Ординатура / Офтальмология / Английские материалы / New Treatments in Noninfectious Uveitis_Miserocchi, Modorati, Foster_2012

Christoph Tappeiner, MD, FEBO

Department of Ophthalmology, Inselspital, University of Bern

CH–3010 Bern (Switzerland)

Tel. +41 31 632 85 03, E-Mail christoph.tappeiner@insel.ch

Miserocchi E, Modorati G, Foster CS (eds): New Treatments in Noninfectious Uveitis.

Dev Ophthalmol. Basel, Karger, 2012, vol 51, pp 90–97

Interferon-α Therapy in Noninfectious Uveitis

Christoph Deutera Nicole Stübigerb Manfred Zierhuta

aCentre for Ophthalmology, University of Tübingen, Tübingen, and bDepartment of Ophthalmology, Campus Benjamin Franklin, Charité, Universitätsmedizin Berlin, Berlin, Germany

Abstract

Interferon (IFN)-α and IFN-β are naturally occurring cytokines which seem to have similar effects on the immune system. One of the effects of IFN seems to increase regulatory T cells. There are numerous case reports and studies reporting about the effect of IFN-α against Behçet’s disease (BD), but also against chronic uveitic macular edema and a few other types of uveitis. Within 2–4 weeks, approximately 94% of patients reach complete or partial remission in the case of BD-associated uveitis. So far, IFN-α is the only drug that leads to stable remission even after discontinuation of the treatment. It is recommended to start treatment with 3–6 million IU per day. Administering less than daily dosages seems to increase the recurrence rate for BD-associated uveitis. Flu-like symptoms are expected in all patients as a sign of nonexisting anti-IFN antibodies. They are treated with nonsteroidal anti-inflammatory drugs like paracetamol and disappear normally after some days. Depression (8%) and mild leukopenia (30%) are additional side effects of concern; all other side effects are reported to appear in ≤1% of cases. This chapter updates the mechanisms and pharmacology of IFN and its effects in experimental studies. This is followed by a summary of clinical studies in intraocular inflammation and the spectrum of side effects.

Interferon (IFN)-α and IFN-β, which belong to the type I IFNs, are naturally occurring cytokines. There is about 30% homology of amino acid sequence. Both IFNs are sharing the same receptor; therefore, the therapeutic effect of these IFNs seems to be quite similar. Besides being approved as single agents for the treatment of adults with chronic hepatitis B and C, various hematologic malignancies, malignant melanoma and multiple sclerosis [1–4], there is growing evidence that especially IFN-α is highly effective in the treatment of Behçet’s disease (BD) and also chronic uveitic macular edema.

Mechanisms and Pharmacology

IFN-α is a naturally occurring cytokine and belongs, same as IFN-β, to the type I IFNs. In general, any cell can produce type I IFNs, but antigen-presenting cells,

Table 1. Overview regarding the commercially available IFN-α and IFN-β

especially plasmacytoid dendritic cells, are the main producers of type I IFNs, already at early stages of the immune response. Thus, type I IFNs, especially IFN-α, may be the essential cytokines linking the innate with the adaptive immune system. Low levels of type I IFNs seem to be preconditions for the upregulation of type I IFNs as a reaction to viral infection and subsequent induction of IFN-γ production. This finally leads to the induction and maintenance of T helper type 1 cells, CD8+ cytotoxic T cells, and natural killer cells. In contrast, type I IFNs have also been shown to exert an antiproliferative and an apoptotic effect on T cells. Another IFN effect is the development of tolerance-promoting regulatory T cells. There has been a positive as well as an inhibitory effect described on B cell development and survival [5, 6].

Using in vitro studies, Plskova et al. [7] had found that plasmacytoid dendritic cells of patients with posterior uveitis induce less IFN-α after stimulation than cells from healthy controls. In addition, TNF-α was able to reduce the IFN-α levels by inhibition of number and function of IFN-α-generating dendritic cells [8].

It has been shown that numbers of γ-δ T cells were normalized [9] and soluble TNF receptors increased in BD patients treated with IFN [10]. Regulatory T cells also seem to play a key role in the effect of IFN. Therefore, a significant increase in Foxp3 expression of regulatory T cells (CD4+CD25high) has been demonstrated for patients with BD treated for 6 months with IFN-α, and also for patients with multiple sclerosis treated for 12 months with IFN-β [11, 12]. This effect was not detectable in BD patients treated with immunosuppression.

IFN-α was the first cytokine to be produced in the recombinant form in the early 1980s. Nowadays, different types of human recombinant IFN-α and IFN-β (table 1) given subcutaneously are available. In general, the original formulation requires daily injections, but the development of pegylated versions, with the addition of polyethylene glycol to the standard structure, allows for much lower doses and convenient application only once a week. The pegylation results in a biologically active molecule with more sustained absorption and a longer half-life [13].

During tubular reabsorption, IFN undergoes proteolytic degradation, and it is completely filtered in the kidneys. Depending on the mode of application (subcutaneously, intramuscularly, or intravenously), the mean half-life of the standard IFNs is 2–5 h [14]. IFN is not considered to be safe in pregnancy [14].

Experimental Work

Today, there is only limited information about the effect of IFN in experimental uveitis work. In 1998, Okada et al. [15] used the IRBP model to show suppression of inflammation in IFN type I-treated rats, suggesting that this suppression may be mediated in part by a reduction in TNF-α [15]. This group [16] found the same effect based on an increased production of NK cells and NKT cells. Recently, it has been shown that subretinal delivery of AAV2.hIFN-α can lead to an effective expression within the eye for at least 3 months, and that it significantly attenuates experimental autoimmune uveoretinitis activity [17].

Clinical Effects

Today, the most common indication for IFN-α in ophthalmology is ocular involvement due to BD. BD is a systemic immune-mediated vasculitis of unclear origin. Major symptoms include oral aphthous ulcers, genital ulcerations, skin manifestations, and intraocular inflammation. The latter is characterized by a recurrent posterior or panuveitis and by an occlusive retinal vasculitis that is responsible for the poor visual prognosis of this uveitis entity [18]. It is estimated that without treatment more than 90% of patients become blind after less than 4 years of disease [19]. Since the mid-1980s, a rising number of case series and open studies reported about the favorable effect of IFN-α in the treatment of BD, and especially of acute episodes of severe uveitis. A review of the literature by Kötter et al. [20] analyzing 32 original reports and 4 selected abstracts revealed that between 1986 and 2002 a total of 338 BD patients have been treated with IFN-α; in 182 of them acute uveitis was the indication. Within 2–4 weeks, approximately 94% of patients achieved complete or partial remission of ocular disease. The data of a prospective open study conducted by our group showed that IFN-α works fast enough to be suitable as a rescue therapy for acute relapses of BD uveitis. The study included 50 patients with active sight-threatening panuveitis and/or retinal vasculitis unresponsive to at least one immunosuppressive drug. Treatment efficacy was assessed using the ‘uveitis scoring system’ by BenEzra et al. [21]. More than 90% of patients responded to treatment and achieved complete remission of ocular disease within a median of 4 weeks. Mean posterior uveitis score fell by 46% per week. Cystoid macular edema (CME), if present, disappeared in all eyes [22]. Similar results have been published by Tugal-Tutkun et al. [23]. In a

Table 2. Long-term data for IFN-α in ocular BD from different studies

retrospective study on 44 BD patients with unresponsive BD uveitis, 91% of patients showed complete or partial response. A significant improvement in visual acuity also occurred. However, the authors postulated possible differences in therapeutic efficacy and side effect profile of IFN-α in different patient populations. Under treatment with IFN-α, the reperfusion of occluded retinal vessels as well as a complete regression of retinal neovascularization have been reported [24, 25]. Thus, we found that, if IFN-α is used in time, retinal laser photocoagulation can be avoided in almost all patients with ocular BD.

A major problem in the treatment of BD uveitis is the fact that despite early use of immunosuppressive drugs like cyclosporine or azathioprine, a substantial proportion of patients will lose useful vision over time. Thus, we have to redefine the goal in the treatment of BD uveitis which today has to be preservation of good visual function by avoiding relapses. Recently, three studies with a total of 130 patients [26–28] demonstrated that this goal can be achieved with the use of IFN-α (table 2). So far, this cytokine is the only drug that allows patients with BD uveitis to stay in remission even after complete discontinuation of treatment. As a consequence of the favorable therapeutic effects, IFN-α has been included in the EULAR recommendation for treatment of BD equal to TNF-blocking agents [29].

Despite the long-standing experience with IFN-α in BD, uniform dosing regimens still do not exist. An analysis of the literature suggests that intermediate to high doses are more effective and long-term remission seems to be associated with higher doses of IFN-α but not with longer treatment durations [20]. Therefore, we tend to start IFN-α treatment with high initial doses such as 3–6 million IU per day, depending on the body weight of the patients. We also highly recommend to stop other immunosuppressive drugs completely on the day before start of IFN-α and to taper systemic corticosteroids

to a dose of 10 mg prednisolone equivalent per day as soon as possible because it has been postulated that these drugs may antagonize the therapeutic effect of IFN-α [18].

Based on the observation that the use of IFN-α alone (without other drugs like corticosteroids, acetazolamide and immunosuppressives) leads to complete regression of CME in ocular BD, the idea came up to use this drug also for chronic CME due to noninfectious non-BD uveitis. Although we have to assume meanwhile that the mode of action is probably different in both entities, the treatment of chronic uveitic CME with IFN-α passed through a very promising development. In 2009, we reported on 24 patients that we have treated with IFN-α for chronic long-standing uveitic CME unresponsive to systemic or local corticosteroids, acetazolamide and immunosuppressives. Within 3 months, IFN-α led to complete or partial resorption of CME in 87.5% of patients. It was impressive how fast IFN-α works in this indication. So, in most patients a response of CME was already seen after 3 days (fig. 1). However, in contrast to ocular BD, the vast majority of patients with chronic uveitic CME is not able to discontinue IFN-α but needs a long-term treatment at very low maintenance doses to keep absence of CME [30]. To date, we started IFN-α in 58 patients

of whom 38 completed a follow-up of at least 24 months. Of the latter, 74% were still on IFN-α treatment after a mean follow-up of 56 months [Deuter et al., unpubl. data]. Meanwhile, our experiences have been confirmed by a group from France that treated 6 patients with chronic uveitic CME. All of them responded to treatment with IFN-α [31]. As aggressive anti-inflammatory treatment with immunosuppressive or even TNF-blocking agents does not work in chronic uveitic CME but IFN-α does, the mode of action of IFN-α cannot or cannot only be anti-inflammatory in this indication. Fitting with this hypothesis, in vitro experiments showed that IFN-α improves the endothelial barrier function of small retinal vessels [32]. Interestingly, IFN-α shows also promising effects in another form of chronic CME with an inflammatory background that is Irvine-Gass syndrome [33], but in our experience it is less or not effective in other (not primary inflammatory) types of CME (e.g. due to diabetes, central vein occlusion, retinitis pigmentosa). In contrast to ocular BD, previous immunosuppressive treatment does not have to be discontinued when IFN-α is given for chronic uveitic CME.

One of the most devastating forms of intraocular inflammation is serpiginous choroiditis. One case series reports on the successful use of IFN-α in this indication. Sobaci et al. [34] treated 5 patients with active sight-threatening serpiginous choroiditis that was refractory to conventional immunosuppressive treatment, with IFN-α. All active lesions resolved within 6 months, recurrences could be prevented, useful vision recovered or maintained during a follow-up of 16–48 months.

Side Effects

Ninety percent of the patients suffer from flu-like symptoms, which mostly resolve during the first weeks after initiation of IFN. Application of nonsteroidal antiinflammatory drugs (e.g. paracetamol) can often ease this problem. However, the development of these symptoms is a good marker that the IFN therapy is effective. The absence of flu-like symptoms seems to be an indicator for preexisting (or newly formed) anti-IFN autoantibodies [20, 30, 35]. Other adverse side effects are reddening at the side of injection, mild leukopenia (30%), alopecia (10%), depression (8%), gastrointestinal disturbances (>1%), increase in liver enzymes (<1%), transient paresthesias (<1%) and other central nervous system symptoms, e.g. epilepsy (<1%) [7, 20, 22, 35]. Another severe adverse event is the development of anti-DNA and antithyroid antibodies (less than 1% of treated patients), which can rarely cause exacerbation or new onset of autoimmune disease [20, 22, 36].

Apart from that, the occurrence of sarcoidosis and Vogt-Koyanagi-Harada syndrome has been observed during therapy with IFN-α [13, 37]. Interestingly, the known development of an IFN retinopathy in hepatitis patients and in patients with posterior uveitis, which is not BD associated, was never found in patients with ocular BD [7, 20, 22].

In general, 4–7.5% of patients experienced side effects during IFN therapy, which were severe enough to warrant discontinuation [22, 25, 35].

Conclusion

The use of IFN-α has strongly improved the prognosis of BD. It seems to be the only drug available which can be stopped and still lead to lasting remission. There is no general agreement about the dosage, but it seems that starting with dosages less than daily may lead to a higher recurrence rate. In addition, IFN-α also has shown to be very effective for the treatment of chronic uveitic macular edema. In contrast to BD uveitis, most of the patients require a minimal basic dosage for continuing a dry macula. How IFN reduces the inflammation and also the edema of the macula is unclear at this moment, but the effectiveness has been shown in various studies.

References

Manfred Zierhut

Centre for Ophthalmology, University of Tübingen

Schleichstrasse 12–16

DE–72076 Tübingen (Germany)

Tel. +49 7071 298 4008, E-Mail manfred.zierhut@med.uni-tuebingen.de