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Rheumatology Advance Access originally published online on May 20, 2008
Rheumatology 2008 47(7):1051-1053; doi:10.1093/rheumatology/ken172
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Interferon-{alpha}—a new therapeutic option in refractory juvenile Behçet's disease with CNS involvement

J. B. Kuemmerle-Deschner1, N. Tzaribachev1, C. Deuter2, M. Zierhut2, M. Batra3 and I. Koetter4

1Division of Paediatric Rheumatology, University Children's Hospital Tuebingen, 2Centre for Ophthalmology, 3Department of Neuroradiology and 4Department of Internal Medicine, Division of Haematology, Oncology, Immunology, Rheumatology and Pulmology, University Hospital Tuebingen, Tuebingen, Germany.

Correspondence to: J. B. Kuemmerle-Deschner, Division of Pediatric Rheumatology, University Children's Hospital Tuebingen, Hoppe-Seyler-Strasse 1, 72076 Tübingen, Germany. E-mail: kuemmerle.deschner{at}uni-tuebingen.de


   Abstract
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 Abstract
Introduction
 Case reports
 Discussion
 References
 
Objective. To report the successful treatment with recombinant human IFN- {alpha} 2a (rhIFN-{alpha}2a) in two male adolescents suffering from severe treatment-resistant Behçet's disease (BD) with central nervous system (CNS) involvement.

Methods. The patients were 14- and 15-yrs old. Both met the International Study Group for Behçet's disease, O’Duffy and the Japanese criteria for the classification or diagnosis of BD. Signs of CNS involvement were impaired sensorimotor function of the left arm, hemiparesis of right arm and leg, dizziness and walking instability in Patient 1, weakness of both legs, impaired bladder-, bowel- and sexual function in Patient 2 and vasculitic lesions on cranial MRI in both patients. RhIFN-{alpha}2a was administered initially at 3 million IU/day for 4 weeks followed by 3 x 3 million IU/week.

Results. Complete remission was achieved in Patient 1 (reduction in BD activity score from 17 to 2). Patient 2 experienced remarkable improvement (reduction of BD activity score from 23 to 15). In both patients the MRI lesions improved. Patient 2 had mild flu-like symptoms as adverse effect.

Conclusion. RhIFN-{alpha}2a was effective and well tolerated in these juvenile patients with severe neurological BD. Regarding the serious consequences following ocular and CNS affection and adverse effects of steroid dependency, administration of rhIFN-{alpha}2a at an earlier time point needs to be considered.

KEY WORDS: Behçet's disease, Juvenile, Central nervous system, Interferon-{alpha}


   Introduction
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 Abstract
 Introduction
Case reports
 Discussion
 References
 
Behçet's disease (BD) is a multisystem vasculitis affecting arteries and veins of all sizes. It is characterized by oral aphthous ulcers, genital ulcers, skin lesions and ocular inflammation. Other manifestations such as arthritis, thrombophlebitis, arterial aneurysms, epidydimitis, gastrointestinal ulcerations and central nervous system (CNS) vasculitis or meningoencephalitis are less common [1]. The CNS is affected in 5–15% of children with BD [2]. Manifestations include headaches, paresis, seizures and benign intracranial hypertension. The prognosis of BD is mainly influenced by its ocular, neurological or vascular manifestations. Although the prognosis has improved with early and aggressive immunosuppressive treatment, many patients have refractory disease and require treatment with combination of various immunosuppressants or cytotoxic agents, like low-dose MTX, chlorambucil or TNF-inhibitors, which in the long term may lead to serious infections or secondary malignancy. Furthermore neurological complications represent a major side-effect of ciclosporin in the treatment of patients with BD [3, 4]. Consequently, new therapeutic options are required.

RhIFN-{alpha}2a has been shown to be effective and safe in adult patients with BD [5]. No reports are available regarding the use of rhIFN-{alpha}2a in children with BD. So far, no long-term side-effect of rhIFN-{alpha}2a is known. Adverse events like depression, alopecia, weight loss, leukopenia, flu-like symptoms and fibromyalgia arise early in the course of therapy and vanish with discontinuation of treatment.

We report on the disease course of two male adolescents suffering from treatment-resistant BD with CNS involvement. The devastating disease course in spite of immunosuppressive therapy led us to consider treatment with rhIFN-{alpha}2a.


   Case reports
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 Abstract
 Introduction
 Case reports
Discussion
 References
 
Diagnosis
The patients met the International Study Group for Behçet's disease [6], O’Duffy [7] and the Japanese criteria [8] for the classification and diagnosis of BD.

Clinical data and follow-up
The patients were followed in the out-patient clinics of a university paediatric rheumatology centre. Follow-up assessments were recorded monthly from the beginning of rhIFN-{alpha}2a treatment for 3 months and at follow-up every 3 months. Intervals were re-assigned if a flare occurred. At each visit a complete physical examination assessed all organ systems potentially affected by BD. Standardized laboratory testing at each visit included renal function tests, inflammatory markers, haematology and liver function tests. Disease activity was determined utilizing physician and patient global assessment scale (range 1–10) and BD Activity Form [9]. Treatment protocols, changes in dosing, adverse events and intolerance to treatment were documented using ARDIS (Arthritis and Rheumatology Documentation and Information System).

IFN treatment
RhIFN-{alpha}2a (Roferon-A®, Grenzach-Wyhlen, Germany) was initially administered subcutaneously (s.c.) at a dosage of 3 million IU/day and for maintenance of 3 million IU 3 times/week s.c. until improvement of the neurological symptoms. RhIFN-{alpha}2a dosage was determined according to a protocol that had been successful in the treatment of uveitis [10]. Duration of treatment, rhIFN-{alpha}2a dosage, additional medication and type and frequency of adverse effects were documented and analysed.

Imaging
Cranial MRI including time-of-flight MR-angiography was initially performed with 1.5 Tesla (Siemens, Sonata, Munich, Germany) when CNS symptoms occurred as well as 4 and 8 months after the initiation of rhIFN-{alpha}2a treatment. Axial and coronary T2 and T1, diffusion-weighted and FLAIR-images with contrast administration [Gadolinium - Diethylenetriamine penta-acetic acid (Gd-DTPA)] were obtained in order to assess new vascular lesions.

Written informed consent was obtained from the parents for off-label treatment.

Case 1
This male patient was diagnosed with BD at the age of 6 yrs. First BD manifestations included panuveitis and retinal vasculitis with loss of vision in the left eye that required vitrectomy, recurrent oral aphthous ulcers and arthritis. He was HLA-B35, HLA-B50 and ANA positive. Analysis of coagulation factors was normal. Tests for aCLs, cryoglobulins and hepatitis serology were negative. The treatment initially consisted of AZA 2 mg/kg. In addition, colchicine, mycophenolate mofetil (2 x 500 mg/day) and oral prednisolone (2 mg/kg) were administered. However, disease activity was only controlled occasionally with i.v. methylprednisolone pulse therapy (30 mg/kg/day) that led to obesity, hypertension, diabetes and depression.

At the age of 14 yrs, he presented with two episodes of neurological manifestations, the first consisting of impaired sensorimotor function of the left arm and the second of hemiparesis of the right arm and leg, dizziness, walking instability and headache. MRI on flair images revealed new lesions in the periventricular white matter and the corona radiata on the right side (Fig. 1A). Furthermore, lesions were localized laterally to the right trigonum, as well as around the right cerebral peduncle. Contrast enhancement indicating brain barrier impairment as a sign of acute inflammation was visible (Fig. 1A). Although site and appearance of these lesions are not specific for vasculitis, causal connection to BD is very likely in a child with the proven clinical diagnosis and CNS symptoms.


Figure 1
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  		FIG. 1. Patient 1, cranial MRI. (A) Central demyelinization. (B) Resolution of lesions 3 months after rhIFN-{alpha}2a therapy with only faint residues visible.

 
After the first flare of neurological symptoms, i.v. cyclophosphamide pulses and methylprednisolone pulses were added but did not prevent progression of neurological disease. Symptoms also persisted during a 2-month trial of mycophenolate mofetil. RhIFN-{alpha}2a was started with an initial dosage of 3 million IU/day. After 1 month, the maintenance dose was 3 million IU 3 times/week. He achieved complete remission after 1 month including all CNS symptoms, uveitis and oral ulcers, which lasts for 29 months now, the longest symptom-free period in the disease course. After 2 yrs we were able to reduce the dose to 3 million IU 2 times/week. No disease activity occurred and CNS lesions on MRI have also improved (Fig. 1B).

Case 2
The second male patient was diagnosed with BD at the age of 14 yrs. His symptoms were oral aphthous lesions, erythema nodosum and genital ulcers. Posterior uveitis developed later during AZA therapy and retinal vasculitis of both eyes was also documented. He was HLA-B51 positive and ANA negative. Analysis of coagulation factors was normal. Tests for aCLs, cryoglobulins and hepatitis serology were negative. In spite of treatment with AZA (2 mg/kg) in combination with oral prednisolone (2 mg/kg) and colchicine, which was added to prevent further flares, disease activity persisted and oral steroids could not be reduced.

At the age of 15 yrs he presented with weakness in both legs, and impaired bladder-, bowel- and sexual function. The MRI of the brain revealed lesions periventricularly near the occipital horn as well as in the medulla oblongata. MRI of the cervical spine showed a small central lesion at the level of C 5/6.

AZA was stopped and rhIFN-{alpha}2a was started with an initial dosage of 3 million IU/day. After 1 month, the maintenance dose was 3 million IU 3 times/week. The neurological symptoms like leg weakness and impaired bladder-, bowel- and sexual function improved, but there are still some residues of mucocutaneous manifestations. MRI lesions did not progress, but were still visible on control examination (images not shown).

In both patients, steroids could be tapered and finally discontinued without flare within 6 and 5 months, respectively. In Patient 2, colchicine was continued because of persistent genital ulcers.

Adverse events
Patient 1 reported no side-effects at all, even with the initial higher rhIFN-{alpha}2a dosage. Patient 2 experienced mild side-effects such as headache and flu-like symptoms. These were only observed at the beginning of rhIFN-{alpha}2a therapy and subsided in the course of therapy with lower dosage. No laboratory evidence of adverse effects such as leucopenia or elevated liver enzymes was observed.


   Discussion
Top
 Abstract
 Introduction
 Case reports
 Discussion
References
 
These two cases show that rhIFN-{alpha}2a is effective and well tolerated in adolescents with severe treatment-resistant BD with CNS and ocular involvement. Multiple CNS manifestations have been described in BD including parenchymal lesions, meningoencephalitis, vascular lesions or oligoclonal bands [4]. As the prognosis of BD is mainly influenced by ocular and neurological manifestations [11], this therapeutic success is particularly meaningful. While in adults standard treatment for BD with CNS involvement consists of cyclophosphamide and chlorambucil [12], in children these substances are used only in exceptional and urgent cases because of the long-term side-effects. RhIFN-{alpha}2a has been reported to be successful in severe and refractory ocular manifestations of BD [10, 13, 14]. So far, rhIFN-{alpha}2a has only rarely been used in CNS manifestations [15].

The clinical response to rhIFN-{alpha}2a was impressive. After only 4 weeks of treatment, Patient 1 showed no clinical symptoms at all and Patient 2 had improved. In both patients, glucocorticosteroids could be tapered without relapse. There were no serious adverse events. The typical flu-like symptoms and headache in one patient were not severe and dose dependent.

If the neurological symptoms in Patient 2 should persist, TNF-blocking agents could be another therapeutic option. There are few case reports about the successful use of TNF-blocking agents in BD, even with CNS vasculitis [16].

Regarding the serious consequences following ocular and CNS involvement and the side-effects of long-term steroid dependency, especially in children and adolescents, rhIFN-{alpha}2a as therapeutic agent may be considered in the course of severe juvenile BD. In children, rhIFN-{alpha}2a may be justified in cases who fail AZA therapy but before cyclophosphamide is used or steroid dependency is achieved. In adults with acute CNS vasculitis, high-dose steroids and cyclophosphamide would be given for induction and AZA for maintenance therapy. Should this regimen be ineffective, rhIFN-{alpha}2a or TNF-inhibitors were tried. Whether rhIFN-{alpha}2a is superior to conventional immunosuppressive agents regarding its rapid onset of action and the possibility of long-term remission [10, 17] needs to be confirmed by larger case series and longer follow-up periods. In these two patients, rhIFN-{alpha}2a was safe and effective over a short period of follow-up.

Formula

Disclosure statement: C.D. and M.Z. have received reimbursement for attending a symposium and funds for research by Roche Pharma. I.K. has received research funding from Hoffmann-La Roche. All other authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Case reports
 Discussion
 References
 

  1. Sakane T, Takeno M, Suzuki N, Inaba G. Behçet's disease. N Engl J Med (1999) 341:1284–91.[Free Full Text]
  2. Kone-Paut I, Yurdakul S, Bahabri SA, et al. Clinical features of Behçet's disease in children: an international collaborative study of 86 cases. J Pediatr (1998) 132:721–5.[CrossRef][Web of Science][Medline]
  3. Kotake S, Higashi K, Yoshikawa K, Sasamoto Y, Okamoto T, Matsuda H. Central nervous system symptoms in patients with Behçet disease receiving cyclosporine therapy. Ophthalmology (1999) 106:589–9.
  4. Kötter I, Günaydin I, Batra M, et al. CNS involvement occurs more frequently in patients with Behçet's disease under cyclosporin A (CSA) than under other medications–results of a retrospective analysis of 117 cases. Clin Rheumatol (2006) 25:482–6.[CrossRef][Web of Science][Medline]
  5. Kotter I, Vonthein R, Zierhut M, et al. Differential efficacy of human recombinant interferon-alpha2a on ocular and extraocular manifestations of Behçet disease: results of an open 4-center trial. Semin Arthritis Rheum (2004) 33:311–9.[CrossRef][Web of Science][Medline]
  6. International Study Group for Behçet's Disease. Criteria for diagnosis of Behçet's disease. Lancet (1990) 335:1078–80.[Web of Science][Medline]
  7. O’Duffy JD. Proposed criteria for the diagnosis of Behçet's; disease. Rev Med (1974) 36:2371–9.
  8. Mizushima Y. Revised diagnostic criteria for Behçet's disease in 1987. Ryumachi (1988) 28:66–70.[Medline]
  9. Rigby AS, Chamberlain MA, Bhakta B. Behçet's disease. In: Classification and assessment of rheumatic diseases: Part I. Ballieres Clin Rheumatol (1995) 9:375–95.[CrossRef][Web of Science][Medline]
  10. Koetter I, Zierhut M, Eckstein AK, et al. Human recombinant interferon alfa-2a for the treatment of Behçet's disease with sight threatening posterior or panuveitis. Br J Ophthalmol (2003) 87:423–31.[Abstract/Free Full Text]
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  14. Tugal-Tutkun I, Güney-Tefekli E, Urgancioglu M. Results of interferon-alfa therapy in patients with Behçet uveitis. Graefeés Arch Clin Exp Ophthalmol (2006) 244:1692–5.[CrossRef]
  15. Çalgüneri M, Onat AM, Öztürk MA, et al. Transverse myelitis in a patient with Behçet's disease: favorable outcome with a combination of interferon-a. Clin Rheumatol (2005) 25:64–6.
  16. Ribi C, Sztajzel R, Delavelle J, Chizzolini C. Efficacy of TNF {alpha} blockade in cyclophosphamide resistant neuro-Behçet disease. J Neurol Neurosurg Psychiatry (2005) 76:1733–5.[Abstract/Free Full Text]
  17. Deuter CME, Zierhut M, Stübiger N, Kötter I. Ocular Behçet's disease: evaluation of long-term remissions after treatment with interferon alfa-2a. Clin Exp Rheumatol (2006) 24:S27.
Submitted 6 August 2007; revised version accepted 2 April 2008.
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