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Rheumatology 2006 45(3):245-247; doi:10.1093/rheumatology/kei257
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIAL

Treatment of Behçet's syndrome

C. G. Barnes

The Hon. Consulting Rheumatologist, Royal London Hospital, London E1 1BB, UK

Correspondence to: C.G. Barnes, Little Hoopern, Chagford, TQ13, 8B2, UK. E-mail: cgbarnes{at}btinternet.com

Whenever an article on Behçet's syndrome (BS) is published the introduction almost always is repetitive, reminding the reader that this is a multisystem disorder of unknown aetiology the underlying pathology being a vasculitis, which follows a chronic and relapsing course. The paper by Mat et al. [1] in this journal is no exception. The use of the name ‘Behçet's syndrome’, rather than ‘Behçet's disease’, is preferred by many of those interested in the condition since it may present with considerable variation in manifestations and severity between patients, and indeed in the prevalence of individual manifestations in different parts of the world, especially that of gut involvement [2].

As is shown below, the wide variation in the manifestations with which the patient may present may lead to referral to one of a number of different specialities: (alphabetically) dermatology, genitourinary medicine, gynaecology, internal medicine, ophthalmology, oral medicine, rheumatology, etc. Diagnosis, in the individual patient, depends on the occurrence and grouping together of sufficient manifestations to allow the physician or surgeon to either suspect, or definitely diagnose, the condition based on clinical acumen. Over the years a number of diagnostic criteria have been suggested to assist physicians reach a diagnosis [3–6]. It must be stressed that the set of International Criteria [7] should be regarded as classification criteria for the grouping together of comparable groups of patients for research purposes and should not be used as an aid to diagnosis in the individual patient.

The aims of this editorial are to outline the many treatments recommended for the various manifestations and severity of the syndrome, indicating relevant source references for further reading, and to draw attention to the first placebo-controlled trial of corticosteroids in BS [1]. The various therapeutic possibilities are indicated but the dosage schedules, the potential for side-effects and drug combinations must be a matter of clinical decision in the individual case.

The manifestations of the syndrome can be broadly divided into the following:

Mucocutaneous: (i) oral aphthous ulceration, present in 98% of patients with similar genital (scrotal/labial) ulceration in 80%; and (ii) skin lesions (acneiform folliculitis, erythema nodosum and occasionally ulceration) and pathergy reaction [8].

Arthritis/arthralgia: in up to 50% of patients, usually non-destructive.

Ophthalmic involvement: panuveitis and retinal vasculitis in 50% of patients.

Systemic vasculitis: thrombophlebitis, arteritis and aneurysm formation.

Additionally, gastrointestinal ulceration, epididymitis, central nervous system lesions and pulmonary lesions may all occur on the basis of the underlying vasculitis.

The extent and severity of the syndrome in the individual patient inevitably determines the treatment required. Although it has been clearly shown that the syndrome runs a more severe course in males and among those in whom it starts at a young age (arbitrarily taken as less than 25 yr) of either gender, many patients will have limited disease manifestations [9].

Many patients, therefore, will require no more than symptomatic treatment with, for example, simple or anti-inflammatory analgesics or colchicine for arthralgia or modest arthritis, topical applications for acne, or mouthwashes and local steroid applications (e.g. Adcortyl in Orabase®) for oral ulceration [8]. However, orogenital ulceration can be of such severity as to cause gross discomfort, inability to eat or swallow, or perforation of the labia. In such cases colchicine (for genital ulceration in the female patient) [10], azathioprine [11], cyclosporin A [12, 13], interferon {alpha} [14, 15] and thalidomide [16] have all been shown to be of benefit. The known teratogenicity and neurotoxicity [17] of thalidomide have to be taken into consideration in consideration of its use in BS. Anti-TNF-{alpha} treatment with infliximab and etanercept have also been shown, in open and placebo-controlled studies, respectively [18–20], to be effective in controlling orogenital ulceration. Severe erythema nodosum may require systemic corticosteroid treatment. More severe inflammatory joint disease may be controlled by interferon {alpha} [21, 22].

The manifestation that causes most morbidity is inflammatory eye disease, in the form of panuveitis and retinal vasculitis, which may lead to blindness. The patients who are considered to be most at risk are young men in particular. Acute episodes of eye disease, both posterior uveitis and retinal vasculitis, are usually controlled with corticosteroids and either cyclosporin [23, 24] or a cytotoxic immunosuppressive (azathioprine [11] or cyclophosphamide [23]). Interferon {alpha} [14, 25, 26] is also beneficial in eye disease and is usually used alone both for better effect and less toxicity. Azathioprine has been shown to reduce or prevent recurrences of inflammatory eye disease and preserve visual acuity [27]. Infliximab has also been shown to control panuveitis and reduce recurrences of active inflammation [28].

Overt vascular involvement, thrombophlebitis or arteritis, requires special attention. Thrombophlebitis is considered to be due to an active inflammation of the endothelium with resultant superficial or deep venous thrombosis. It is not a disorder of coagulation, and embolization has not been convincingly demonstrated [29–31]. Although some recommend anticoagulation, there is no good evidence that it is beneficial and it may be harmful in patients, typically young men, with pulmonary arteritis and aneurysm formation [32] in whom fatal pulmonary haemorrhage may occur. Azathioprine is recommended for the treatment of active thrombophlebitis of such severity as to cause significant morbidity.

Acute arterial involvement must be regarded as a medical emergency. The treatment of arteritis follows one of the standard protocols of pulsed intravenous corticosteroids and cyclophosphamide, followed by maintenance oral corticosteroids [27, 32].

The paper by Mat et al. [1], from the Department of Rheumatology of the Cerrahpasa Medical Faculty of the University of Istanbul, from where a significant number of controlled clinical trials in BS have originated, is an important contribution to knowledge of the treatment of BS. Despite the extensive use of corticosteroids in the management of patients with BS, with the well-known potential for adverse effects, this is the first double-blind placebo-controlled trial of its type. Controlled trials of corticosteroids have not been considered possible in patients with, for example, acute inflammatory eye or vascular disease as treatment protocols in these situations are drawn from other diseases with similar manifestations and placebo control has not been regarded as ethical. For this reason, Mat et al. confined their study population to patients with mucocutaneous manifestations of BS, specifically genital ulceration. Patients who had received corticosteroids or immunosuppressives in the preceding month, who had severe organ involvement or eye disease, or who had conditions which contraindicated the use of corticosteroids were excluded.


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  		TABLE 1. Outline of drug treatment of Behçet's syndrome

 
Mat et al. compared intramuscular depot corticosteroid injections (methylprednisolone acetate 40 mg) with placebo injections of isotonic saline solution given at 3-week intervals for 27 weeks. In addition to recording the number and type of mucocutaneous lesions present the number of joints with inflammatory arthritis was also recorded at each 3-weekly visit during the treatment period and at post-treatment visits 4 and 8 weeks later. Of the 86 patients (equal numbers of males and females) enrolled, 42 were randomized to receive corticosteroids and 44 to placebo, of whom 35 and 41, respectively, completed the treatment period and 34 and 38 respectively completed the treatment and post-treatment assessment periods. One male from each group was withdrawn from the trial because of the development of eye disease.

No change was demonstrated between the treatment and placebo groups in respect of genital ulcers, oral ulceration, folliculitis or arthritis in either the treatment or post-treatment follow-up periods. Erythema nodosum was significantly reduced during treatment with corticosteroids in women but not in men, but this reduction did not persist through the 8-week post-treatment period. One female patient from each group had to be treated with a short course of thalidomide, one for genital and one for severe oral ulceration. No significant side-effects were recorded.

One may conclude that corticosteroids, given in this trial as low-dose depot injections, are not effective in controlling orogenital ulceration or arthritis in BS. The authors do point out that the mean half-life of intramuscular methylprednisolone is approximately 139 h (range 56–886 h) and a possible conclusion is that the medication was either not given in a sufficiently large dosage, intentionally to avoid unwanted side-effects, or not sufficiently frequently. It would have been interesting had the patients been asked to keep a diary record of the incidence of genital ulceration (and other mucocutaneous manifestations and arthritis) to assess if there was an effect of the medication that disappeared before the next clinical assessment 3 weeks later.

Reports of therapeutic trials with negative results are rare and it is, therefore, unusual that this study has been reported by Mat et al. However, the result of this trial is important as it demonstrates that corticosteroids are not indicated for these common manifestations of BS, mucocutaneous and arthritic, at least in the doses used in this trial, despite the underlying vasculitic pathology of the condition. A further point to consider is that skin infection might play a role in the pathogenesis of some of the manifestations of BS, as has recently been suggested by the same group that performed this study. In brief, they have recently shown that the arthritis and acne of BS may be associated [33, 34] and, contrary to conventional wisdom, the pustular skin lesions in BS are not sterile [35].

The author has declared no conflicts of interest.

References

  1. Mat C, Yurdakul S, Uysal S et al. A double-blind trial of depot corticosteroids in Behçet's Syndrome. Rheumatology 2005;44.
  2. Yazici H, Fresko I, Tunc R, Melikoglu M. Behcet's syndrome: pathogenesis, clinical manifestations and treatment. In: Ball G, Bridges SL, eds. Vasculitis. New York: Oxford University Press, 2002:406–32.
  3. Mason RM, Barnes CG. Behçet's syndrome with arthritis. Ann Rheum Dis 1969;28:95–103.[Free Full Text]
  4. Dilsen N, Konice M, Ardal O. Our diagnostic criteria of Behçet's disease – an overview. In: Lehner T, Barnes CG, eds. Recent advances in Behçet's disease. International Congress and Symposium Series, no. 103. London: Royal Society of Medicine Service, 1986:177–80.
  5. O’Duffy JD. Suggested criteria for diagnosis of Behçet's Disease. J Rheumatol 1974;1(Suppl 1):abstract 32:18.
  6. Mizushima Y. Recent research into Behçet's disease in Japan. Int J Tiss React 1988;10:59–65.
  7. International Study Group for Behçet's Disease. Criteria for diagnosis of Behcet's disease. Lancet 1990;335:1078–80.[Web of Science][Medline]
  8. Alpsoy E. Behçet's disease: treatment of mucocutaneous lesions. Clin Exp Rheumatol 2005;23:532–9.[Web of Science][Medline]
  9. Yazici H, Tuzun Y, Pazarli H et al. Influence of age of onset and patient's sex on the prevalence and severity of manifestations of Behçet's syndrome. Ann Rheum Dis 1984;43:783–9.[Abstract/Free Full Text]
  10. Yurdakul S, Mat C, Tuzun Y et al. A double blind trial of colchicine in Behçet's syndrome. Ann Rheum Dis 2001;44:2686–92.
  11. Yazici H, Pazarli H, Barnes CG et al. A controlled trial of azathioprine in Behçet's syndrome. N Engl J Med 1990;322:139–41.
  12. Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, Inaba G. Double-masked trial of cyclosporine versus colchicine and long-term open study of cyclosporine in Behçet's disease. Lancet 1989;20:1093–6.
  13. Avci O, Gurler N, Gunes AT. Efficacy of cyclosporine on mucocutaneous manifestations of Behçet's disease. J Am Acad Dermatol 1997;36:796–7.[Medline]
  14. Zouboulis CC, Orfanos CE. Treatment of Adamantiades-Behçet disease with systemic interferon alpha. Arch Dermatol 1998;134:1010–6.[Abstract/Free Full Text]
  15. Alpsoy E, Durusoy C, Yilmaz E et al. Interferon alpha-2a in the treatment of Behçet's disease. A randomized placebo-controlled and double blind study. Arch Dermatol 2002;138:467–71.[Abstract/Free Full Text]
  16. Hamuryudan V, Mat C, Saip S et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;128:443–50.[Abstract/Free Full Text]
  17. Ochonisky S, Verroust J, Bastuji-Garin S, Gheradi R, Revuz J. Thalidomide neuropathy incidence and clinico-electrophysiologic findings in 42 patients. Arch Dermatol 1994;130:66–9.[Abstract/Free Full Text]
  18. Robertson LP, Hickling P. Treatment of recalcitrant orogenital ulceration of Behçet's syndrome with infliximab. Rheumatology 2001;40:473–4.[Free Full Text]
  19. Goossens PH, Verburg RJ, Breedveld FC. Remission of Behçet's syndrome with tumour necrosis factor alpha blocking. Ann Rheum Dis 2001;63:744–5.
  20. Melikoglu M, Fresco I, Mat C et al. Short-term trial of etanercept in Behçet's disease: a double blind, placebo controlled study. J Rheumatol 2005;32:98–105.[Abstract/Free Full Text]
  21. Hamuryudan V, Moral F, Yurdakul S et al. Systemic interferon alpha 2b treatment in Behçet's syndrome. J Rheumatol 1994;21:1098–100.[Web of Science][Medline]
  22. Kötter I, Vonthein R, Zierhut M et al. Differential efficacy of human recombinant interferon-alpha 2a on ocular and extraocular manifestations of Behçet's disease: results of an open 4-center trial. Semin Arthritis Rheum 2004;33:311–9.[CrossRef][Web of Science][Medline]
  23. Ozyazgan Y, Yurdakul S, Yazici H et al. Low dose cyclosporine A versus pulsed cyclophosphamide in Behçet's syndrome: a single masked trial. Br J Ophthalmol 1992;76:241–3.[Abstract/Free Full Text]
  24. BenEzra D, Cohen E, Chajek T et al. Evaluation of conventional therapy versus cyclosporine A in Behçet's syndrome. Transplant Proc 1988;20:136–43.[Medline]
  25. Kötter I, Zierhut M, Eckstein AK et al. Human recombinant interferon alfa-2a for treatment of Behçet's disease with sight threatening posterior or panuveitis. Br J Ophthalmol 2003;87: 423–31.[Abstract/Free Full Text]
  26. Kötter I, Günaydin I, Zierhut M, Stübiger N. The use of interferon alpha in Behçet disease: review of the literature. Semin Arthritis Rheum 2004;33:320–35.[CrossRef][Web of Science][Medline]
  27. Hamuryudan V, Ozyazgan Y, Hizli N et al. Azathioprine in Behçet's syndrome: effects on long-term prognosis. Arthritis Rheum 1997;40:769–74.[Web of Science][Medline]
  28. Tugal-Tutkun I, Mudun A, Urgancioglu M et al. Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine and corticosteroids in Behçet's disease: an open-label trial. Arthritis Rheum 2005;52:2478–84.[CrossRef][Web of Science][Medline]
  29. Hampton KK, Chamberlain MA, Menon DK, Davies JA. Coagulation and fibrinolytic activity in Behçet's disease. Thromb Haemost 1991;66:292–4.[Web of Science][Medline]
  30. Mader R, Ziv M, Adawi M, Mader R, Lavi I. Thrombophilic factors and their relation to thromboembolic and other clinical manifestations in Behçet's disease. J Rheumatol 1999;26:2404–8.[Web of Science][Medline]
  31. Efthimiou J, Johnston C, Spiro SG, Turner-Warwick M. Pulmonary disease in Behçet's syndrome. Quart J Med 1986;58: 259–80.[Abstract/Free Full Text]
  32. Hamuryudan V, Er T, Seyahi E et al. Pulmonary artery aneurysms in Behçet syndrome. Am J Med 2004;117:867–70.[CrossRef][Web of Science][Medline]
  33. Diri E, Mat C, Hamuryudan V, Yurdakul S, Hizli N, Yazici H. Papulopustular skin lesions are seen more frequently in patients with Behçet's syndrome who have arthritis: a controlled and masked study. Ann Rheum Dis 2001;60:1074–76.[Abstract/Free Full Text]
  34. Tunc R, Keyman E, Melikoglu M, Fresko I, Yazici H. Target organ associations in Turkish patients with Behçet's disease: a cross sectional study by exploratory factor analysis. J Rheumatol 2002;29:2393–6.[Abstract/Free Full Text]
  35. Hatemi G, Bahar H, Uysal S et al. The pustular skin lesion of Behçet's syndrome are not sterile. Ann Rheum Dis 2004;63:1450–2.[Abstract/Free Full Text]

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