Impact of Azathioprine use in chronic hypersensitivity pneumonitis patients

Journal Pre-proof Impact of Azathioprine use in chronic hypersensitivity pneumonitis patients André Terras Alexandre, Natália Martins, Sara Raimundo, Natália Melo, Patrícia Caetano Mota, Hélder Novais e Bastos, José Miguel Pereira, Rui Cunha, Susana Guimarães, Conceição Souto Moura, António Morais PII:

S1094-5539(19)30304-9

DOI:

https://doi.org/10.1016/j.pupt.2019.101878

Reference:

YPUPT 101878

To appear in:

Pulmonary Pharmacology & Therapeutics

Received Date: 12 December 2019 Accepted Date: 16 December 2019

Please cite this article as: Terras Alexandre André, Martins Natá, Raimundo S, Melo Natá, Mota PatríCaetano, Novais e Bastos Hé, Pereira JoséMiguel, Cunha R, Guimarães S, Moura ConceiçãSouto, Morais Antó, Impact of Azathioprine use in chronic hypersensitivity pneumonitis patients, Pulmonary Pharmacology & Therapeutics (2020), doi: https://doi.org/10.1016/j.pupt.2019.101878. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.

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Impact of Azathioprine use in Chronic Hypersensitivity Pneumonitis patients

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André Terras Alexandre 1, Natália Martins

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Patrícia Caetano Mota

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Cunha 3,5, Susana Guimarães 3,6, Conceição Souto Moura 3,6, António Morais 2,3

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2,3,4

, Sara Raimundo 1, Natália Melo 2,

, Hélder Novais e Bastos

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, José Miguel Pereira

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, Rui

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Real, Portugal

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Pulmonology Department, Centro Hospitalar de Trás-os-Montes e Alto Douro, Vila

Pulmonology Department, Centro Hospitalar Universitário de São João, Porto,

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Portugal

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Faculty of Medicine, University of Porto, Portugal

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Institute for research and Innovation in Health (i3S), University of Porto, Portugal

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Radiology Department, Centro Hospitalar Universitário de São João, Porto, Portugal

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Pathology Department, Centro Hospitalar Universitário de São João, Porto, Portugal

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Corresponding author

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André Terras Alexandre

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Address: Centro Hospitalar de Trás-os-Montes e Alto Douro, Avenida da Noruega,

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5000-508 Lordelo, Vila Real

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Phone number: +351 918 936 084

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E-mail: [email protected]

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Abstract

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Introduction: Systemic corticosteroids are widely used in chronic hypersensitivity

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pneumonitis (CHP); however, there is not much evidence to support their use, besides

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being associated with significant side effects. Azathioprine (AZA) use is common in

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CHP, although not prospectively tested in randomized controlled trials. Our objective

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was to evaluate the lung function trajectory of CHP patients after AZA initiation, as

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well as to assess the safety profile of this drug.

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Methods: Retrospective analysis of patients initiated on AZA following a

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multidisciplinary team diagnosis of CHP. The longitudinal trajectory of lung function

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in the first 2 years of treatment was assessed.

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Results: Thirty-five out of 62 patients (56.5%) remained on treatment after 2 years.

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AZA treatment was associated with a significant improvement in forced vital capacity

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(FVC) at 12 and 24 months (p=0.015 and p<0.001, respectively). A slight increase in

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total lung capacity (TLC) and 6-minute walking test (6MWT) were also reported,

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although it did not reach statistical differences at the end of 2 years. No changes in

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diffusion capacity for carbon monoxide (DLCO) were observed.

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Conclusions: This is the first study identifying an improvement in lung function

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(FVC) of CHP patients on AZA treatment for 2 years. Prospective studies are needed

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to confirm these results and to more adequately select CHP patients who may benefit

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from AZA.

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Keywords: Azathioprine, Interstitial Lung Disease, Hypersensitivity Pneumonitis.

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Introduction

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Hypersensitivity Pneumonitis (HP) is a heterogeneous disease characterized by an

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inflammatory reaction in response to exposure to a sensitizing antigen [1]. Numerous

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inciting agents have been described, from both organic and inorganic sources [1].The

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multiple agents potentially involved and the varying magnitude of exposure explain

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the significant differences found in disease presentation, severity and natural history

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[2].

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From the clinical point of view, HP is classically subdivided into acute, subacute and

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chronic forms [3]. More recently, Vasakova et al. [4] proposed a new classification

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into two main categories: acute/inflammatory and chronic/fibrotic HP, based on

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clinical, radiologic and pathologic correlation, hoping that this division will be a

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valuable tool for prognostic purposes.

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Chronic HP (CHP) is thought to reflect a prolonged or repetitive course of acute HP

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over several months, leading to a delayed T-helper lymphocyte-mediated

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hypersensitivity reaction, which promotes lung inflammation and granuloma

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formation [5]. CHP is typically defined by the presence of radiographic and/or

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histological fibrosis and is associated with a poor prognosis, with 5-year survival as

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low as 25-30% [6].

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The initial, and arguably one of the most important steps in CHP treatment, is the

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identification and elimination of the triggering antigen [7]. Unfortunately, in many

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cases, an inciting antigen cannot be identified even after a thorough search for

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potential exposures [7].

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Systemic corticosteroids are considered the mainstay of pharmacological treatment,

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although the dosage and duration of treatment are not well established and most

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evidence for their use comes from studies on acute/subacute HP [8-10]. The

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frequently progressive nature of this disease, despite corticosteroids’ use, as well as

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the significant side effects associated with this treatment, have promoted an active

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search for new therapeutic alternatives. Azathioprine (AZA) is a cell cycle inhibitor

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used in the treatment of many inflammatory interstitial lung diseases (ILD), such as

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those related to connective tissue disease (CTD-ILD). The use of this drug is also

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common in CHP, although it is not prospectively tested in randomized controlled

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trials. In this sense, we performed a retrospective longitudinal analysis with CHP

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patients to evaluate the lung function trajectory after AZA treatment initiation. We

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also aimed to assess the safety profile of this drug in this group of patients.

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Methods

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Study Population

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The study cohort included patients followed at the ILD clinic of Centro Hospitalar e

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Universitário de São João, Porto, Portugal, diagnosed with CHP, who were under

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AZA treatment. Patients were identified from retrospective review of medical records.

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CHP diagnosis in all patients was established at a multidisciplinary meeting including

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at least one physician, one radiologist and one pathologist experienced in ILD.

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Clinical data extracted from medical records included age, gender, smoking history,

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causative antigen (if identified), corticosteroid use and adverse effects associated with

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AZA treatment.

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Outcomes

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The primary outcome was the longitudinal trajectory of respiratory function in the

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first 2 years of treatment: predicted % of forced vital capacity (FVC) and predicted %

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of diffusion capacity for carbon monoxide (DLCO).

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We also analyzed the trajectory of other respiratory function-related variables, namely

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the predicted % of total lung capacity (TLC), resting partial oxygen blood pressure

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(pO2), distance walked in the 6-minute walk test (6MWT) and peripheral oxygen

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saturation (sO2) immediately before and after this test.

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Statistical Analysis

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Statistical analysis was performed using the Statistical Package for the Social

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Sciences (SPSS, IBM Corp., USA) software, version 25. Continuous variables were

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reported as mean ± standard deviation, and median, minimum and maximum values,

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when appropriate. Paired samples t-test was used to assess the changes occurred in the

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referred variables between the different time points considered. P values less than

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0.05 were considered statistically significant.

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Results

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Of the 62 CHP patients receiving AZA enrolled in this study (Table 1), with a mean

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age of 58.7±13.3 years, more than half (64.5%, n=40) were females. Regarding

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smoking habits, most patients were non-smokers (80.6%), with this status being more

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frequent in females (78.0% vs 22.0%), while smoking (100% vs 0%) and former

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smoking (87.5% vs 12.5%) habits were more often observed in males (p<0.001). With

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regards to the main triggering agents for HP, birds (64.5%) and fungi (9.7%) were the

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most commonly found, while in 21% of cases the cause remained unknown. Fifty-six

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of the 62 patients (90.3%) were under systemic corticosteroid therapy, with an

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average dose of 12.3±9.3 mg of prednisolone or equivalent. AZA was administered at

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a dose of 2 mg/Kg, with a maximum dose of 150 mg per day. Treatment

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discontinuation was necessary in 43.5% of patients, mostly due to disease worsening

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(33.3%) and liver toxicity (25.9%) (Table 1). Of these patients, whose treatment

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discontinuation was needed, in most of them (70.4%; n=19) occurred within the first

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6 months.

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When analyzing the lung function trajectory (Table 2, Figure 1), a significant

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improvement in FVC was stated at 12 and 24 months (p=0.015 and p<0.001,

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respectively), after treatment initiation, and a slight increase in TLC was also reported

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over time, although the most pronounced increase was stated at 6 months (p=0.040).

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Initial SpO2 varied significantly between the baseline and the end of study (p=0.040),

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while no changes were observed to DLCO, final SpO2, and pO2 over the study period.

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Not least interesting to underline was the sustained increase in the 6MWT (Figure 2).

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Although there were no statistically significant differences between the three time

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points considered, the benefit triggered by AZA treatment in these patients is evident.

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Discussion

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In this retrospective analysis, we demonstrated that CHP treatment with AZA for 2

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years was associated with improved lung function and other related parameters.

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Previous works, such as the retrospective study by Morrisset and colleagues [11]

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showed only an improvement in gas exchange, expressed by DLCO. Our longitudinal

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analysis of lung function parameters suggests that, besides to the improvement in

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FVC and sO2, the other parameters, including DLCO, remained relatively stable over

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the period analyzed, which is interesting, considering the progressive nature of this

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disease. In addition, the 6MWT improved right after one year of AZA. We are

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confident that this improvement would have been statistically significant if the

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number of patients was larger.

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The patients included in the study by Morrisset and colleagues [11] had more severe

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disease at treatment initiation (mean FVC=65.2% vs 72.7% in our study). We can

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hypothesize that perhaps our patients had less fibrosis and, therefore, more

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“rescuable” lung, hence justifying the improved FVC.

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Twenty-seven of the 62 CHP patients discontinued AZA for several reasons,

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including side effects, rapid disease worsening, death, and lung transplantation. Liver

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toxicity was a relatively frequent side effect that limited the treatment of a

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considerable number of patients. Rapid disease progression was also an important

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reason to discontinue AZA treatment and most of these patients were switched to

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other immunosuppressive drugs, such as mycophenolate mofetil (MMF).

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A previous work by Adegunsoye et al. [12] reported better patient tolerance with

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MMF than with AZA, with more patients moving from AZA to MMF than otherwise.

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MMF can, therefore, be a reasonable choice if a lack of tolerance of AZA is expected.

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As above stated, antigen removal, when possible, is recommended as the first step in

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treating CHP. Corticosteroid use has generally been adopted for these patients

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because of data reporting efficacy in farmer’s lung disease, an acute HP form [8-10].

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However, there are no studies evaluating the efficacy of corticosteroids in the chronic

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form of this disease. Concurrent corticosteroids and AZA therapy was extremely

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frequent in our cohort of patients, which precludes the ability to evaluate AZA as

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monotherapy. Nevertheless, there is currently no evidence that corticosteroids

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improve lung function in these patients. This fact, together with the relatively low

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dose of steroids that our patients were taking, leads us to conclude that the lung

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function improvement was most likely due to AZA treatment.

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Our study has some strengths. This is an observational analysis of well-characterized

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CHP patients, all with a firm diagnosis established by an experienced

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multidisciplinary team, and is the first study to objectively identify an improvement in

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lung function in CHP patients receiving AZA for 2 years. On the other hand, our

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study has also some limitations. First, being a retrospective analysis, it was not

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possible to systematically monitor drug dosage, and minor unreported adverse effects

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may have been missed. Second, it is impossible to control unmeasured factors, like

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exposure levels, which may vary over time and potentially have impact on patients’

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lung function. Last, due to the small number of patients in this cohort, our study lacks

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comparison with an untreated control group.

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Conclusions

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We have shown that AZA treatment for 2 years improved lung function in a cohort of

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CHP patients, and is a promising therapy for long-term management of this disease.

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Prospective studies are needed to confirm these results and to more adequately select

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these CHP patients who may benefit from AZA and those who may be more suitable

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for other treatments, such as antifibrotic therapy.

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Acknowledgements

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N. Martins would like to thank the Portuguese Foundation for Science and

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Technology (FCT–Portugal) for the Strategic project ref. UID/BIM/04293/2013 and

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“NORTE2020 - Programa Operacional Regional do Norte” (NORTE-01-0145-

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FEDER-000012).

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Conflict of interests

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The authors declare no conflict of interests.

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References

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Table 1. Baseline patients’ characteristics. Characteristics Age (years) Gender, n (%) Males Females Smoking, n (%) Smoker No-smoker Ex-smoker Cause, n (%) Birds Fungi Cork Inks Unknown Biopsy, n (%) Yes Treatment interruption, n (%) Yes Interruption reason, n (%) Liver toxicity Nauseas and vomiting Myalgias Disease worsening Transplant Death

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Total (N=62) 58.7±13.3 22 (35.5) 40 (64.5) 4 (6.5) 50 (80.6) 8 (12.9) 40 (64.5) 6 (9.7) 1 (1.6) 2 (3.2) 13 (21.0) 26 (41.9) 27 (43.5) 7 (25.9) 4 (14.8) 1 (3.7) 9 (33.3) 2 (7.4) 4 (14.8)

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Table 2. Lung function parameters’ variation over time in CHP patients that completed 2 years of AZA treatment.

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Time (months) Lung function parameters T0 T6 T12 (N=62) (N=43) (N=39) FVC (%) 72.7±20.4 76.1±22.9 77.4±24.6* TLC (%) 75.4±21.9 79.2±18.8* 77.7±21.0 DLCO (%) 43.9±17.1 48.7±18.3 54.0±38.9 6MWT (m) n.d. 362.2±130.5 387.6±109.7 n.d. Initial SpO2 (%) 94.0±7.6 94.2±3.5 Final SpO2 (%) n.d. 82.9±8.3 82.3±7.5 pO2 (mmHg) 69.6±13.4 70.7±11.2 68.4±15.2 * p<0.05 and **p<0.001 from the corresponding time to the beginning of the study (T0); n.d., not determined.

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T18 (N=36) 75.2±22.7 79.4±22.0 44.9±18.5 n.d. n.d. n.d. n.d.

T24 (N=35) 76.3±24.2** 81.2±20.4 44.3±15.8 402.7±93.2 95.4±2.4* 83.6±8.2 n.d.

90

80

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Percentage (%)

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50

40

30

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0 0

6

12

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Time (months) %F VC

%TLC

%DLCO

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Figure 1. Variation in FVC, TLC and DLCO over time in CHP patients under AZA treatment.

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410

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Distance (m)

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370

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340 0

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Time (months)

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Figure 2. Variation in the 6MWT over time in CHP patients under AZA treatment.

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