Behçet's syndrome

C. G. Barnes and H. Yazici1

The Royal London Hospital, London E1 1BB, UK and
1 Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Turkey

Correspondence to: C. G. Barnes, Little Hoopern, Chagford, Devon TQ13 8BZ, UK.

It may be asked why rheumatologists have interested themselves in Behçet's syndrome (BS). The obvious answer must be that BS is a vasculitis and a common feature with which it may present is an inflammatory arthritis. Most papers on BS start with a statement that it is a multi-system inflammatory disease of uncertain aetiology, now classified as a vasculitis. It has been shown to be uncommon in western Europe and the USA, while being much more prevalent in the eastern Mediterranean countries, South East Asia and Japan in particular. Young onset (before the age of 25 yr) and males have been shown to have more severe disease [1, 2]. Although the commonest age of development is in the third decade of life, children may be affected with apparently identical features [3].

It may seem curious that there remains a debate on which terminology, Behçet's syndrome (BS) or Behçet's disease (BD), is preferable. Although these two terms are sometimes thought to be readily exchangeable they are also the subject of debate and disagreement. Some colleagues regard BD as a specific disease and should be accepted as such. To others, including the authors, the lack of a known pathogenesis or a definitive diagnostic test, and the variability in prevalence and incidence of the condition and its constituent manifestations, suggest that the terminology BS is preferable. As with many eponymous titles Behçet was not the first to describe the condition; that can probably be credited to Hippocrates in the 5th century BC , while descriptions of almost certainly the same condition were published from Europe and the Far East in the early 20th century [414].

Traditionally the manifestations of BS have been divided into major and minor (Table 1Go) based on their frequency, although that differs in different parts of the world, and not on their clinical severity. Thus, vasculitic lesions, neurological involvement and arthritis are classified as `minor'. However, vasculitis may be clinically severe or even life-threatening and arthritis occurs in ~45% of patients and may be destructive in a minority. From the list of manifestations it can be seen that patients may be referred from primary care, or may present, to about a dozen different medical or surgical specialities, so that not only is this a multi-system condition, but it also requires multi-disciplinary co-operation. Some of the distinguishing features of clinical manifestations are shown in Table 2Go. Nevertheless the most common feature is recurrent oral ulceration, major, minor or aphthous, occurring in 97–98% of patients. Therefore, although oral aphthous ulceration has been shown to occur in up to 20% of the normal Western population [15], its presence may be considered to be an essential enquiry in history taking.


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TABLE 1.  Major and minor manifestations of Behçet's syndrome (prevalence %)
 

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TABLE 2.  International criteria for the classification of Behçet's disease
 
Diagnosis has always depended on the grouping together of sufficient features in the individual patient to satisfy the physician that a secure diagnosis can be made. Various schemes have been in use over the years requiring, for example, three major features, or two major and two minor ± a positive pathergy test. However, it must be emphasized that in the absence of any specific diagnostic feature, or clinical or laboratory test, diagnosis must depend on the clinical acumen of the physician [1623]. Awareness of the existence, and a knowledge, of the condition, clinical suspicion and clinical judgement are the basis for diagnosis, although assistance may be obtained from diagnostic criteria or a diagnostic tree as has been developed in Iran [24].

International classification criteria have now been developed (Table 2Go) to ensure comparability of groups of patients entered into epidemiological, clinical, laboratory or therapeutic studies. Whether such studies are undertaken in a single research unit, or as part of a multi-centre and possibly international study, it is mandatory that the patients studied, and hence the results obtained, are comparable and acceptable [2527]. Again it is important to stress that these classification criteria are not to be used for the diagnosis of the individual patient and this follows the pattern of classification criteria for rheumatoid arthritis [28], systemic lupus erythematosus [29], ankylosing spondylitis [30] and osteoarthritis [31].

The pathergy test [32, 33] has often proved to be a problem in terms of the way in which it is performed, its specificity and its geographical variability. It is now internationally recommended that the test should be performed by insertion of a 20-gauge needle through the skin under sterile conditions, without injection of saline, and read for erythema, papule or pustule formation at 48 h.

Rheumatologically we are concerned with the presentation of joint disease and vasculitis in particular, diagnosis and the severity of the condition in terms of both morbidity and possible mortality in the individual patient [34]. However, differential diagnosis has rarely been addressed in discussions of BS. In the past BS has been grouped with the seronegative spondarthropathies but this is now recognized to be incorrect. The important features to be taken into consideration in differential diagnosis are (Table 3Go):


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TABLE 3.  Highlights of the clinical manifestations of Behçet's syndrome and differential diagnosis
 

Therefore, BS is a condition which produces distressing symptoms of, often painful, recurrent orogenital ulceration and skin lesions with an inflammatory arthritis which occasionally may be destructive, due to a vasculitis which may include potential fatal involvement of major arteries and veins and the central nervous system [36], and which may lead to blindness. Management, in the absence of knowledge of a cure of a condition of uncertain aetiology, must consist of the control of symptoms and suppression of the inflammatory vasculitis [37, 38]. Treatment may, therefore, be considered under three broad categories:

Symptomatic treatment consists of anti-inflammatory analgesics for joint involvement, there being no convincing evidence that, for example, immunosuppressives have any beneficial effect on this aspect of the condition. Orogenital ulceration may be treated with local corticosteroid preparations (e.g. adcortyl in orabase) and very rarely is severe enough to require thalidomide [39, 40]. Colchicine has been recommended as basic treatment of BS but recently it has again been confirmed in a controlled trial that it is only effective in relieving arthralgia/arthritis, erythema nodosum and orogenital ulceration, the latter mainly in females [41, 42].

Inflammatory eye disease if retinal involvement is not detected, and thus only consists of modest panuveitis, may be treated with local corticosteroid drops only. However, there is good evidence that, while cyclosporin may control acute severe uveitis, azathioprine is effective in treating established uveitis/retinitis, preventing recurrences and the development of de novo involvement of an unaffected eye, and in the preservation of vision [38, 43, 44]. At the same time high-dose corticosteroids and cyclophosphamide may be required to control acute and severe exacerbations. Alpha interferon seems to be emerging as a potentially useful drug in the treatment of the inflammatory eye disease of BS [38, 45].

Vasculitis is treated following conventional methods of using combinations of corticosteroids, orally or parenterally, with immunosuppressives. In that the thrombophlebitis of BS is not believed to embolize, anti-coagulation is not recommended and may be positively contraindicated in, for example, the presence of pulmonary artery aneurysm formation because of the fear of fatal haemorrhage.

In conclusion the treatment of the mucocutaneous and eye manifestations of BS has become much more effective in recent years but the same cannot be claimed for venous thrombosis, arterial involvement or neurological manifestations.

References

  1.  Yazici H, Yurdakul S, Tüzün Y et al. Influence of age and onset and patient's sex on the prevalence and severity of manifestations of Behçet's syndrome. Ann Rheum Dis 1984;43:783–9.[Abstract]
  2.  Yazici H, Tüzün Y, Tanman AB et al. Male patients with Behçet's syndrome have stronger pathergy reactions. Clin Exp Rheumatol 1985;3:137–41.[ISI][Medline]
  3.  Kone-Paut I, Yurdakul S, Bahabari SA et al. Clinical features of Behçet's disease in children: an international collaborative study of 86 cases. J Pediatr 1998;132:721–5.[ISI][Medline]
  4.  Adams F. The genuine works of Hippocrates, translated from the Greek. London: Sydenham Society, 1849:403–4.
  5.  Feigenbaum A. Description of Behçet's syndrome in the Hippocratic third book of endemic diseases. Br J Ophthalmol 1956;40:355–7.
  6.  Adamantiades B. Sur un cas d'iritis à hypopyon récidivant. Ann Oculist 1931;168:271–8.
  7.  Dascoupoulos N. Sur deux cas d'uveite récidivante. Ann Oculist 1932;169:387.
  8.  Gilbert W. Über die rezidivierende eitrige Iridozyklitis (I. septica) und ihre Beziehungen zur septischen Allgemeinerkrankung. Arch Augenheilkd 1920;86:29–49.
  9.  Planner H, Remenovsky F. Beitrag zur Kenntnis der ulcerationen am ausseren weiblichen Genitalien. Arch Dermatol Syph (Berlin) 1922;111:162–88.
  10. Shigeta T. Recurrent iritis with hypopyon and its pathological findings. Acta Soc Ophthalmol Jpn 1924;28:516.
  11. Whitwell GPB. Recurrent buccal and vulval ulcers with associated embolic phenomena in the skin and eye. Br J Dermatol 1934;46:414.
  12. Behçet H. Über rezidivierende Aphthose, durch ein Virus verursachte Geschwüre am Mund, am Auge und an Genitalien. Dermatol Wochenschr 1937;105:1152–7.
  13. Behçet H. Considerations sur les lesions aphtheuses de la bouche at des parties genitales, ainsi que sur les manifestations oculaires d'origine probablement virutique et observations concernant leur foyer d'infection. Arch Dermatol Syph 1937;23–4:1521–9.
  14. Behçet H. Some observations on clinical picture of the so-called triple symptom complex. Dermatologica Basel 1940;81:73–83.
  15. Sircus W, Church R, Kelleher J. Recurrent ulceration of the mouth. Q J Med 1957;26:235–49.[Medline]
  16. Mason RM, Barnes CG. Behçet's syndrome with arthritis. Ann Rheum Dis 1969;28:95–103.[ISI][Medline]
  17. Behçet's Disease Research Committee of Japan (1972)—quoted by Shimizu T. Clinicopathological studies on Behçet's disease. In: Dilsen N, Konice M, Ovul C, eds. Behçet's disease. Amsterdam: Excerpta Medica International Congress Series no. 467, 1979:9–43.
  18. Behçet's Disease Research Committee of Japan. Behçet's disease: guide to diagnosis of Behçet's disease. Jpn J Ophthalmol 1974;18:291–4.[ISI]
  19. Mizushima Y. Recent research into Behçet's disease in Japan. Int J Tissue React 1998;10:59–65.
  20. O'Duffy JD. Critères proposés pour le diagnostic de la maladie de Behçet et notes thérapeutiques. Rev Med 1974;36:2371–9.
  21. O'Duffy JD. Suggested criteria for diagnosis of Behçet's disease. J Rheumatol 1974;1(Suppl. 1):Abstr. 32:18.
  22. Chen, SP. Some special clinical manifestations of Behçet's disease—report of illustrative cases and review of literature (author's translation) (in Chinese). Chinese J Int Med 1980;19:15–22.
  23. Dilsen N, Konice M, Aral O. Our diagnostic criteria of Behçet's disease—an overview. In: Lehner T, Barnes CG, eds. Recent advances in Behçet's disease. London: Royal Society of Medicine Services: International Congress and Symposium Series 103, 1986:177–80.
  24. Davatchi F, Shahram M, Akbarian M et al. Classification tree for the diagnosis of Behçet's disease. In: Wechsler B, Godeau P, eds. Behçet's disease. Amsterdam: Excerpta Medica International Congress Series 1037, 1993:245–8.
  25. International Study Group for Behçet's Disease. Criteria for diagnosis of Behçet's disease. Lancet 1990; 335:1078–80.[ISI][Medline]
  26. International Study Group for Behçet's Disease. Evaluation of diagnostic (classification) criteria in Behçet's disease—towards internationally agreed criteria. Br J Rheumatol 1992;31:299–308.[ISI][Medline]
  27. Barnes CG. Diagnostic (classification) criteria in Behçet's syndrome. In: Hamza M, ed. Behçet's disease, Tunis: Pud Adhoua, 1997:209–11.
  28. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24.[ISI][Medline]
  29. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.[ISI][Medline]
  30. Bennet PM, Wood PHN. Recommendations–ankylosing spondylitis. In: Bennet PM, Wood PHN, eds. Population studies of the rheumatic diseases. Amsterdam: Excerpta Medica Foundation, International Congress Series 148, Ch. 64, 1966:456–7.
  31. Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K et al. Development of criteria for the classification and reporting of osteoarthritis. Arthritis Rheum 1986;29:1039–49.[ISI][Medline]
  32. Dilsen N, Koniçe M, Aral O, Gül A, Öcal L. Important implications of skin pathergy in Behçet's disease. In: Wechsler B, Godeau P, eds. Behçet's disease. Amsterdam: Excerpta Medica International Congress Series 1037, 1993:229–33.
  33. Budak-Alpdogan T, Demircay Z, Alpdogan O et al. Skin hyperreactivity of Behçet's patients (pathergy reaction) is also positive in interferon alpha treated chronic myeloid leukemia patients, indicating similarly altered neutrophil functions in both disorders. Br J Rheumatol 1998;37:1148–56.[ISI][Medline]
  34. Yazici H, Basaran G, Hamuryudan V et al. The ten-year mortality in Behçet's syndrome. Br J Rheumatol 1996;35:139–41.[ISI][Medline]
  35. Hamuryudan V, Yurdakul S, Moral F et al. Pulmonary artery aneurysms in Behçet's syndrome: a report of 24 cases. Br J Rheumatol 1994;33:48–51.[ISI][Medline]
  36. Serdaroglu P. Behçet's disease and the nervous system. J Neurol 1998;245:150–6.
  37. Yazici H, Yurdakul S, Hamuryudan V. The management of Behçet's syndrome: how are we doing? Clin Exp Rheumatol 1999;17:145–7.[ISI][Medline]
  38. Yazici H, Ozyazgan Y. Medical management of Behçet's syndrome. In: BenEzra D, ed. Uveitis update. Dev Ophthalmol 1999;3:118–31.
  39. Hamza M. Treatment of Behçet's disease with thalidomide. Clin Rheumatol 1986;5:365–71.[ISI][Medline]
  40. Hamuryudan V, Mat C, Saip S et al. Thalidomide in the treatment of mucocutaneous lesions of the Behçet syndrome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;128:443–50.[Abstract/Free Full Text]
  41. Aktulga A, Altac M, Muftuoglu A et al. A double blind study of colchicine in Behçet's disease. Haematologica 1980;65:399–402.[ISI][Medline]
  42. Yurdakul S, Mat C, Ozyazgan Y et al. A double blind study of colchicine in Behçet's syndrome. Arthritis Rheum 1998;suppl. 41:S356.
  43. Yazici H, Pazarli H, Barnes CG et al. A controlled trial of azathioprine in Behçet's syndrome. N Engl J Med 1990;322:281–5.[Abstract]
  44. Hamuryudan V, Ozyazgan Y, Hizli N et al. Azathioprine in Behçet's syndrome; effects on long term prognosis. Arthritis Rheum 1997;40:769–74.[ISI][Medline]
  45. Zouboulis CS, Orfanos CE. Treatment of Adamantiades–Behçet disease with systemic interferon alfa. Arch Dermatol 1998;134:1910–6.