) data point delineates productions of cells after stimulation with plate bound anti-CD3 antibody. These paired specimens (control and stimulated) are also connected by lines. CD4⁺CD28^null cells from IPF patients (open circles with paired specimens connected by dashed lines) tend to elaborate greater amounts of pro-inflammatory and T_H1 cytokines (top two rows), whereas CD4⁺CD28⁺ cells (open squares with paired specimens connected by solid lines) have an apparent T_H2 bias, with the exception of IL-4 production (bottom row) (n = 6 randomly-selected specimens in each measure).</p

Segregated autologous CD4⁺CD28⁺ and CD4⁺CD28^null cells from peripheral blood of IPF patients (n = 9) had similar proliferations (determined by BrdU incorporation) in 5-day control (unstimulated) cultures, as well as after stimulation with plate-bound anti-CD3 monoclonal antibody.

<p>Segregated autologous CD4⁺CD28⁺ and CD4⁺CD28^null cells from peripheral blood of IPF patients (n = 9) had similar proliferations (determined by BrdU incorporation) in 5-day control (unstimulated) cultures, as well as after stimulation with plate-bound anti-CD3 monoclonal antibody.</p

Subject Characteristics.

<p>CD28% High denotes those subjects in whom ≥82% of their circulating CD4 T-cells co-express CD28. CD28% Low denotes those subjects in whom <82% of their circulating CD4 T-cells express CD28. CD28% is defined here as the proportion of circulating CD4 T-cells that also express CD28. FVC; forced vital capacity, FVC%p percentage of normal predicted FVC, FEV1/FVC; forced expiratory volume in 1 second, DLCO; diffusing capacity for carbon monoxide, DLCO%p; percentage of normal predicted DLCO. One CD28% High biopsy showed end-stage, honeycombed fibrotic lung, whereas all other histologic patterns were usual, interstitial pneumonia. *p<0.0001, **p = 0.007; †p<0.045.</p