In the current classification of pulmonary hypertension, pulmonary arterial hypertension (PAH) because of drug or toxin exposure belongs to group 1 because of many similarities in pathophysiology and histopathology with idiopathic PAH [1,2▪▪]. For a very long time, most cases of PAH induced by drugs were mainly due to massive exposure of populations to appetite suppressant drugs, leading to PAH epidemics. More recently, the development of targeted therapies lead to the emergence of new drugs with pulmonary vascular adverse effects. Among them, IFN-α and IFN-β have recently been added to the list of possible risk factors for PAH  (Table 1). This was justified by multiple publications of cases of pulmonary hypertension potentially associated with IFN-α or IFN-β exposure in the past decade [3–9,10▪,11–15,16▪▪,17]. Moreover, information derived from clinical experience has been enriched by basic science research on this topic that seems to demonstrate an involvement of interferon in both human and experimental pulmonary hypertension .
The interferons family corresponds to a group of secreted proteins that participate as extracellular messengers in a wide variety of responses, including antiviral, antiproliferative, immunomodulatory and developmental activities that act to maintain homeostasis and in-host defense. Type I includes several subgroups as IFN-α and IFN-β, type II corresponds to IFN-γ and type III to IFN-λ. All these subtypes of molecules, which were likely to have arisen from a common ancestral gene, have a common intracellular signaling pathway. From the 1990s onwards, therapeutic effects of the three types of interferon were discovered leading to their clinical use. For a long time, IFN-α has been extensively used in the treatment of chronic hepatitis C infection, usually in combination with ribavirin. Moreover, its antitumoral activity was exploited to treat solid and hematological tumors like melanoma, renal carcinoma or chronic myeloid leukemia. IFN-β remains today the first-line treatment of multiple sclerosis (MS). Its mechanism of action is unknown although it has been suggested that it could have a neuroprotective effect inhibiting migration and activation of T cells in the central nervous system. IFN-γ is used to treat chronic granulomatous disease. Its immunomodulatory effect reduces the occurrence of fungal and bacterial infections with this rare genetic disorder.
The major drawback of interferon therapies is linked to its many adverse effects, responsible for poor patient compliance and leading to reduced efficacy. Most commonly reported adverse events are psychiatric disorders, flu-like symptoms, skin effects at the injection site and hematological toxicity. Pulmonary side effects are much rarer but can lead to life-threatening conditions like interstitial lung disease or PAH. Indeed, careful attention should be paid to these respiratory side effects that may affect the functional and vital prognosis of patients.
Cases of pulmonary arterial hypertension associated with IFN-α
The first suspected case of IFN-α-induced PAH was described in 1993 in a patient treated for metastatic kidney cancer who developed severe pulmonary hypertension that was reversible after discontinuation of treatment . Nevertheless, this first case was not documented by right heart catheterization (RHC). From the 2000s onwards, many similar cases of PAH possibly induced by IFN-α and confirmed by RHC were published. In the first instance, the reported cases were only related to patients treated for neoplastic disease. Fruehauf et al. described the case of a patient treated with IFN-α for chronic myeloid leukemia who developed PAH 6 months after initiation of treatment. PAH was confirmed by RHC and described as reversible after discontinuation of therapy. Another partially reversible case was observed and reported in 2005 in a patient treated for a melanoma . The reversibility of PAH after exposure to drugs or toxins is not always observed. Nevertheless, when a partial or total improvement can be achieved after cessation of exposure, it is strongly suggestive of a causal link and direct effect of the drug on the pulmonary vascular bed.
After that, the use of IFN-α therapy in the treatment of cancer was gradually abandoned in favor of new therapies like the advent of tyrosine kinase inhibitors for chronic myeloid leukemia or other targeted therapies for kidney cancer or melanoma. Until the recent development of direct-acting antivirals, the most common use of IFN-α was in the treatment of hepatitis C virus (HCV) infection most often in combination with ribavirin. Several observations of PAH possibly induced by IFN-α in these patients have been reported [6,8,13,15,16▪▪]. Despite strong clinical and temporal suspicion, it remains a great challenge to definitively confirm the causal role of interferon in patients treated for HVC because of frequent concomitant PAH risk factors in this context such as portal hypertension and/or HIV infection. In the French reference centre for severe pulmonary hypertension, 47 patients exposed to IFN-α and suffering from PAH were identified between 1998 and 2012 . Over 70% of them have developed pulmonary vascular disease in the 3 years following the onset of exposure to interferon. More than 10 other cases of patients treated for HCV infection have been reported in the literature. We cannot exclude that interferon therapy may potentially act as an additional trigger for portopulmonary hypertension and/or HIV-associated PAH. However, in patients with concomitant risk factors, no case of reversible PAH was observed in our experience or in observations reported in the literature. We also retrospectively analyzed the effect of interferon on the evolution of preexisting PAH in 12 patients with chronic hepatitis C. We observed a hemodynamic worsening in 10/12 patients, with an increase in pulmonary vascular resistance by 43% (Fig. 1). More significantly, PAH worsening was usually transient even in the absence of reinforcement of PAH therapy. These observations lead us to take precautions when using interferon in patients with preexisting PAH. When interferon therapy is considered mandatory in a patient with PAH, we recommend a complete baseline clinical and hemodynamic assessment, optimization of PAH treatment prior to cautious initiation of interferon treatment, and close clinical monitoring during and after interferon therapy [16▪▪].
Cases of pulmonary arterial hypertension associated with IFN-β (Table 2)
IFN-β is mainly used in the treatment of MS. The occurrence of PAH in these patients is particularly informative as most of them do not present an associated risk factor for pulmonary hypertension in contrast to patients exposed to IFN-α. Between 2009 and today, 13 cases of PAH possibly induced by IFN-β have been reported in the literature [7–9,10▪,11,12,14,17]. Only one of them had an atrial communication as a concomitant risk factor for PAH. Significantly, all patients concerned by IFN-β-induced PAH were women (13/13), whereas the MS sex ratio is between 2.3 and 2.5 women for one man. This observation is in accordance with the characteristic female predominance of PAH. Oestrogen metabolism that is potentially implicated in the pathogenis of PAH may also be relevant in interferon-induced PAH. Female predominance was also reported in PAH induced by other drugs like dasatinib or anorectic agents [19,20]. The time between the start of interferon exposure and diagnosis of vascular disease can be long (up to 10 years). However, all the patients were still being treated at the time of PAH diagnosis. PAH is often very severe at baseline leading to early deaths of two patients and one lung transplantation [8,14]. In one case reported by Fok et al., PAH worsened due to continuation of interferon therapy, leading to pulmonary transplantation. Histopathological findings described by authors were similar to those observed in idiopathic PAH with a marked inflammatory component. In other cases, a significant improvement or even a reversibility of the pulmonary vascular disorder was observed after cessation of exposure and targeted treatment of PAH. The reversibility of some of these cases and the description of pure cases without associated risk factors for PAH is highly suggestive of a causal link between pulmonary hypertension and interferon therapy.
However, only a minority of patients exposed to interferon developed PAH suggesting that other unknown co-factors or a genetic predisposition are required for the development of pulmonary vascular adverse effects. We have no robust epidemiological data to estimate the prevalence of PAH among patients treated with interferon. It is probably a very rare side effect but healthcare professionals need to be aware of it because of its potential life-threatening characteristic as suggested by the two fatal cases reported in the literature.
Interferon involvement in pathophysiology of experimental and human pulmonary hypertension
One of the key points to analyze and reinforce the link between a drug and a potential adverse event is the search for pharmacological and physiological explanations. Therefore, it is essential to combine clinical and fundamental studies to support the potential role of the incriminated drug in triggering endothelial dysfunction and pulmonary vascular remodeling . Clinical experience with interferon therapy has been enriched by basic science research on this topic suggesting that interferon is involved in both human and experimental pulmonary hypertension.
Interferon and experimental pulmonary hypertension
Hanaoka et al. published the first experimental data concerning the effects of IFN-α on pulmonary vasculature. They described a transient rise of pulmonary vascular resistance after a single i.v. infusion of natural IFN-α in sheep. Hemodynamic effects of interferon were associated with the stimulation of the thromboxane cascade and were inhibited by a selective thromboxane synthase inhibitor. This was the first evidence of a potential implication of interferon on pulmonary vascular pathophysiology before human cases of interferon-induced PAH were reported. However, this experimental study only demonstrated an acute effect of interferon on pulmonary vascular hemodynamics without highlighting a potential role of interferon on the development of chronic pulmonary vascular remodeling.
More recently, many other experimental studies suggested that interferon could be involved in endothelial dysfunction by promoting stimulation of many factors implicated in PAH pathophysiology such as IP-10 and endothelin-1 release by pulmonary vascular smooth muscle cells . There is evidence of a ‘sensitising’ effect of TNF on the interferon responsiveness in human pulmonary artery smooth muscle cells. This experimental findings supports the idea that inflammatory diseases such as portal hypertension or HIV infection could induce a more deleterious effect of interferon on the pulmonary circulation. Furthermore, it has recently been demonstrated that type I interferon receptor knockout [interferon alpha receptor 1 (IFNAR1)(−/−)] mice were protected from the effects of hypoxia on the right heart, vascular remodeling, and raised serum ET-1 levels . These data suggested that type I interferon could mediate PAH via an action of IFNAR1. Further studies are required to confirm this effect of interferon on other animal models of pulmonary hypertension, such as pulmonary hypertension induced by monocrotaline or chronic hypoxia.
Interferon and human pulmonary hypertension
Some clinical observations suggest the direct or indirect involvement of interferon in the pathophysiology of PAH associated with inflammatory conditions such as HIV infection or scleroderma. An ‘interferon signature’ characterized by increased expression and activation of interferon-regulated genes has been described in circulating monocytes in patients with systemic scleroderma or systemic lupus erythematosus . Significantly, the effect of IFN-α was evaluated in systemic sclerosis. The results of the placebo-controlled trial demonstrated conversely no improvement of systemic sclerosis with interferon. Moreover, there was a greater deterioration of lung function and diffusion capacity for carbon monoxide . Later, it was even suggested that interferon may be involved in the development of fibrosis or PAH in patients with scleroderma .
Similarly, it has been suggested that HIV infection could promote PAH through indirect mechanisms and release of inflammatory mediators or growth factors. Patients with HIV infection have a chronically increased production of interferon [27,28], the level of which correlates with HIV disease progression . In the cohort of interferon-induced PAH, there was a higher proportion of patients with HIV coinfection than is usually observed in patients with chronic HCV infection. We could therefore speculate that these patients are more susceptible to the development of PAH when exposed to exogenous interferon because of underlying predispositions.
The development of interferon treatment has undoubtedly helped to improve the prognosis of tumoral, viral or immunological diseases. The effectiveness of these molecules has been offset and often hampered by the frequent occurrence of side effects, some of which (such as PAH or infiltrative pulmonary disease) can involve the vital prognosis of the patient. For each of these complications the benefit/risk ratio should be discussed to decide whether to continue treatment taking into account the severity of the side effect or to consider alternative therapeutic options. The use of interferon is gradually waning. Its antitumoral activity has been supplemented in recent years by other targeted-therapies especially in melanoma, renal cancer or chronic myelogenous leukemia. The development of direct acting agents in the treatment of chronic hepatitis C currently overshadows the antiviral activity of interferon. Finally, new treatments are currently under development in MS, such as daclizumab, which has just recently shown a greater effect than IFN-β . As with all new drugs, vigilance will also be required with these new therapies for their potential to cause pulmonary adverse events. The improvement that occurred over the past decade in the organization of the management of PAH, around the creation of national and international networks and registries, should facilitate detection of pulmonary vascular side effects like PAH.
We acknowledge the French pulmonary hypertension pharmacovigilance network, VIGIAPATH, supported by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM).Figure 1 has been reproduced with permission of the European Respiratory Society: European Respiratory Journal Dec 2014, 44 (6) 1627–1634; DOI: 10.1183/09031936.00057914.
Financial support and sponsorship
Conflicts of interest
L.S. is a member of scientific advisory boards and has received lecture fees from Actelion, Bayer, GlaxoSmithKline and Pfizer. O.S. has relationships with Actelion, Bayer, Glaxo SmithKline, Pfizer and United Therapeutics. In addition to being an investigator involving these compounds, relationships include consulting services, fees for lectures and funds for research. M.H. has relationships with Actelion, Bayer, GlaxoSmithKline, Novartis, Pfizer and Gilead. In addition to being an investigator in trials involving thèse compounds, he has received grants for research, lecture and consultancy fees. M.-C.C. received funding from Actelion to attend a scientific meeting. C.O’C. has no 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.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as
▪ of special interest
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