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Rheumatology Advance Access originally published online on August 16, 2007
Rheumatology 2007 46(10):1570-1573; doi:10.1093/rheumatology/kem199
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Efficacy and safety of interferon-{alpha} in the treatment of corticodependent uveitis of paediatric Behçet's disease

S. Guillaume-Czitrom, C. Berger1, C. Pajot2, B. Bodaghi3, B. Wechsler4 and I. Kone-Paut

Department of Paediatrics and Paediatric Rheumatology, Bicêtre Hospital, Le Kremlin-Bicêtre, 1Department of Paediatrics, Saint-Etienne Hospital, Saint Priest en Jarez, 2Department of Paediatrics, Purpan Hospital, Toulouse, 3Department of Ophthalmology, Pitié-Salpétrière Hospital, Paris and 4Department of Internal Medicine, Pitié-Salpétrière Hospital, Paris, France.

Correspondence to: S. Guillaume-Czitrom, Department of Paediatrics and Paediatric Rheumatology, Bicêtre Hospital, 78 rue du Général Leclerc, 94270, Le Kremlin-Bicêtre, France. E-mail: severine.guillaume{at}bct.aphp.fr


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. To report both the efficacy and safety of interferon-{alpha}-2a (IFN-{alpha}) therapy in corticodependent uveitis of paediatric Behçet's disease (BD).

Methods. Data from seven children affected with corticodependent uveitis of BD and treated with IFN-{alpha} were reviewed retrospectively. IFN-{alpha} was injected sub-cutaneously thrice a week at dosages of 1.5–3 Mons IU according to the children's weight. Efficacy was judged on the ability of IFN-{alpha} to induce a corticosteroid (CS)-sparing effect while maintaining remission. All adverse events (AE) were recorded.

Results. The children included four boys and three girls. Mean age at onset of uveitis was 8.6 yrs and mean follow-up duration was 7.14 yrs. All children had a high level of corticodependence and five of them received additional DMARDs. A remarkable CS-sparing effect with remission maintenance was achieved in 5 out of 7 patients after a mean period of 14.6 months of IFN-{alpha} administration. The remission was sustained in four of the five patients (mean = 4.8 yrs), even after IFN-{alpha} was discontinued in three of them. The other patient relapsed 1.5 yrs after IFN-{alpha} discontinuation. The last two patients faced early severe adverse events attributed to IFN-{alpha}: retinal venous thrombosis and major depression.

Conclusion. IFN-{alpha} has a potent CS-sparing effect in paediatric BD patients suffering from severe uveitis. However, the possibility of major side-effects with this treatment calls for careful monitoring.

KEY WORDS: Behçet's disease in children, Uveitis, Treatment, Interferon-{alpha}


   Introduction
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 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Behçet's disease (BD) is a multisystemic inflammatory disorder that is classified among the vasculitic syndromes. BD is characterized by an association of bipolar aphthosis with uveitis as well as with skin, articular, neurological and potentially life-threatening vascular lesions [1]. Ocular manifestations represent a key feature of BD, ranging in frequency from 30% in children to 60–80% in adults [2–7]. The most typical lesions include posterior or total non-granulomatous uveitis affecting both eyes asymmetrically and retinal occlusive vasculitis [8]. The course of uveitis is more severe in children than in adults, being characterized by recurrent explosive attacks whose frequency and severity can result in permanent damage to visual structures, calling for fast-acting and efficient treatment [9].

Prompt remission of BD-uveitis can usually be obtained with high doses of corticosteroids (CSs); however, most children develop CS dependence together with their known side-effects. To spare CS and avoid recurrences, patients often require non-specific drugs like colchicine, azathioprine, cyclosporine, methotrexate or cyclophosphamide [1]. Despite these aggressive treatments, blindness occurs in 16–25% of the patients after 5 yrs [2–4]. More recently, adult patients suffering from sight-threatening BD-uveitis were successfully treated with anti- tumour necrosis factor (TNF)-{alpha} drugs, monoclonal antibodies giving seemingly better results than soluble TNF-R in this indication [10–12]; unfortunately, monoclonal anti-TNF-{alpha} antibodies are not currently allowed for use in children in France. Encouraging results have been published from case reports of adult BD patients treated with interferon-{alpha}-2a (IFN-{alpha}) for severe uveitis, as well as from a placebo-controlled study involving a whole population of BD patients, few of whom had uveitis [13–17]. Indeed, IFN-{alpha} was shown to be efficient not only on ocular manifestions of BD, but also on muco-cutaneous, neurological, articular symptoms and some vascular lesions [1]. While a recent publication showed the efficacy and safety of IFN-{alpha} in 19/23 adults with BD-uveitis (82.6%) [18], no specific paediatric series has been published. We report herein our experience with IFN-{alpha} treatment of seven paediatric BD patients affected with high-level corticodependent uveitis, who were followed for a mean period of 4.8 yrs starting with IFN-{alpha} introduction.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Patient selection and study design
The charts of seven children with BD-uveitis occurring before the age of 16 yrs, and treated with IFN-{alpha}, were retrospectively studied. The parents’ written consent was obtained according to the Declaration of Helsinki and the design of the work conformed to standards applied in France. Patients originated from three hospitals (St-Etienne, Toulouse and Pitié-Salpétrière-Paris) and were all referred to two BD experts (B.W. and I.K-P.) for therapeutic management. Extensive work-ups were performed in all cases to exclude other possible causes of uveitis. Microbial investigations included bacterial cultures and PCRs of Herpes viridae, Spirochetae cDNAs in the ocular fluid and serologies of Herpes viridae, HIV, Spirochetae, Leptospirae, Toxocara, Toxoplasma, Mycoplasma, Chlamydia and Gram-negative germs known to induce reactive arthritis; ANA, RF, ANCA and HLA B typing were performed. Since the ISG diagnostic criteria for BD [19] are not suitable for children, BD was diagnosed according to the combination of: (i) at least recurrent aphthous stomatitis and/or a familial history of BD since familial cases were shown to be more frequent when BD starts early in life [20, 21]; (ii) typical relapsing BD-uveitis and (iii) elimination of other causes of uveitis. All eyes were examined by an ophthalmologist who was an expert in ocular manifestations of BD, and who could thus certify the diagnosis of BD. Signs typical of BD-uveitis included the attack of the posterior or total uvea, the bilateral involvement, the non-granulomatous aspect of inflammation, the presence of vitreous haze, retinal vasculitis with limited foci of necrosis, retinal vein occlusions with haemorrhages and the relapsing nature of the uveitis. Ocular evaluation included measurement of the best corrected visual acuity (VA), tonometry, slit lamp examination and fundus examination before IFN-{alpha} onset and during follow-up. Candidates for IFN-{alpha} therapy had all developed unacceptable steroid dependence and toxicity.

Treatment of uveitis relapses
Uveitis relapses were treated with high-dose CS. Patients with either pan- or posterior or severe uveitis (with severity being defined by a VA of below 2/10 and/or the presence of a cystoid macular oedema) received oral CS (1–2 mg/kg/day) for 1 month. Thereafter, improvement of ocular inflammation was confirmed, allowing cautious CS decrease up to their arrest or to alternate low dose administration (0.2 mg/kg/2day). Relapses of anterior uveitis were treated with repeated CS eyedrops.

IFN-{alpha} was introduced when a corticodependence threshold of 0.6 mg/kg/day was surpassed and/or when CS-induced cataracts or ocular hypertonia precluded further use of CS. IFN-{alpha} was introduced during the first week of CS therapy, subcutaneously in the evening at a dosage of 1.5 or 3 million IU thrice a week in children weighing 20–30 kg or 30–50 kg, respectively. Flu-like symptoms were prevented with paracetamol (20mg/kg orally), administered 1 h before the IFN-{alpha} injection.

Prior to IFN-{alpha} therapy, all patients had received antithrombotic doses of salicylates and colchicine, which were allowed to be continued. Other agents, such as G penicillin, which has been described as being useful for preventing BD relapse [22] and immunosuppressive drugs, were discontinued at the time of IFN-{alpha} initiation, except when uveitis relapses met the severity criteria.

The efficacy of IFN-{alpha} was judged based on: (i) the achievement of at least a CS-sparing effect of 0.2mg/kg/2day, and (ii) the resolution of eye inflammation with a final VA of above 8/10. Adverse events were recorded during IFN-{alpha} therapy to assess its safety.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Patient characteristics
The children included four boys and three girls. Their mean age at uveitis onset was 8.6 yrs. Mean follow-up duration was 7.14 yrs. Four of the seven patients were French. A family history of BD was present in two patients. At uveitis onset, only patient no. 2 fulfilled the ISG criteria for BD [19] (Table 1). BD-uveitis was inaugural in two patients, while in the others uveitis had been preceded by relapsing aphthous stomatitis for 2–7 yrs. Interestingly, despite a long follow-up (7.14 yrs), only one additional patient (no. 7) completed the full clinical picture of BD according to the ISG criteria during his disease course. All tested patients (6/6) were HLA B51-positive (Table 1) and negative for autoimmune tests; other causes of uveitis were carefully discarded.


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  		TABLE 1. Clinical and demographic characteristics of seven children affected with BD-uveitis

 
Ocular disease before IFN-{alpha} initiation
Four of the seven patients had a panuveitis, two had a posterior uveitis and one an anterior uveitis. Bilateral ocular involvement concerned all patients but one. Retinal vasculitis was present in five patients, two of whom had cystoid macular oedema (nos. 3 and 4). The left eye of patient no. 2 was irreversibly damaged (VA = 1.5/10) due to treatment-resistant macular retinitis at disease onset. As shown in Table 2, VA was impaired (ranging from 1/10 to 7/10) in all but one patient (no. 6) with bilateral anterior uveitis; child no. 6, however, had developed topical CS-induced cataracts and an intractable elevation of intraocular pressure. All patients required initially high-dose systemic CS, except for patient no. 6 who received repeated topical CS. Five of the patients were receiving various combinations of immunosuppressors and/or G penicillin before IFN-{alpha} initiation (Table 2). These medications were interrupted, except for patients nos. 3 and 4 who had severe uveitis relapses (Table 2) and were allowed to continue with azathioprine in combination with IFN-{alpha}. Prior to IFN-{alpha} introduction, the median duration of uveitis was 1.4 yrs and ranged from 0.5 to 6.8 yrs. The mean number of relapses before IFN-{alpha} initiation was 3.4, ranging from 2 to 7.


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  		TABLE 2. IFN-{alpha} efficacy in seven children affected with BD-uveitis

 
IFN-{alpha} efficacy
IFN-{alpha} was efficacious in 5 out of 7 patients: in these five patients, after a mean period of 14.6 months, it was possible to stop the CS treatment (patient nos. 1, 3) or to lower the dose to 0.2 mg/kg/2day (patient nos. 4,5,7), allowing growth restoration (Table 2). In two severely affected children (nos. 3 and 4), combined treatment with azathioprine was also interrupted shortly after CS cessation or stabilization at low doses. Ophthalmological examination at this time allowed the absence of ocular inflammation and disappearance of retinal vasculitis to be confirmed. Visual acuities normalized after a mean period of 2.2 months in these five children (Table 2).The left eye of patient no. 2 was blind long before the BD diagnosis was considered. In spite of CS-induced cataracts and ocular hypertonia, patient no. 5 did not require any surgery.

A long-term follow-up study after IFN-{alpha} initiation, extending to 4.8 yrs for the whole cohort, showed that remission (absence of ocular inflammation and VA >8/10) was maintained in four of these five patients for a mean period of 6 yrs (patient nos. 1,4,5,7). The mean IFN-{alpha} treatment duration in these four children was 3.4 yrs (range: 0.5–4.6). Three of them (nos. 1,5,7) have now interrupted IFN-{alpha} treatment for 1.5, 6.6 and 3 yrs, respectively.

In patient no. 3, panuveitis in the right eye recurred 1.5 yrs after whole treatment cessation. Treatment of this relapse required high-dose CS. IFN-{alpha} was rapidly reintroduced, and had to be increased to 6 million IU thrice a week to obtain both a reduction of CS and a resolution of ocular inflammation. Patient no. 6 could not be evaluated for efficacy since he developed an early adverse effect with IFN-{alpha} 0.08 yrs (1 month) after starting the treatment. Patient no. 2 did not respond to 6 months of IFN-{alpha} treatment, as he required more than 0.7 mg/kg/day of CS and relapsed four times. Finally, in this cohort, the mean number of relapses after IFN-{alpha} initiation was 0.67 and ranged from 0 to 4, all of them occurring in patient no. 2.

IFN-{alpha} tolerance
The safety of IFN-{alpha} was good in 5 out of 7 patients. Only minor transient events occurred: mild lymphopenia in patient no. 3, dizziness in patient no. 4, fever and myalgia in patient no. 5 and fluctuating neutropenia in patient no. 7. In the other two patients (nos. 2, 6), IFN-{alpha} was withdrawn because of severe side-effects. Eye inflammation in patient no. 6 was quickly controlled and he underwent cataract extraction under CS treatment. He developed venous retinal thrombosis soon after the surgical procedure; it was possible to exclude a possible relationship between this serious side-effect and BD because CS were stopped 3 weeks later without any relapse, arguing strongly against an active BD-related manifestation. Accordingly, IFN-{alpha} was considered responsible for the venous retinal thrombosis and was withdrawn. Later on, the patient no. 6 was successfully switched to azathioprine, because of a bilateral panuveitis. Patient no. 2 was not only resistant to IFN-{alpha}, but also showed signs of major depression with suicidal thoughts, requiring tricyclic medication. IFN-{alpha} was interrupted and the patient was switched to etanercept. In less than 6 months, the tricyclic and CS were stopped. All signs of BD activity vanished. The follow-up is currently too short to reach any definitive conclusions about the efficacy of etanercept.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
This is the first long-term retrospective analysis of IFN-{alpha} treatment in a paediatric cohort of BD-uveitis. IFN-{alpha} allowed the abrogation of corticodependence in five out of seven patients, although severe side-effects developed in two patients.

The characteristics of BD-uveitis in our patients were in accordance with those described in the literature [3–4]. Despite a long follow-up, only two of our patients fulfilled the ISG criteria for BD. Our results illustrate why the ISG criteria are not applicable to children and why they necessitate specific adaptations to be useful for the diagnosis of paediatric-onset BD. It is obvious that most BDs are missed when ISG criteria are used to classify paediatric patients: genital ulceration, as well as other skin manifestations are absent up to adulthood; moreover, pathergy test is not helpful in paediatrics (personal observation). In contrast, familial aggregation is far more prevalent when BD starts early in life [20, 21], and this criterium belongs to the Mason and Barnes criteria for BD [23]. Recurrent aphthous stomatitis is not specific of BD, but when combined with the typical BD aspect of a severe relapsing uveitis and with an exhaustive and negative work-up for other causes of uveitis, we do think that the diagnosis of BD is correct; further follow-up of these children into adulthood is obviously necessary. In addition, it is frequently observed that adult patients who develop the most severe uveitis have fewer extra-ocular features than those who do not [4]. This may also make the diagnosis of BD more difficult.

Reported experience with IFN-{alpha} in BD-uveitis is scarce. The open study of Kötter et al. [17] showed prompt remission of ocular manifestations in 50 adult patients receiving high doses of IFN-{alpha} (6–9 million IU daily for at least 14 days) in association with up to 10 mg/day CS. After a mean follow-up period of 36.4 months, 40% of the patients were free of treatment, with the remainder receiving 3 million IU IFN-{alpha} daily. In our study, 5 out of 7 patients quickly entered remission (mean of 14.6 months) with initially higher doses of CS combined with lower doses of IFN-{alpha}. It was possible to stop CS treatment in 2 out of 7 patients and lower their dosage in 3 out of 7, and IFN-{alpha} was discontinued in 3 out of 7. Our results are similar to those of Bodaghi et al. [18] whose treatment regimen was similar to ours: uveitis was controlled in 19/23 (82.6%) adult BD patients with a good CS-sparing effect. The combination of IFN-{alpha} with azathioprine also gave significant improvement in two of our patients with severe uveitis, and might be of great interest in the management of refractory BD-uveitis [24]. A high rate of long-term remission was obtained in 4 out of 7 children, three of whom were able to stop their IFN-{alpha} therapy without relapse after a mean period of 3.7 yrs. Only one of our IFN-{alpha} responder patients relapsed, with a long delay of 1.5 yrs. In adults, Bodaghi et al.[18] reported an IFN-{alpha} interruption rate of 52.6% in responder patients (10/19), 40% of whom relapsed in less than 6 months (4/10).

Although the side-effects were generally limited, they were severe in two cases. Serious depression has been reported in 8% of BD patients receiving IFN-{alpha} therapy, generally resolving after treatment cessation but sometimes requiring specific medication [14–17]. The occurrence of ocular side-effects mimicking BD, such as arteriolar or venous occlusion, has been previously described in cancer and hepatitis patients treated with IFN-{alpha} [25, 26].

In summary, our results with IFN-{alpha} treatment alone or combined with azathioprine for severe BD-uveitis in children are encouraging in terms of the treatment's rapid CS-sparing effect in five out of seven patients. Sustained remission was obtained in 4 out of 7 patients (among whom three are IFN-{alpha}-free), which had never before been described for any other drug. However, the efficacy of IFN-{alpha} in paediatric onset BD-uveitis may be irregular or suspensive. Cautious use of IFN-{alpha} should be required in children, due to the possible occurrence of severe side-effects. The experience described in the literature is too limited to allow the definition of recommendations in terms of dosage, duration of treatment and discontinuation modalities. Finally, TNF-{alpha} blockers such as anti-TNF-{alpha} monoclonal antibodies already used with success in adult BD patients should also be evaluated in these severely affected paediatric BD patients, particularly in situations of IFN-{alpha} failure [10, 12, 27, 28].

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors greatly thank PR P. Le Hoang for the clinical management of most of the patients presented in this article.

The authors have declared no conflicts of interest.


   References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 26 March 2007; revised version accepted 3 July 2007.
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