Potential of Pegylated Interferon Alpha-2a in Behçet Uveitis: A Report of Five Cases

This article is referred to by:

Safety of Interferon Alpha-2a in Patients with Severe Ophthalmic Behçet’s Disease: Response to Bielefeld et al.’s Letter

Interferon alpha-2a is an advantageous therapeutical alternative in case of severe uveitis due to Behçet disease (BD). It is administered subcutaneously 3 times a week at doses ranging from 3 up to 9 million IU per injection.1^,2 Interferon alpha (IFN-alpha) rarely promotes infections and is not carcinogenic. Pegylated interferon (peg-IFN) is administered once a week, sometimes every other week, and shows better tolerance.3 Peg-IFN-alpha-2a has been widely used to treat chronic hepatitis C,4 but its use in BD has not yet been documented. We report on 5 patients treated with peg-IFN-alpha-2a for severe uveitis due to BD. They first received 6 months standard IFN-alpha-2a, then peg-IFN-alpha-2a 180 µg once a week initially.

Five patients, 3 men and 2 women (3 European and 2 North African patients), median age (range) 34 (32–36) years, received peg-IFN-alpha-2a because of severe uveitis for a median (range) 30 (12–48) months. The main characteristics of the patients are summarized in Table 1. One eye was affected in 4 patients and both eyes in 1 patient: in this case only the worst eye was considered for analysis.

TABLE 1. Characteristics of patients suffering from Behçet disease and treated with pegylated interferon alpha-2a.

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Gender	Female	Male	Male	Male	Female
Oral ulcerations	Yes	Yes	Yes	Yes	Yes
Genital ulcerations	Yes	Yes	No	Yes	Yes
Erythema nodosum	No	No	Yes	No	No
Age at peg IFN onset	34	36	32	25	60
Anterior/intermediate/posterior uveitis	Yes/vitritis 2+/retinal vasculitis	No/vitritis 2+/retinal vasculitis	Yes/no/retinal vasculitis	Yes/vitritis 3+/no	No/no/bilateral macular edema
Visual acuity before IFN-alpha (logMAR)	1.0	0.4	0.2	0.2	0.7
Central retinal thickness on OCT before IFN (µm)	238	457	266	ND	668
IFN indication	Resistance to steroids and refusal of IS	Resistance to steroids and refusal of IS	Corticodepen dent 20 mg/d with AZA	Corticodependent 25 mg/d with AZA	Non compliant (steroids/AZA)
Duration peg-IFN alpha-2a treatment (months)	12	36	30	48	12
Visual acuity right eye after 6 months of peg-IFN alpha-2a	0.0	0.3	0.0	0.0	0.4
Central retinal thickness on OCT 12 months after peg-IFN-alpha-2a (µm)	268	311	266	ND	214
Visual acuity after 30 months of peg-IFN	0.0	0.2	0.0	0.0	0.3
Steroid dosage at peg-IFN alpha-2a initiation	20 mg/d	25 mg/d	20 mg/d	25 mg/d	15 mg/d
OCT after 30 months of peg IFN	254	313	257	ND	180

Peg, pegylated; IFN, interferon; logMAR, logarithm of the minimum angle of resolution; OCT, optical coherence tomography; AZA, azathioprine; ND, not done; IS, immunosuppressive drugs.

Material and Methods

The diagnosis of BD was made according to the criteria of the International Study Group for Behçet's Disease5 with uveitis associated with oral and genital ulcerations (4 cases), and recurrent oral ulcers with erythema nodosum (1 case). In each case, uveitis was the first manifestation of BD. Four patients were HLA-B51-positive.

The indications of IFN-alpha-2a were resistance to corticosteroids alone (need for more than 0.15 mg/kg/day at 6 months, with immediate transition to IFN due to a refusal of immunosuppressants) (n = 2) and resistance to oral corticosteroids and azathioprine (n = 3). The median initial visual acuity was 0.4 (0.2–1.0) logMAR (logarithm of the minimum angle of resolution) and the median initial central retinal thickness on OCT (optical coherence tomography) was 362 (238–668) µm. Each patient was initially treated for 6 months with IFN-alpha-2a, 3 million units 3 times a week subcutaneously, which was then replaced by peg-IFN-alpha-2a 180 µg/week subcutaneously. In fact, the first patient we treated asked for fewer injections after 6 months of conventional interferon therapy, leading us to start pegylated IFN. We then applied the same treatment scheme to the 4 other patients reported here. Besides, there is no recommendation about mean treatment duration so far in the literature.6 Because depression is described as “common” during IFN therapy, and may necessitate discontinuation, 4 of the 5 patients systematically received antidepressant treatment, although we acknowledge this is not a recommended so far. All patients received paracetamol before and after injection for the prevention of influenza-like illness.

Results

All patients had improved after 6 months of nonpegylated IFN-alpha. After 1 year of IFN, 6 months after the start of peg-IFN-alpha-2a, visual acuity increased in all 5 patients with a median 0 (0–0.4) logMAR (p = 0.0579, Wilcoxon test). Central retinal thickness was decreased at 6 months without reaching statistical significance, 267 (214–311) µm, p = 0.375, Wilcoxon test), and retinal vasculitis was reduced in all cases as observed on fluorescein angiography. All patients discontinued systemic corticosteroids after 6 months of peg-IFN-alpha-2a. After 1 year of peg-IFN-alpha-2a, visual acuity remained stable. From that date, peg-IFN-alpha-2a injections were spaced every 15 days and visual acuity remained stable. In 4 patients, after 30 months of treatment with peg-IFN-alpha-2a, visual acuity was 0.0 (0.0–0.3) logMAR (p = 0.0545, Wilcoxon test) and the median OCT value was 255 (180–313) µm, (p = 0.375, Wilcoxon test). Overall tolerability was good; 1 patient had to stop peg-IFN-alpha-2a after 12 months because of cytolytic hepatitis, probably due to multidrug toxicity. No patient had disabling fever, and debilitating fatigue was greatly reduced by weekly administration, compared to 3 times per week for the standard IFN phase. None of these patients had a severe depressive episode requiring hospitalization. There were no relapses or no new extraocular manifestations (mainly dermatological) in our patients under treatment.

Discussion

The use of IFN-alpha-2 was first reported in BD in 1986. The rationale was a hypothetic viral origin of the disease.7 A complete review of the literature by Kötter et al.8 in 2004 analyzing 32 original reports and 4 selected abstracts revealed that between 1986 and 2002 a total of 338 BD patients had been treated with IFN-alpha-2; in 182 of them acute uveitis was the indication. IFN-alpha-2a has been used more often than IFN-alpha-2b and 75% of patients with ocular BD were in total remission, 19% in partial remission. Only one study was randomized versus placebo, but the results were not statistically significant9 and the patients had nonocular BD. Other studies reported a good outcome after use of IFN in combination with azathioprine10 initially, then azathioprine alone; nevertheless, in this series, there was no additional effect, but additive adverse effects of both medications. Two other recent studies report the use of IFN alone with success in 87.5 and 71.6% of patients.11

Treatment recommendations for BD are based on a literature review from 1966 to 2006.12 IFN-alpha-2 alone or in combination with corticosteroids is an alternative to associations of cyclosporine or infliximab to corticosteroids or azathioprine for severe or refractory uveitis.12 Nevertheless, IFN's side effects, such as flu-like syndrome, neutropenia, and depression, limit its use.

IFN-alpha-2 in BD is the first therapy that is associated with persistent and prolonged remission (20–40% of patients), after treatment is stopped.13 Recent data seem to prove that anti- TNF-alpha has the same favorable effect.14

The pegylation process was developed in the 1970s by Abuchowski.15 The polyethylene molecules (peg) are nontoxic, nonimmunogenic, and highly water-soluble, allowing them to be rapidly eliminated from the organism.15 Given that IFN has a short half-life, pegylation can increase the half-life and consequently reduce the number of injections. Two types of peg-IFN-alpha are available: pegylated IFN-alpha-2a and alpha-2b. Type 2a has more pegylated chains than type 2b. Therefore, because of its higher molecular weight, peg-IFN-alpha-2a retains only 7% of the antiviral activity of the native protein, whereas peg-IFN-alpha-2b retains 28%. It should therefore be logical that peg-IFN-alpha-2a doses are higher than peg-IFN-alpha-2b doses, but this has not been verified in vivo because peg-IFN-alpha-2a has a longer half-life. The distribution volume is considerably greater for peg-IFN-alpha-2b (69 L) than for peg-IFN-alpha-2a (6–14 L). A molecule with a high molecular weight has a smaller distribution volume and thus a reduced capacity to diffuse into the tissues.15 The size and number of binding sites thus give peg-IFN in vitro pharmacological properties that are a subtle balance between faculty receptor binding, half-life, preserving the activity of the standard molecule, and diffusion in tissues. These effects are known for their anti-viral activity and are extrapolated to immunomodulatory activity.

The complexity of the pharmacology of peg-IFN is increased by the fact that patient weight affects therapeutical efficacy.15 Dosage adjustment of peg-IFN-alpha-2a remains a problem because the recommended dose is fixed, while peg-IFN-alpha-2b is adapted to the patient's weight (1.5 mg/kg and weekly injection). Patients with low body weight may therefore be overdosed with peg-IFN. Nevertheless, we chose the same dose for all patients, namely peg-IFN-alpha-2a 180 µg, without encountering obvious overdose problems. This, however, remains to be assessed in larger series.

Both existing pegylated interferons therefore have better anti-viral efficacy compared with their nonpegylated counterparts.16 Both have the advantage of single weekly dosing without increased toxicity. Pegylation optimizes the action of interferon by decreasing clearance, allowing stable pharmacological rates and the benefits of increased circulation time. These characteristics, known for the anti-viral activity of IFN, are possibly applicable to the immunomodulatory effect. However, results on anti-viral activity may not be applicable to the immunoregulatory effect. Therefore, we need to be careful about any extrapolation.

Very few studies exist about peg-IFN in BD. In fact, the immunological effects of continuously high IFN levels may be totally different from intermittent high levels, which is the case with the unpegylated form. However, one study showed that pegylated interferon alpha-2b reduced corticosteroid requirement in patients with Behcet disease with upregulation of circulating regulatory T cells and reduction of Th17.17

Due to better efficacy as reported in the literature with IFN-alpha-2a in uveitis, we then selected the pegylated form of this IFN-alpha-2a for administration to our patients. To assess side effects and tolerability of peg-IFN-alpha-2a and -2b, we reviewed the series of patients treated for hepatitis B and C in the literature. The same complications occur as with standard IFN-alpha18: mild leukopenia, alopecia, depression, gastrointestinal disturbances, increased liver enzymes, transient paresthesias, and other central nervous system symptoms, such as epilepsy. The development of anti-DNA and anti-thyroid antibodies, which can rarely exacerbate or induce an autoimmune disease, is seen in less than 1% of patients. Apart from these classical complications, granulomatous diseases, uveitis, sarcoidosis, and retinal vascular occlusions may occur. A case of Vogt Koyanagi Harada has been reported as a complication of hepatitis C treated with peg-IFN-alpha-2a.3 We did not encounter such side effects in our small series of patients. In addition, some authors have even reported a decrease in side effects with peg-IFN-alpha-2a.3

This small series shows the potential value of this formulation of IFN for the treatment of BD uveitis, showing efficacy with fewer injections, and thus reduced side effects and improved quality of life. However, since we did not have a control group without any maintenance treatment after 6 months, a firm conclusion cannot be drawn. The marketing of anti-TNF shortly after the marketing of IFN probably decreased the interest in this drug. The use of peg-IFN-alpha-2a should be studied on larger series of patients, especially compared to anti-TNF-alpha.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.