Leukocyte telomere length and mycophenolate therapy in chronic hypersensitivity pneumonitis
- Ayodeji Adegunsoye1,2,9⇑,
- Julie Morisset3,9,
- Chad A. Newton4,
- Justin M. Oldham5,
- Eric Vittinghoff6,
- Angela L. Linderholm5,
- Mary E. Strek1,
- Imre Noth7,
- Christine Kim Garcia8,
- Paul J. Wolters6 and
- Brett Ley6
- 1Section of Pulmonary and Critical Care, Dept of Medicine, The University of Chicago, Chicago, IL, USA
- 2Committee on Genetics, Genomics and Systems Biology, The University of Chicago, Chicago, IL, USA
- 3Dept of Pulmonary Medicine, Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada
- 4Division of Pulmonary and Critical Care Medicine, Dept of Internal Medicine, University of Texas Southwestern, Dallas, TX, USA
- 5Division of Pulmonary, Critical Care and Sleep Medicine, Dept of Medicine, University of California at Davis, Davis, CA, USA
- 6Section of Pulmonary and Critical Care Medicine, Dept of Medicine, University of California San Francisco, San Francisco, CA, USA
- 7Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA
- 8Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University Medical Center, New York, NY, USA
- 9These authors contributed equally
- Ayodeji Adegunsoye, Section of Pulmonary and Critical Care, Dept of Medicine, The University of Chicago, 5841 S. Maryland Ave. Chicago, IL 60637, USA. E-mail: deji{at}uchicago.edu
Abstract
Patients with chronic hypersensitivity pneumonitis and telomere lengths above the first quartile may have improved survival with mycophenolate therapy. https://bit.ly/3maRXih
To the Editor:
Recent prospective clinical trials have shown antifibrotic therapies slow lung function decline in patients with idiopathic pulmonary fibrosis (IPF) [1, 2] and progressive fibrosing interstitial lung disease (ILD). Similar findings were demonstrated in scleroderma-associated ILD [3], despite use of the immunosuppressive therapy mycophenolate mofetil (MMF). Prospective data for the treatment of other forms of ILD, such as chronic hypersensitivity pneumonitis (CHP) are lacking. Our groups previously reported that the treatment of CHP with MMF was associated with a decreased incidence of adverse events, a reduction in prednisone dose, and improved lung function when compared to prednisone alone [4, 5], but prospective studies are needed to confirm these findings. Short leukocyte telomere length (TL) is associated with increased mortality in patients with ILD, including CHP and IPF [6–8]. A recent investigation also showed TL may influence the response to immunosuppressive therapy. In that study, patients with IPF and short TL had a higher risk of death, lung transplantation and forced vital capacity (FVC) decline, when exposed to immunosuppressive therapy, including MMF [9]. In this investigation we sought to determine whether similar findings occurred in patients with CHP. We hypothesised that patients with CHP and short TL would experience a higher prevalence of death and disease progression when compared to those with longer TL.
The study population consisted of a multicentre cohort of prospectively enrolled consenting patients with a confident multidisciplinary diagnosis of CHP at the University of Chicago (UChicago), University of California San Francisco (UCSF), University of California Davis (UCDavis), and University of Texas Southwestern, Dallas (UTSW) between September 2003 and December 2019 (institutional review boards: UC#14163A, UCSF#10-01592 and #10-00198, UCD#585448-7 and #875917-2, UTSW#082010-127, #AAAS0753). Genomic DNA was isolated from peripheral blood leukocytes, TL measurement performed using quantitative PCR in triplicate [10], and age-adjusted TL calculated using normal controls. Standardised TLs were obtained by normalisation across study sites and categorised into quartiles. The electronic medical record was used to extract pertinent clinical information and determine vital status, which was confirmed using the US Social Security death index. Patients who received azathioprine prior to or during the study period were excluded (n=19). A binary categorisation was applied to the study population based on MMF therapy ≤500 mg·per day for at least a month during the study period.
A propensity score approach was utilised to predict the conditional probability for an individual to receive MMF treatment, and model covariates included: age, sex, smoking status, prednisone therapy, physiological indices of disease severity, such as FVC and diffusing capacity of the lung for carbon monoxide (DLCO), severity of fibrosis, distribution of fibrosis, traction bronchiectasis, usual interstitial pneumonia pattern, ground glass opacities and mosaic attenuation. Inverse probability of treatment weighting (IPTW) was used to estimate the average treatment effect on time-to-event outcomes [11]. Survival functions were plotted using the Kaplan–Meier estimator. Cox models were used for hazard ratio estimation, calculating transplant-free survival time as time from commencing immunosuppressive therapy to death, lung transplantation, loss to follow-up, or end of study period, while adjusting for imbalanced variables and controlling for centre in all multivariable outcome models. We applied multiple imputation using chained equations to account for missing covariates (<20%). IPTW-weighted longitudinal trajectories of FVC % predicted and DLCO % predicted were analysed using linear mixed-effects models with restricted maximum likelihood modelling and an autoregressive structure [4], and grouped pulmonary function tests (PFTs) into 90-day epochs, allowing for time-course alignment in all patients. The changes in FVC % predicted and DLCO % predicted were evaluated, and characteristics compared using two-sided t-tests, or chi-square tests, as appropriate. Statistical analyses were conducted using Stata (2019.R.16; StataCorp).
In this investigation, 208 patients with CHP were enrolled, of which 19 were excluded because they had received azathioprine before or during the study period. The remaining 189 patients with 1420 unique PFTs were included. Median age was 65 years (interquartile range (IQR) 58–71 years), 97 (51%) were female, 160 (85%) were white, 89 (47%) had a history of tobacco use and a mean±sd of 15±22 pack years, and 129 (68%) had a history of environmental antigens. Baseline FVC % predicted and DLCO % predicted were 65%±19% and 53%±23%, respectively; 99 (52%) patients had undergone surgical lung biopsy, and 142 (75%) received corticosteroids. Clinical characteristics across study centres are summarised in figure 1a. Median MMF exposure time was similar between patients with TL in the first quartile (Q1) and those in the second to fourth quartiles (Q2–Q4) (10 months (IQR 5–16 months) versus 10 months (IQR 4–23 months); p=0.86). Use of corticosteroid therapy was similar between both groups (Q1 77.1% versus Q2–Q4 74.5%; p=0.72). Baseline FVC was lower in Q1 patients that received MMF when compared to those that did not receive MMF (63.2±18.2% versus 74.1±14.7% pred; p=0.029). Similarly, baseline DLCO was lower in Q2–Q4 patients who received MMF than those that did not receive MMF (48.2±20.3% versus 58.2±24.4% pred; p=0.011).
Each quartile decrease in TL was associated with a stepwise decrease in transplant-free survival (figure 1b). Crude mortality rates were higher for Q1 patients when compared to Q2–Q4 (27.3 deaths per 100 person-years versus 8.4 deaths per 100 person-years; p=0.0002). In propensity score-adjusted analyses, Q1 patients had increased mortality overall when compared to Q2–Q4 (HR 3.29, 95% CI 1.56–6.95; p=0.002). When compared to Q1 patients who did not receive MMF, survival was improved in Q2–Q4 patients who received MMF (HR for interaction term 0.17, 95% CI 0.05–0.61; p=0.007), but not in Q2–Q4 patients who did not receive MMF (p=0.13), or in Q1 patients who received MMF (p=0.87) (figure 1c and d). Significant interaction existed between MMF and TL for Q3 (HR 0.19, 95% CI 0.05–0.70; p=0.013) and Q4 (HR 0.18, 95% CI 0.06–0.57; p=0.003), but not for Q1 (p=0.72) or Q2 (p=0.37). Seven patients were censored due to lung transplantation, all with TL above the first quartile. Those who received MMF appeared more likely to undergo lung transplantation (n=6; 10%) compared to those who did not receive MMF (n=1, 2%; p=0.066). Importantly, irrespective of TL, annualised change in FVC and DLCO measurements did not differ with MMF use (figure 1e and f).
Our observation that MMF therapy is not associated with improved survival or lung function in patients with CHP and short telomeres is similar to the association in IPF, and likely reflects a final common pathway in the pathophysiological processes of advanced fibrosis that underlie these two diseases. This is further evidenced by the demonstrated benefit of antifibrotic therapy in reducing lung function decline for patients with IPF or CHP, with increasing evidence of the benefit of nintedanib and pirfenidone in progressive fibrosis irrespective of TL [12, 13]. As patients with CHP are often prescribed immunosuppressive medications, increased recognition of the potentially harmful effects of these therapies in IPF subjects with short telomeres has engendered increased scrutiny around their use in other types of pulmonary fibrosis.
In the absence of short TL, the improved survival associated with MMF in CHP may suggest fundamental differences between IPF and CHP. While IPF is not characterised by inflammation, CHP has an inflammatory component, and immunosuppressive therapy may ameliorate the exposure-related alveolar inflammation earlier in the disease course. Additionally, while specific genetic variants are common to both diseases, the repertoire of telomere-related mutations and susceptibility-associated gene polymorphisms such as MUC5B appear to differ in their associations with lung function decline and survival across different types of ILD [8, 14]. Of note, in this observational study, we restricted our analysis to assessing the influence of MMF on CHP outcomes, and did not evaluate potential adverse effects, such as haematological and hepatic effects. Thus, the retrospective nature of this study limits our findings to the identification of association, not causality; however, the consistency of our findings with previous investigations supports these results.
Ultimately, as the management of CHP continues to evolve, larger, carefully conducted studies examining the value of immunosuppressive therapy in patients with telomere mutation-related ILD remain much needed, given the widespread use of these medications and their presumed value in diverse forms of ILD.
Shareable PDF
Supplementary Material
This one-page PDF can be shared freely online.
Shareable PDF ERJ-02872-2020.Shareable
Footnotes
Author contributions: Conception and design: A. Adegunsoye, J. Morisset, J.M. Oldham and B. Ley; acquisition of data for the work: A. Adegunsoye, J. Morisset, C.A. Newton, E. Vittinghoff, A.L. Linderholm, P.J. Wolters, M.E. Strek, I. Noth, C.K. Garcia, J.M. Oldham and B. Ley; analysis and interpretation: A. Adegunsoye, J. Morisset, C.A. Newton, E. Vittinghoff, J.M. Oldham and B. Ley; drafting the manuscript for important intellectual content: A. Adegunsoye, J. Morisset, C.A. Newton, E. Vittinghoff, A.L. Linderholm, P.J. Wolters, M.E. Strek, I. Noth, C.K. Garcia, J.M. Oldham and B. Ley; critical revision for important intellectual content: all authors (A. Adegunsoye, J. Morisset, C.A. Newton, E. Vittinghoff, A.L. Linderholm, P.J. Wolters, M.E. Strek, I. Noth, C.K. Garcia, J.M. Oldham and B. Ley); final approval of the submitted manuscript and accountability for all aspects of the work: all authors (A. Adegunsoye, J. Morisset, C.A. Newton, E. Vittinghoff, A.L. Linderholm, P.J. Wolters, M.E. Strek, I. Noth, C.K. Garcia, J.M. Oldham and B. Ley).
Conflict of interest: A. Adegunsoye reports personal fees from Genentech and Boehringer Ingelheim, outside the submitted work.
Conflict of interest: J. Morisset has nothing to disclose.
Conflict of interest: C.A. Newton has nothing to disclose.
Conflict of interest: J.M. Oldham reports personal fees from Boehringer Ingelheim and Genentech, outside the submitted work.
Conflict of interest: E. Vittinghoff has nothing to disclose.
Conflict of interest: A.L. Linderholm has nothing to disclose.
Conflict of interest: M.E. Strek reports grants from Boehringer Ingelheim, Galapagos and Novartis, outside the submitted work.
Conflict of interest: I. Noth reports grants and personal fees from Boehringer Ingelheim (advisory boards), and personal fees from Intermune (advisory boards), Anthera (advisory boards), GSK (speaking honoraria) and Immuneworks (consulting fees), outside the submitted work.
Conflict of interest: C.K. Garcia has nothing to disclose.
Conflict of interest: P.J. Wolters reports grants and personal fees from Boehringer Ingelheim, personal fees from Blade therapeutics and Roche, and grants from Genentech, outside the submitted work.
Conflict of interest: B. Ley reports grants from Nina Ireland Program for Lung Health, during the conduct of the study; personal fees from Genentech, outside the submitted work.
Support statement: NIH K23HL146942, NIH K23HL138190, NIH K23HL148498, NIH R01HL130796, NIH R01 HL093096, NIH KL2TR001870, and Nina Ireland Program for Lung Health. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received July 22, 2020.
- Accepted October 17, 2020.
- Copyright ©ERS 2021