Biological therapy for ocular Behçet’s disease with off-label drug prescription in Turkey

Abstract

Objective

The use of biological agents in the treatment of ocular Behçet’s disease has recently become more frequent. The use of two agents, infliximab (IFX) and adalimumab (ADA), for the treatment of Behçet’s disease requires prior approval by the Turkish Medicines and Medical Devices Agency. We report on a review of such applications with a view to informing on how such agents are used off-label in Turkey.

Methods

Prescriptions for off-label use of IFX or ADA sent from hospitals in Turkey to the Turkish Medicines and Medical Devices Agency in 2018 were evaluated. Demographic data, previous treatment regimens and reasons for referral were extracted from the files of the cases.

Results

A total of 662 patients were considered for off-label use of IFX or ADA for the treatment of ocular Behçet’s disease. The mean age of the patients was 35.7±10.8 years (range 12–76); 61.5% of patients were men and 38.5% were women. Of the applications, 345 (52.1%) were for IFX and 317 (47.9%) for ADA. Among the referring hospitals, the public university hospitals ranked first, accounting for 77.9% of IFX and 88.6% of ADA prescriptions. Most applications were made after the failure of conventional therapy, which included steroids and immunosuppressive agents.

Conclusion

IFX and ADA are rarely used as initial therapy. Stepwise treatment is still preferred in the treatment of ocular Behçet’s disease in Turkey. Our report informs on the management of this difficult-to-treat condition.

Introduction

After the efficacy of a drug in certain health conditions is proven in randomised studies, the approval of the relevant authority is obtained for that drug to be legally prescribed by physicians.^{1 2} For example, the practice in the USA is as follows. After the effectiveness is proven, Food and Drug Administration (FDA) approval is obtained.^{1 2} The FDA identifies this drug in such a way that it is suitable for identified diseases, designated doses and a specific patient population.^{1 2} However, even without FDA approval, there may be clinical trials and other evidence demonstrating that a drug works for off-label use. Physicians may prescribe a drug for label areas with FDA approval and also for other diseases they consider effective. The licensing period of a drug can take years in many countries and it is not always possible to wait until it is licensed, so physicians tend to use off-label drugs for some diseases.

Off-label drug use is very common in many medical fields including ophthalmology in Turkey as well as all over the world, despite its legal problems.^{3 4} According to the guidelines on the use of off-label drugs published by the Ministry of Health in Turkey, most of the off-label drugs in ophthalmology can be used without the need to obtain permission from the authority, while some of them can be used after obtaining permission from the Ministry of Health. This situation has made the use of off-label drugs more common in Turkey. Periocular and intraocular augmented antibiotics, antivirals and antifungals in various eye infections, topical antineoplastic agents such as mitomycin-C and 5-fluorouracil in glaucoma surgery, periocular and intravitreal bevacizumab for ocular neovascularisation, and also the use of immunosuppressive and immunomodulatory drugs in ocular Behçet’s disease (OBD) are among the frequently used off-label drugs in an ophthalmology practice.

Behçet’s disease is a relapsing-remitting inflammatory disorder that affects multiple systems and organs including the eye. OBD is characterised by non-granulomatous inflammatory attacks and spontaneous resolutions. Permanent eye damage and severe vision loss occur as the frequency and duration of attacks in OBD increase; its treatment aims to rapidly suppress acute inflammation and prevent the development of new attacks.^{5 6} Systemic corticosteroids in combination with conventional therapies consisting of antimetabolites (azathioprine, methotrexate, mycophenolate mofetil), T-cell inhibitors (ciclosporin-A, tacrolimus) and alkylating agents (cyclophosphamide, chlorambucil) as monotherapy or combined therapy are widely used in the treatment of OBD. However, azathioprine and ciclosporin-A are the preferred drugs with proven efficacy in OBD.^7–10 Interferon (IFN-α) and anti-TNFα (infliximab (IFX), adalimumab (ADA)) treatment have been suggested as more powerful immunosuppressive therapy in patients with refractory Behçet’s uveitis.¹¹ IFN-α and anti-TNFα are off-label drugs used in the treatment of Behçet uveitis. IFN-α is prescribed without the need for off-label application and anti-TNFα is prescribed with the need for off-label application in Turkey.

This study aims to present the results of off-label prescriptions of biological agents for OBD in Turkey.

Materials and methods

Applications for the off-label use of biological agents (IFX, ADA) from hospitals in Turkey to the Turkish Medicines and Medical Devices Agency (TMMDA) in 2018 were evaluated retrospectively. The status alteration made regarding the agents and the use of both drugs became easier in Turkey in December 2018. For this reason, 11-month data in 2018 were evaluated in our study. After obtaining written permission from the TMMDA, the study received approval from the Ethics Committee of the Ankara Diskapi Training and Research Hospital (report number 2019-63/09) and conformed to the tenets of the Declaration of Helsinki.

The files of applications were evaluated retrospectively in terms of demographic data, previous treatment regimens, reasons for application and application results. The off-label biological agents were evaluated. The distribution of applications was analysed according to hospital type (public university, foundation university, training and research hospital, public hospital, branch hospital, private hospital).

Statistical analysis was performed with Statistical Package for Social Sciences (SPSS) version 22.0 for Windows software (SPSS, Chicago, Illinois, USA). The Kolmogorov–Smirnov test was used to confirm the data had a normal distribution. Descriptive statistical methods (frequency, percentage, average, SD) were also used.

Results

The files of 662 patients who were permitted off-label use of biological agents for OBD were retrospectively examined. Of the applications, 345 (52.1%) were for IFX and 317 (47.9%) were for ADA. The mean age of the patients was 35.7±10.8 years (range 12–76) and 35.6±12.4 years (range 9–69) for IFX and ADA, respectively. Considering all applications, 61.5% of the patients were men and 38.5% were women (IFX: 67.8% men, 32.2% women; ADA: 54.6% men, 45.4% women). While there was no significant difference in age between the groups (p=0.8), there was a significant difference in terms of gender (p=0.001).

When the applying hospitals were examined, public universities were ranked first with ratios of 77.9% for IFX and 88.6% for ADA, training and research hospitals were second with ratios of 19.7% for IFX and 9.1% for ADA and foundation universities were third with ratios of 2.0% for IFX and 2.2% for ADA. There was only one application from a private hospital only for IFX.

The treatment regimens of the patients before the applications were analysed. For IFX, 287 patients had received systemic steroid treatment as part of the combined therapy and, for ADA, 303 patients had received systemic steroid treatment as part of the combined therapy. Previous treatment regimens of patients applying for IFX and ADA are shown in figure 1. In this study, 6.2% of patients received IFX and 17.9% received ADA as first-line therapy.

Figure 1.

Previous treatment regimens of patients applying for infliximab and adalimumab for ocular Behçet’s disease in Turkey.

The most common reason for applications for both IFX and ADA was similar rates of unresponsiveness to other systemic treatment regimens (57.4% for IFX, 57.1% for ADA), while the second most common reason was side effects related to previous IFNα therapy (25.8% for IFX, 29.7% for ADA). Other less common reasons for applications for both IFX and ADA were immunosuppressive-related side effects, complete loss of vision in the other eye due to OBD, IFX-related side effects, neuro-Behçet disease, steroid-related side effects and ADA-related side effects.

Of the applications, 18.3% for IFX and 10.1% for ADA were rejected by the authorities. The most common reason for rejection was incomplete filling of the application documents.

Discussion

The most appropriate usage of a drug is to use it according to the indications and conditions specified in its licence. The use of a drug outside the licence of indication, dose and administration is called ‘off-label drug use’. The rate of off-label drug use worldwide has been reported to be 21%.⁴ In Turkey it is known to be widespread in many medical departments, including ophthalmology, despite no known precise data. Studies evaluating off-label drug applications made for certain eye diseases in 2013 have been published.^{12 13} However, the prevalence of off-label drugs that can be prescribed without the need for off-label applications to the TMMDA in Turkey suggests that the actual data are higher. A non-indication drug use guide is produced by the Ministry of Health in Turkey and the off-label drugs and their usage areas in this guide are updated frequently. Physicians can apply to the TMMDA online or by post for medicines that can be obtained by making the application specified in this guide. This study aims to evaluate the applications to the TMMDA for the off-label use of biological agents for OBD seen commonly in Turkey in 2018.

Behçet’s disease was first described as a triple symptomatic disease with repetitive oral, genital aphthous ulcers, and hypopyon uveitis in 1937 by Turkish dermatologist Dr Hulusi Behçet.¹⁴ The disease is significantly more common in the Mediterranean basin and Far and Middle Eastern countries, including Turkey, especially in areas corresponding to the Old Silk Road.^{15 16} The eye is the most frequently affected organ in Behçet’s disease, which is a multisystem disease and has been reported with a rate of 75%. OBD is often seen as bilateral panuveitis with retinal vasculitis and it includes periods of attack and remission. The attacks involving the posterior segment do not achieve complete remission and cause permanent damage and loss of vision, which has prompted physicians to seek more potent treatments to control the attacks immediately and achieve long-term remission.^{6 17} Therefore, many immunosuppressive or immunomodulatory therapies are currently applied. Treatment with biological agents (eg, anti-TNFα) has recently become popular because of their potency and rapid effect despite the side effect profiles, off-label use and legal problems. The choice of agent depends on the stage of the disease, factors related to the patient, the experience of the physicians and the health system of the country. A gradual treatment approach is generally preferred by physicians in Turkey for the treatment of OBD involving the posterior segment.¹¹ Steroid and immunosuppressive therapies are preferred as the main treatment. IFN-α and anti-TNFα agents such as IFX and ADA are used in cases who fail to respond to the main treatment.

Interferons, with their immunomodulatory effects, have been used successfully in resistant OBD involving the posterior segment, providing long-term remission and rapid response.^{18 19} Despite the problems of tolerability due to its common side effect profile, the fact that no off-label application is needed has made its use more widespread in Turkey. There was no off-label application for IFN-α in Turkey. The human-mouse chimeric monoclonal IgG1 antibody IFX and the human protein-based IgG1 monoclonal antibody ADA are the anti-TNFα off-label biological agents most commonly used in the treatment of refractory OBD involving the posterior segment.

Unlike IFNα, application for an off-label biological agent must be made to the TMMDA for anti-TNFα drugs to be used in the treatment of OBD. The use of anti-TNFα in refractory OBD is usually preferred after conventional therapy. The anti-TNFα drugs IFX and ADA provide faster and longer remission, and decrease the frequency of new attacks in OBD. In this study, 345 (52.1%) of the applications were made for IFX and 317 (47.9%) for ADA. While previously there was a preference for IFX in the treatment of OBD in Turkey, more recently both drugs have frequently been used. As shown in this study, the application rates for both drugs were very similar. The gradual decrease in the effectiveness of IFX due to increased autoantibodies in the blood related to its high immunoreactivity property is a disadvantage of IFX. Moreover, IFX must be administered intravenously in hospital hile ADA can be administered subcutaneously. There may be increased use of ADA due to these disadvantages of IFX.^{20 21} The number of applications for primary therapy with ADA was almost one-third of those for IFX (8 (2.6%) vs 21 (6.2%)). Although IFX and ADA have similar effects, some studies suggest that ADA is superior to IFX.²⁰ We think that, despite the lower preference of ADA as primary therapy in our study, a higher switch ratio from IFX to ADA also supports the advantage of ADA over IFX.

When the previous treatment regimens of patients who applied for IFX were examined, the highest rate was the group that received steroid immunosuppressive therapy first and then interferon treatment. The highest rate for ADA was the group that previously received steroid and immunosuppressive therapy. These data in figure 1 show the stepwise treatment approach for OBD in Turkey.

The updated European League Against Rheumatism (EULAR) recommendations in 2018 have suggested that biological agents can be used as initial therapy in some selected patients in whom their sight is threatened.²² Expert recommendations for the use of anti-TNFα agents to treat ocular inflammatory diseases published by Levy-Clarke et al ²³ also recommended IFX and ADA as first-line treatment for only OBD. This is because anti-TNFα provides more successful visual results when started in the early stages of the disease. In this study, 6.2% of patients received IFX and 17.9% patients received ADA as first-line treatment.

Martín-Varillas and colleagues evaluated the effectiveness, safety and cost-effectiveness of ADA treatment optimisation in patients with uveitis due to Behçet’s disease in 2018. ADA was optimised in 35.4% of patients with Behçet’s uveitis who achieved remission after a median ADA treatment period of 6 months. Most ocular results were similar in the optimised and non-optimised groups, while the relevant side effects were seen only in the non-optimised group. Average ADA treatment costs were found to be lower in the optimised group than in the non-optimised group.²⁴ In 2014, Calvo-Río and colleagues evaluated the effectiveness of anti-TNFα therapy in resistant uveitis due to Behçet’s disease and found that IFX was the first choice in 62% of cases and ADA was the first choice in 38% of cases.²⁵ In our study, according to 2018 data, 52.1% of the applications were made for IFX and 47.9% for ADA.

There are several limitations to this study. First, the details of the medical history of the patients, which are likely to affect the use of the investigated biological drugs, could not be examined in detail, as with the accompanying diseases. Second, the vast majority of applications were from public universities. This can be explained by the fact that these hospitals have Behçet outpatient clinics that can take care of more patients daily, and have many experts in the uvea department. In addition, we think that the referral of resistant patients from other hospitals to these hospitals with an easy referral chain without any additional charges also contributes to this high ratio.

Conclusion

In this study it was found that off-label applications for biological agents for the treatment of OBD were mostly made by public universities for male patients aged 25–45 years with bilateral eye disease. Although there were relatively more applications for IFX, the application numbers were similar for both drugs. Although biological agents are rarely used as initial therapy, the stepwise treatment approach is still preferred for the treatment of OBD in Turkey.

What is this paper adds.

What is known on this subject

• Behçet’s disease is a relapsing-remitting inflammatory disorder that affects multiple systems and organs including the eye.

• Biological agents have recently been used more frequently in the treatment of ocular Behçet’s disease.

• The aim of this study is to share the results of off-label biological agent prescriptions in ocular Behçet’s disease in Turkey.

What this study adds

• Although there are relatively more applications for infliximab (IFX), the application numbers were similar for both IFX and adalimumab (ADA).

• IFX and ADA are rarely used as initial therapy.

• Stepwise treatment is still preferred in the treatment of ocular Behçet’s disease in Turkey.

• This report informs on the management of this difficult-to-treat condition.

Data availability statement

Data are available upon reasonable request.

Ethics statements

Patient consent for publication

Not required.

Ethics approval

This study was approved by the Ethical Committee of Ankara Diskapi Training and Research Hospital.