Introduction
The aims of therapy in patients with inflammatory eye disease (IED) are to control ocular inflammation, limit the progression of disease, preserve vision, maintain the quality of life and prevent local and systemic side effects. The treatment of severe IED with immunosuppressive (IS) therapy is a dilemma for the physician in determining whether the benefits of such therapy outweigh the risk of inducing other diseases, such as infection and malignancy. Literature regarding the use of IS therapy in the treatment of patients with autoimmune diseases indicates that these drugs induce secondary or
de novo malignancies [
1‐
3]. A crucial clinical question is if the manipulation of the immune system in patients with autoimmune diseases and transplant patients results in an increase in skin and other malignancies, does this mean that patients with IED treated with similar long-term IS therapy are also at such risk? Studies examining the risk of malignancies in transplant recipients, patients with human immunodeficiency virus (HIV) and autoimmune diseases show that suppressing the immune system predisposes the patients to carcinogenesis [
4,
5].
The importance of tumour immunosurveillance in humans has been inferred from clinical observations. The majority of evidence concerning the effects of IS therapy on the host immune response and tumour development is derived from studies of transplant recipients. The effectiveness of IS therapy in improving the outcome of organ transplantation has resulted in the development of malignancies and cardiovascular disease emerging as the major causes of patient mortality, rather than graft rejection as previously observed [
1,
3,
6]. Solid organ transplant recipients given systemic immunosuppressive therapy require lifelong therapy. In contrast, patients with systemic inflammatory diseases are frequently treated with a number of immunosuppressive drugs, often concurrently and over a shorter time course, but nonetheless may still be predisposed to increased tumour risk [
7].
Patients with severe IED are often treated with systemic immunosuppressive therapy. These patients either do not respond to topical or local therapies, have a type of IED not controlled by systemic corticosteroids or require aggressive therapy to prevent progressive vision loss [
8]. The treatment of patients with chronic IED typically encompasses the use of corticosteroids with additional agents. This is primarily due to the significant side effects associated with long-term steroid therapy, and hence agents such as methotrexate (MTX), azathioprine (AZA), cyclosporine (CSA), mycophenolate mofetil (MMF) and, occasionally, alkylating agents (cyclophosphamide and chlorambucil) are given concurrently as steroid-sparing medications. Similarly, the efficacy of IS therapy in the treatment of a number of diseases such as ocular cicatricial pemphigoid [
9], Behçet's disease [
10] and Wegener granulomatosis [
11] has been well documented.
Patients with idiopathic IED do not have an underlying systemic disease. Thus, these patients are a suitable group to examine the effect of immunosuppression and malignancy development in otherwise healthy individuals.
This review examines the evidence regarding the risk of malignancies in patients treated with systemic immunosuppressive therapy. The focus of the review is the evaluation of the evidence in the settings of transplant recipient, patients with autoimmune disease and IED. The aims are to evaluate the available literature and provide recommendations for further studies and prevention strategies to address this important clinical question.
Materials and methods
A search of articles using the MEDLINE database and PubMed (National Library of Medicine) was performed to identify all relevant articles published in the area. Terms and phrases used for the search included immunosuppression, malignancy, transplantation, rheumatoid disease, autoimmune, uveitis, scleritis and ocular cicatricial pemphigoid. Articles were included if they were in English language and if full copies of the articles could be obtained. Articles were only included if they were from peer-reviewed journals. Articles were examined in reference to levels of evidence and recommendations set by the National Health and Medical Research Council. Articles were stratified on evidence strength dependent on study design, which included systematic reviews, randomised controlled trials (RCTs) and cohort study data. Review articles and editorials were also analysed and included if evidence was suitable for inclusion.
Discussion
There is irrefutable evidence derived from studies of transplant recipients and patients with autoimmune diseases that IS therapy is associated with increased malignancy risk. The limited evidence of malignancy associated with systemic immunosuppressive therapy in patients with IED highlights that this clinical issue has not yet been appropriately addressed.
Data derived from transplant registries have strongly established the potential risk of malignancy that results from prolonged IS therapy in order to preserve graft function [
39,
50,
51]. The ability to ascertain whether certain IS drugs are associated with a higher malignancy potential is also influenced by previous patient exposure to other IS therapies. These drugs are typically used in combination or consecutively as the introduction of newer IS agents, such as calcineurin inhibitors and biologics, became more widely used [
34]. Long-term follow-up studies of transplant recipients revealed that neoplasms appeared on average 5 years after transplantation and the commencement of IS therapy [
1,
41]. Immunosuppressive therapy for allograft recipients differs significantly in regards to dosing and cumulative exposure when compared to patients treated for systemic inflammatory diseases. Similarly, the systemic inflammatory state induced by the allograft may drive carcinogenesis, exacerbated by the use of IS therapy [
3]. Therefore, it would be naive to affirm the same risk of developing neoplasia without considering that there may be marked differences in risk between different groups of patients.
The literature on the risk carcinogenesis in patients with RA and other inflammatory diseases treated with IS drugs is divided. Numerous studies indicate an increased risk of malignancy with IS therapy, whilst other studies suggest that the increased risk is due to the disease itself (e.g. rheumatoid arthritis [
7], psoriasis [
28] and Sjögren's disease [
52]). Isomaki et al. suggested that the baseline risk of malignancy in patients with RA might be due to chronic activation of the immune system, leading to an increased incidence of lymphoproliferative disorders. The majority of studies indicate that patients with either rheumatoid arthritis or psoriasis are at an increased risk of neoplasia; however, patients treated with systemic IS therapy have a significantly greater incidence of tumours [
53‐
55]. A number of authors have factored in the baseline risk of neoplasia in patients and compared patients on IS therapy for RA and patients not on such therapy [
56]. Other studies did not account for this baseline risk of malignancy in RA, which may inflate their malignancy incidence findings [
57].
A well-designed study which accurately addresses the concern that systemic IS therapy in IED may predispose to malignancy has not been conducted, and there is limited literature specific to the long-term use of IS therapy in patients with IED. Studies that have examined this important issue have a number of significant shortcomings. The study conducted by Murray et al. established that there was an increased risk of malignancy; however, the findings are affected by a number of important factors. These include a small sample size (
n = 87) and failure to account for pre-exposure risk of malignancy and not addressing IED with systemic disease associations in the analysis of the results [
33]. The limited patient sample size resulted in insufficient statistical power for valid conclusions to be drawn. Lane and associates did not find an increased risk of malignancy in patients treated with IS agents, but it is possible that these results were affected by the relatively short-term follow-up period (mean 1.34 years). It is evident that long-term follow up (often >5 years) is necessary in studies of patients exposed to IS therapy in order to provide a more accurate clinical picture [
1,
58]. Kempen et al. suggested that systemic IS therapy does not increase the risk of cancer mortality in patients with IED [
49]. The study, however, did not address the incidence of non-fatal neoplasia in patients treated with systemic IS therapy for IED. The type of malignancy, grade or histopathology for tumours was not obtained because the primary outcome of this study was defined as the cause of death on certificates identified on the US Death Index. Studies suggest that patients who develop malignancies associated with systemic IS therapy have tumours such as NMSC or lymphomas, which are treatable and may not directly increase mortality; however, they may have a significant impact on morbidity and the patient's quality of life [
7,
48,
54]. Another important issue for ophthalmologists is the need for a regular, focussed and complete physical examination to ensure that the sites of common immunosuppression-related malignancies, such as skin, lymph nodes and cervix, are examined. This by necessity requires a careful systemic review and the assistance of other physicians, which may not be readily available in busy eye clinics.
More recently developed therapeutic agents, which are increasingly utilised in the treatment of ocular inflammation, target the activity of inflammatory cells and cytokine signalling. Limited long-term data exists on whether the use of these agents alters the body's ability to detect defective or pre-cancerous cells [
59]. Data with regards the safety of biologics (e.g. TNF-α inhibitors) in the treatment of patients with IED are limited due to the recent use of these agents in this setting and a lack of long-term follow-up studies. A number of studies have highlighted the possibility of increased risk of malignancy although none of these studies involved a large patient sample with an appropriate long-term follow-up [
60,
61]. Similarly, issues related to pre-exposure to MTX and other systemic IS therapy may act as confounders on data reliability.
Recommendations for future studies
In order to properly address the question of whether the risk of malignancy increases in patients with IED treated with systemic IS therapy, a large collaborative multi-centre prospective cohort study with a long-term follow-up and regular careful systemic evaluation is required. The study design needs to incorporate methodology that addresses possible synergistic factors in carcinogenesis. Examples of such factors include past history and family history of malignancy, smoking status and occupation. In particular reference to NMSC, data on lifetime sun exposure and complexion should be obtained as in the study of Glover et al. [
62]. This would evaluate whether an increase in malignancy in IED patients on systemic IS therapy is due predominantly to the immunosuppression or requires the addition of other factors and thus an indirect causation. Furthermore, comparison of patients with similar IED diseases treated with corticosteroid monotherapy as controls, compared to those treated with systemic IS therapy, would address issues with regard to the baseline malignancy risk in patients with IED. It could be argued that patients who are treated with systemic IS therapy may have more severe disease and thus are at significantly greater risk of carcinogenesis. Whilst this is true in the setting of autoimmune disease and transplant recipients, this same conclusion has not been demonstrated in patients with idiopathic IED.
An investigation of the malignancy risk associated with specific IED entities would provide crucial information. A number of tertiary IED centres would be required to achieve this aim by examination of a sufficiently large number of patients. Another important aspect of establishing the carcinogenesis potential of systemic IS therapy in patients with IED is to evaluate any dose–response relationship, which has not been conducted in patients with IED. This will ascertain whether higher dose IS therapy correlates with an increased risk of malignancy in patients with IED.
The large variety of systemic diseases associated with IED (e.g. Behçet's disease, sarcoidosis, Vogt-Kayangi-Harada disease, etc.) poses a problem in an investigation into malignancy risk. Patients with an associated systemic disease may have a significantly increased risk of malignancy compared to those with IED without an underlying disease. A large study, examining the common diseases associated with uveitis (with sufficient statistical power), is necessary to address this issue. Previous studies have tried to identify whether Behçet's disease is associated with an increased risk of malignant disease, but the available literature, consisting mainly of case reports, suggests no significant association [
63,
64]. An investigation into the baseline risk of neoplasia in patients with sarcoidosis also does not support such a correlation [
65]. The baseline risk of malignancy has not been established for patients with IED, with or without systemic manifestations.
Prevention
A crucial aspect of the issue of the relationship between systemic IS therapy and cancer risk is how this can be minimised or prevented. Until it is proven beyond reasonable doubt that patients with IED treated with IS therapy are not at an increased risk of malignancy, it would seem prudent to adopt strategies to minimise such risk. Our suggestions for such an approach are outlined in Table
4. These are based in part on recommendations from the Kidney Disease: Improving Global Health Outcomes group. In relation to skin and lip cancers, it is recommended that patients should be educated about the risk of skin cancer, especially in subjects with a history of high levels of sun exposure and who are fair-skinned and/or have a history of previous NMSC [
37]. All patients should be encouraged to practice regular self-examination and have annual skin and lip examinations by health professionals. Recommendations for non-skin cancer-related malignancies are the same as for cancer screening of the general population, with emphasis on cervical, breast, colon, renal and haematological examinations [
66]. Immunisation against the human papilloma virus may also help reduce the incidence of cervical cancer in this population. Epidemiological studies of renal transplant patients indicate that the duration and intensity of IS therapy influence the incidence of post-transplant malignancies. Thus, modulation of IS therapy and minimising exposure to drugs known to have a high association with malignancy, such as cyclophosphamide, should be minimised and consideration given to the use of less oncogenic therapy, such as methotrexate and mTOR inhibitors, such as sirolimus [
67]. There is evidence that mTOR inhibitors have a beneficial effect in terms of cancer regression in patients with post-transplant malignancy, and this will need to be confirmed in long-term studies.
Table 4
Strategy to reduce risk of systemic immunosuppressive therapy related malignancies
Pre-treatment | Careful pre-treatment evaluation of patients for presence of immunodeficiency (e.g. HIV), past or family history of malignancy and pre-malignant conditions (e.g. Bowen's disease, CIN of cervix, GIT polyps, leukoplakia of lip) |
Dosages and therapy | Minimise dose and duration of immunosuppressive therapy (e.g. use of alkylating agents, such as cyclophosphamide for <12 months) - consider drugs with less oncogenic potential (e.g. MTX, mTOR inhibitors (sirolimus)) |
Education | Patient education - stop smoking, avoid excessive exposure to UV radiation, immunisation against HPV, regular self-examination (e.g. skin, lips, breast) |
Follow-up | Regular and annual review - screening for common immunosuppressive therapy associated malignancies (e.g. skin, cervix, bladder, lymph nodes) |