Immunosuppressive agents and interstitial lung disease: what are the risks?

Abstract

Idiopathic pulmonary fibrosis is unlikely to respond to immunosuppressive therapies, and patients with idiopathic pulmonary fibrosis may be harmed by such therapy. In contrast, some forms of interstitial lung disease can respond well to treatment with immunosuppressive drug therapies. Such agents can, however, be associated with significant risk of adverse effects such as infection, diabetes, osteoporosis, myopathy, bone marrow suppression, hepatitis, urinary tract injury, and drug-induced pneumonitis. Treating clinicians must be aware of potential adverse reactions to any immunosuppressive drug that they prescribe for their patients, and they should implement appropriate pre-therapy screening (e.g., tuberculosis, hepatitis, renal insufficiency) and monitoring that is recommended to avoid/minimize risk during the treatment period. Some disorders (e.g., cellular non-specific interstitial pneumonia, organizing pneumonia, or sarcoidosis) may respond very well to immunosuppressive therapies including corticosteroids as monotherapy, and the use of steroid-sparing agents can minimize corticosteroid side effects and may enhance treatment efficacy for disorders such as sarcoidosis or connective tissue disease-associated forms of interstitial lung disease.

Keywords::

• immune suppression
• interstitial lung disease
• therapeutics

There are approximately 200 different forms of interstitial lung disease (ILD), and making an accurate diagnosis [1,2] is a critical first step in the evaluation of a patient with suspected ILD. Some forms of ILD may remain stable or even spontaneously regress, others may progressively worsen over time but may respond to immunosuppressive anti-inflammatory therapies, while some may show little or no response to any therapy, especially if extensive pulmonary fibrosis is present. When a diagnosis is made, clinicians must decide whether to treat a patient with an immunosuppressive agent, how to treat, how to monitor response to therapy and how to monitor for potential adverse reactions to an immunosuppressive agent. These decisions are not only difficult to make, but immunosuppressive agents have the potential to cause significant, and possibly, life-threatening complications that can seriously harm patients. Therefore, treating clinicians must be adequately familiar with the risks of immunosuppressive agents as well as with clinical practice guidelines that recommend strategies that should be used to monitor for adverse events associated with their use. Vigilant monitoring can help prevent serious consequences if adverse drug reactions can be detected before irreversible harm has occurred.

What is the evidence for using immunosuppressive therapies to treat ILD?

Since the introduction of adrenocorticotropic-stimulating hormone and hydrocortisone into clinical medicine in the 1940s and the subsequent use of corticosteroids (CS) for the treatment of lung diseases, such as asthma and sarcoidosis, the use of immunosuppressive CS to treat various forms of ILD led to reports (usually case series) that CS could benefit patients with various forms of ILD [3]. Patients who were perceived as potential responders to CS included those diagnosed with what was then known as idiopathic pulmonary fibrosis (IPF) or cryptogenic fibrosing alveolitis (CFA). When immunosuppressive cytotoxic agents came on the market in the 1970s and 1980s, these agents were also incorporated into treatment paradigms for ILDs such as sarcoidosis and IPF/CFA.

We now realize that the lung diseases that were termed IPF or CFA 15–20 years ago actually included a number of ILD entities that we now recognize as having important differences in pathogenesis, clinical characteristics and responses to therapies [4,5]. Indeed, connective tissue disease (CTD)-associated ILD, organizing pneumonia (OP), IPF (idiopathic usual interstitial pneumonia [UIP]), non-IPF idiopathic interstitial pneumonias (e.g., desquamative OP, respiratory bronchiolitis with ILD, acute interstitial pneumonia and OP) were often considered to be one clinicopathological entity by clinicians and termed as CFA or IPF. Clinical trials of CS and/or cytotoxic immunosuppressive therapies (e.g., azathioprine, cyclophosphamide) performed to evaluate the efficacy of such treatments for ‘IPF’ or ‘CFA’ suggested benefit, but this was likely driven by the inclusion of patients with CTD–ILD and other forms of ILD that potentially respond to immunosuppressive drugs in these studies. IPF is now recognized as a specific form of ILD (idiopathic UIP), and immunosuppressive therapies for the chronic treatment of IPF do not appear to have significant impact on this disease [6] and may even be harmful, as suggested by the recently published results from the NIH-sponsored IPF Network study (PANTHER) that demonstrated a significant mortality and hospitalization risk for patients with IPF who were in the azathioprine plus N-acetylcysteine (NAC) treatment arm versus the placebo and NAC only arms [7]. This observation triggered the early termination of the azathioprine/NAC/prednisone arm, and until this study was performed, it was assumed or suggested [8] that azathioprine therapy could provide benefit to patients with IPF. This ‘suggestion’ was generally perceived as a recommendation by readers of the 2000 IPF statement, and only a weak ‘no’ was assigned to therapy with azathioprine when the IPF guideline was published in 2011 [6]. Whether similar risks may exist when azathioprine is given to patients with non-IPF forms of ILD is unknown.

Although very few adequately powered, prospective, randomized, placebo-controlled, double-blind clinical trials to evaluate the safety and efficacy of an immunosuppressive agent have ever been completed for any form of ILD, there are a considerable amount of compelling data in the medical literature to support the use of immunosuppressive drugs to treat progressive pulmonary sarcoidosis (e.g., CS, methotrexate), CTD–ILD (e.g., CS, mycophenolate, other disease-modifying anti-rheumatic drugs) and non-IPF forms of idiopathic interstitial pneumonias such as idiopathic nonspecific interstitial pneumonia and OP. Due to the low incidence of many forms of ILD other than sarcoidosis, IPF or some forms of CTD–ILD, it is unlikely that adequately powered, placebo-controlled clinical trials will be completed for relatively rare forms of ILD.

What are the risks?

Many of the immunosuppressive drugs that may be used to treat specific ILD have undergone extensive testing for safety and efficacy in clinical trials that have evaluated treatment of various forms of CTD, vasculitis, inflammatory bowel disease or post-transplant rejection of solid organs. Systemic CS, which are usually first-line therapy for new onset ILD that is recognized as potentially responding to immunosuppressive therapy, are associated with myriad side effects that include diabetes, hypertension, myopathy, osteoporosis, weight gain and accelerated atherosclerosis. Cytotoxic agents (e.g., azathioprine, cyclophosphamide, methotrexate, leflunomide, mycophenolate) have immunomodulatory properties and are associated with significant risk of adverse drug reactions, but adverse effects vary for different agents, and these agents are usually used as steroid-sparing agents. All can suppress bone marrow function and increase the risk of infection, and most have been linked, albeit infrequently, to pneumotoxic reactions. Patients should be screened prior to starting therapy to exclude active infection (tuberculosis, hepatitis) or significant organ dysfunction (liver or renal impairment) that may affect drug metabolism and excretion. Screening for latent or active tuberculosis should definitely be done before initiating anti-TNF) agents, and, ideally, uniform and careful screening for the presence of latent tuberculosis should be done with before initiating any potent immunosuppressive regimen to detect a risk of reactivating latent tuberculosis. Methotrexate and azathioprine, and to a somewhat lesser extent, leflunomide, have the potential to cause serious liver injury, and periodic liver function testing should be done for patients who are receiving drugs that have been linked to drug-induced hepatitis. Other screening (e.g., measurement of thiopurine methyltransferase levels prior to initiation of azathioprine therapy) may prevent a serious adverse reaction, and coadministration of another drug (e.g., folate for patients receiving methotrexate) can prevent serious toxicity [9,10].

Newer agents of potential benefit include biologic agents (e.g., TNF inhibitors, antilymphocyte therapy with rituximab) and drugs used for post-transplant immunosuppression (calcineurin inhibitors, mTOR agents), but these also confer significant risks and must be monitored carefully [9,10]. When multiple agents are used together (e.g., CS with a cytotoxic agent plus a calcineurin inhibitor), the risks of toxicities such as bone marrow suppression or opportunistic/severe infection are significantly increased. The calcineurin inhibitors are associated with many potential side effects that include renal dysfunction and systemic hypertension; mTOR inhibitors and calcineurin inhibitors can cause significant hyperlipidemia; and transplant recipients are prone to develop post-transplant lymphoproliferative disease as a consequence of sustained, intense immunosuppression. Many drugs should be avoided in pregnant women unless it is absolutely necessary to use them due to life-threatening disease, and frail, elderly patients may have impaired renal or hepatic function such that they have depressed drug metabolism/clearance and are more susceptible to adverse drug reactions.

How should immunosuppressive therapies be monitored?

Monitoring strategies vary according to specific potential toxicities. Prophylactic coadministered drugs may prevent certain treatment-related adverse events (e.g., trimethoprim-sulfamethoxazole to prevent Pneumocystic jiroveci pneumonia, supplemental folate to decrease risk of methotrexate toxicity), and periodic laboratory testing as well as clinic visits may allow early detection of drug toxicity. There is general consensus that patients receiving sustained daily corticosteroid dosing of 20 mg/day of prednisone or equivalent should be given prophylactic trimethoprim-sulfamethoxazole (or another agent if allergic) to reduce the risk of developing Pneumocystis pneumonia, and with intense immunosuppression (e.g., calcineurin inhibitor plus cytotoxic agent plus even low-dose corticosteroid), Pneumocystic prophylaxis should be given; patients who are transplant recipients or have CTD–ILD (e.g., anti-synthetase syndrome) may be especially susceptible to developing Pneumocystis pneumonia if no prophylaxis is given while receiving such therapy. Serum drug levels must be periodically monitored if calcineurin inhibitors (cyclosporine A, tacrolimus) or mTOR inhibitors (sirolimus, everolimus) are used. Complete blood counts, liver function testing and monitoring of renal function should be intermittently obtained while patients are receiving any agent that has the potential to cause significant bone marrow suppression, hepatic injury or renal dysfunction, and patients who receive calcineurin inhibitors or mTOR agents should have their systemic blood pressure and serum lipids monitored.

Would combination therapies be more effective?

Cytotoxic agents are typically administered along with CS with the goal of controlling the disease and reducing the CS dose to avoid side effects, and a recently published large case series of patients with CTD–ILD demonstrated a tendency toward disease stabilization and possible improved lung function plus the ability to considerably reduce CS dosing, even if a UIP pattern of ILD was present [11]. Combination therapy with multiple immunosuppressive agents (e.g., calcineurin inhibitor plus cytotoxic agent plus low-dose CS as is typically used for chronic immunosuppression following solid organ transplantation) may benefit patients with progressive CTD–ILD (e.g., due to antisynthetase syndrome), but risks of toxicity may be increased and careful monitoring must be maintained. Biologic agents (antibodies, cell surface receptor inhibitors) are being increasingly used to treat a variety of immunologically mediated and autoimmune disorders, and various combination therapies may be more effective but could increase the risk of adverse drug reactions. Additionally, combinations of immunosuppressive agents with antifibrotic drugs may enhance efficacy and prevent progression of various forms of ILD, which are characterized by extensive and progressive fibrosis, and a substantial proportion of patients with a difficult-to-treat disorder such as IPF, which has features of autoimmunity [12,13] and progressive fibrosis [14] may well benefit from a combination of immunosuppressive/immunomodulatory and antifibrotic pharmacologic agents.

Future prospects

There can be considerable interindividual variability in genetic abnormalities that have predisposed an individual to develop an ILD, in pathophysiological characteristics of the disease process and in responses to specific drugs. It should be recognized that a subset of patients that may benefit from a promising drug are very unlikely to be identified in a prospective, double-blind, randomized Phase III clinical trial if these patients are combined with a much larger number of enrolled subjects for whom the drug has little or no effect, and the conclusion may be reached that the drug lacks benefit despite its potential to help a subset of patients.

Future studies should focus on promising biologic agents and combination therapies, and improved phenotyping (e.g., biomarkers) may identify subsets of patients who are more likely to respond to specific therapies as well as allowing the identification of patients with a specific form of ILD who have more aggressive disease that is likely to progress rapidly versus patients with the same diagnosis who have more indolent disease and a better prognosis. Patients with specific forms of ILD (e.g., IPF, sarcoidosis, CTD–ILD) should be encouraged to enroll in clinical trials of promising pharmacological therapies when such are available. The potential risks of therapy with immunomodulatory/immunosuppressive agents can be mitigated by coadministered, appropriate prophylactic therapies and by careful monitoring to detect early signs of adverse drug reactions.

Financial & competing interests disclosure

KC Meyer serves on a Clinical Advisory Board for InterMune, and he has received research funding from Abbott, Actelion, Altana, Amgen, Asthmatx, Bayer, Boehringer-Ingelheim, Bristol Meyers Squibb, Chiron, Discovery Labs, DuPont Merck, Fibrogen, Genentech, Gilead, GlaxoSmithKline, Inspire. InterMune, Johnson & Johnson, Novartis, Nycomed, Pfizer, Pharmaxis, PreAnalytiX, Roche, Ross, Vertex and Wyeth. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.