Q J Med 1999; 92: 727-740
© 1999 Association of Physicians
Behçet's syndrome: a multidisciplinary approach to clinical care
From the Heartlands and Solihull NHS Trust, 1 Birmingham and Midland Eye Centre, and 2 Birmingham Dental Hospital, Birmingham, UK
Received 22 April 1999 and in revised form 16 September 1999
Dr A.J. Whallett, Department of Rheumatology, Solihull Hospital, Heartlands and Solihull NHS Trust, Lode Lane, Solihull, West Midlands B91 2JL
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Summary |
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 Top Summary IntroductionMethodsResultsDiscussionAppendix IAppendix IIAppendix IIIReferences |
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Behçet's syndrome is a multisystem disorder characterized by recurrent orogenital ulceration and an occlusive vasculitis. Histologically, there is a combination of a perivascular lymphocytic infiltration with endothelial cell damage coupled with a pro-thrombotic tendency. We present a multidisciplinary approach to the management of Behçet's syndrome, and compare our findings with other published studies. Over a nine-year period, 50 patients with Behçet's syndrome were followed in a multidisciplinary combined clinic. Patients were assessed by an ophthalmologist, a rheumatologist and a specialist in oral medicine. Data on disease activity and damage were collected using a standardized proforma for each speciality. Mean age of onset was 30 years; 56% were male. Recurrent oral ulceration was the commonest manifestation and the presenting feature in 76%. The commonest second systems involved were genital mucosae and eyes. We found a larger proportion of patients with ophthalmic (80%) and central nervous system (14%) manifestations compared with many other studies. There was an association between central nervous system and thrombotic events (p<0.001). Our multidisciplinary approach allowed us to keep each system involved in Behçet's syndrome under careful review. The development of recurrent sight-threatening eye disease was unpredictable and occurred despite aggressive immunosuppression.
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Introduction |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix IAppendix IIAppendix IIIReferences |
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The hallmark of Behçet's syndrome is orogenital ulceration. Nevertheless, this condition can severely affect other organ systems, often unpredictably. Behçet's syndrome is distributed world-wide, although most cases are reported from Japan, the Middle East and the Mediterranean. There is no universally accepted diagnostic test for the syndrome, and a variety of criteria have been proposed from different parts of the world.1–5 Before 1990, there were five sets of diagnostic criteria in common world-wide use. In the UK, the Mason and Barnes Criteria of 19691 were widely accepted and are still commonly used. In 1990, the International Study Group (ISG) for Behçet's Disease studied data on 914 patients from seven countries from which the International Criteria were derived.6 Many feel that these criteria still do not satisfactorily classify the syndrome.
We set out to determine the natural history of Behçet's syndrome as it affects our cohort of patients. We have adopted a multidisciplinary approach to the management of patients with Behçet's syndrome which has allowed us to do this. Our clinic was established in 1990 and patients are seen as tertiary referrals. The referring physician, ophthalmologist or general practitioner has usually established the diagnosis of Behçet's syndrome. Some patients are referred with a diagnosis of `possible' Behçet's syndrome and the definitive diagnosis is made in the clinic. At each visit to the clinic, patients are assessed by a rheumatologist, an ophthalmologist and a specialist in oral medicine. Each patient is usually seen at least annually. Clinics are held four times a year. Advice on therapy depending upon clinical findings is forwarded to the referring clinician. Patients with active eye disease are an exception, as they are then directed into our `sister' uveitis clinic.
We have studied the clinical characteristics of patients in Birmingham diagnosed with Behçet's syndrome. We compared the pattern of disease characteristics and the pattern of disease progression with studies from other countries and assessed the treatment received by our group of patients.
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Methods |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix IAppendix IIAppendix IIIReferences |
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A group of 50 consecutive patients referred to our Behçet's syndrome clinic over a 9-year period (1990–98 inclusive) was identified. Of this group, 36 satisfied the ISG criteria. Of the remaining 14, 11 satisfied the Mason and Barnes criteria.
Within the group of 50 patients, there were three patients who satisfied neither of these two criteria sets. Two of these patients had severe eye disease and one other feature. Of these two, one had recurrent oral ulcers; the other had skin lesions (vasculitis, pustules and subcutaneous nodules). The remaining patient had pathergy and recurrent genital ulcers. These patients were included in the study for analysis. For the purpose of this study, the onset of the disease in these patients was taken as the date of occurrence of the second system involved. The date of syndrome onset in all the other patients was defined as the time at which the ISG or Mason and Barnes criteria were fulfilled.
General disease data were collected on standard activity forms at each visit by the rheumatologist (Appendix I, see reference 7 for discussion of validation). These activity forms gather data on symptoms over the previous 4 weeks only. Fatigue, headache, orogenital ulceration, skin, joint and gastrointestinal features were noted. Nervous system and vessel thrombosis activity were also recorded. The treatment and overall patient and doctor's perception of disease activity were noted. On each visit, disease damage was recorded separately to the form. On the initial visit to the clinic, patients were interviewed at length, and old case notes were reviewed to obtain this information.
The ophthalmologist completed an activity and damage form based on clinical findings (Appendix II) at each visit (validation paper currently submitted by T. James, see Acknowledgements). Visual acuities for distance and near were recorded. Eye disease was assessed in terms of the degree of activity of anterior and/or posterior uveitis, presence of venous occlusion or retinal haemorrhages, presence of macular oedema and retinal infiltrates. Established damage, such as vascular occlusion, macular damage and optic atrophy was noted. Current status of the eyes were scored as having no eye involvement, non-sight-threatening eye involvement, sight-threatening eye disease in one or both eyes, and blindness in one or both eyes.
The specialist in oral medicine completed an activity form based on the previous 4 weeks' oral ulceration and current clinical findings (Appendix III). Each form was used to gather information on the site, number, size, and duration of ulcers. Whether oral ulceration activity occurs with activity of other features of the syndrome was recorded. Smoking history was also noted. The appearance of the ulcers was noted (either major or minor aphthous ulcers or herpetiform ulcers). These different ulcer types are described in reference 8.
We have performed a retrospective analysis of all these data to determine which systems are often involved together in the syndrome. Statistical analysis was achieved by means of a 
2 test with Yates' correction to look for these associations.
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Results |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix IAppendix IIAppendix IIIReferences |
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The mean age of the onset of the first symptom in the group was 30 years, with a range of 16–55 years. The group was 56% male. Recurrent oral ulceration was the most common manifestation of the syndrome, being reported in 46 patients (92%) of the group. Genitourinary ulcers were found in 41 patients (82%), eye problems in 40 (80%), skin lesions in 34 (68%) and arthralgia or arthritis in 31 (62%).
Recurrent oral ulceration
This was both the most prevalent manifestation of Behçet's syndrome and the most frequent initial presenting sign in our patients. The appearance of the ulcers could not be distinguished macroscopically from the aphthous ulceration that affects the general population. In our group, 79% of patients had minor aphthous ulceration, 10% of patients had major aphthae and the remainder could not be definitely classified. No patients were observed to have, nor gave a positive history of, herpetiform ulceration. There was no gender predisposition for recurrent oral ulceration. A total of 52% of patients had a history of recurrent oral ulceration since childhood. In 24% of patients, recurrent oral ulceration did not commence until after the age of 30 years. Of Behçet's patients with recurrent oral ulceration 18/46 (39%) were cigarette smokers.
Skin lesions
A wide variety of skin lesions were found, with some patients having more than one. Twenty patients had a history of pustules, six subcutaneous nodules, four erythema nodosum, two thrombophlebitis, and seven had other forms of cutaneous vasculitis. Only three patients (6%) had a history of a positive pathergy. It was sometimes difficult to determine whether pustules were related to disease activity or the use of corticosteroids.
Ocular disease
Our experience with monitoring all patients in the multidisciplinary clinic for eye involvement has shown that inflammatory disease activity in the eyes was always symptomatic. This is unlike the uveitis found in patients who do not have Behçet's syndrome. If a patient denied ocular symptoms, slit-lamp examination was normal. Nevertheless, previous ocular activity can lead to asymptomatic progression of eye disease such as retinal neovascularization and secondary glaucoma.
Of the 40 patients with a history of ocular involvement, 26 (65%) had non-sight-threatening eye disease alone. This was due to anterior uveitis (8 patients), inactive panuveitis and retinal vasculitis (12 patients), posterior uveitis alone (2 patients), episcleritis (3 patients) and branch retinal vein occlusion (1 patient).
Altogether, seven of the 40 patients with eye involvement (17.5%) had active sight-threatening eye disease. Five of these had unilateral disease due to cystoid macular oedema (3 patients), cataract (1 patient) and active optic disc neovascularization (1 patient). Two patients had bilateral sight-threatening disease: one due to active panuveitis and the other due to active panuveitis in one eye and a superotemporal branch retinal vein occlusion in the other.
A total of seven patients (14%) were blind in one eye. This was due to established damage from retinal vein occlusion (4 patients), optic atrophy secondary to retinal vasculitis (2 patients) and macular scarring (1 patient). These features were evidently the end stage of unsuccessfully-treated, or previously-untreated, sight-threatening eye disease.
Vascular occlusion
The occurrence of peripheral venous occlusion (i.e. in limbs only) was identified in six (12%) of the 50 patients. Central venous occlusion occurred in five patients (10%). The latter included one case of cavernous sinus thrombosis and one of Budd-Chiari syndrome. There was one case of central arterial thrombosis: a left cerebral hemisphere infarct in a 26-year-old man.
Central nervous system involvement
Seven patients (14%) had a history of central nervous system lesions not related to thromboembolic cerebrovascular events. Three patients had cranial nerve involvement with no other CNS feature. There was one patient with an upper and one with a lower facial nerve palsy, and one other who had a history of transient diplopia. Two patients had had an aseptic meningitis and one had cerebral hemisphere involvement (seizures). One other patient had cranial nerve (upper facial nerve and diplopia) and vasculitic cerebral hemisphere involvement (causing a hemiparesis). There was a significant association with central nervous system involvement and peripheral/central venous occlusion (p<0.001). Four patients had suffered both, usually within the same 12-month period (3 cases). One patient had a thrombosis 6 years following the central nervous system event.
Other features
Gastrointestinal and joint involvement were both highly prevalent in our group, being found in 19 (38%) and 31 (62%) patients, respectively. Of patients with joint problems, the most common pattern (12/31) was of large-joint involvement (knee, ankle, shoulder or elbow joints). A total of 7/31 had peripheral (hands and feet) and 5/31 spinal problems. The remainder had polyarthralgia affecting many different sites. Joint problems tended to be pain and swelling rather than joint destruction. Of patients with gastrointestinal problems, 8/19 had upper (oesophageal and stomach) problems only and 3/19 lower gastrointestinal problems only. A further eight had a combination of upper and lower gastrointestinal complaints.
Timing of, and associations between, different system involvement
We assessed the time interval between the onset of the first and second system to be involved in the group of patients (Figure 1
). The first complaint was oral ulceration in 38/50 (76%) of cases. The mean period between first and second system involvement was 6 years (range 0–26 years). The area that most commonly became involved second was genital mucosae, followed by the eyes.
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Although an association between ocular and CNS problems failed to reach statistical significance, all seven patients with CNS problems had eye involvement. In five, the systems became involved within 2 years of each other. One patient's eye disease occurred 7 years after the CNS event. Another patient had CNS involvement develop 6 years after the eyes became involved.
Ocular manifestations were not associated with thromboembolic events, oral or genital ulceration, skin lesions, joint or gastrointestinal lesions. Male gender and young age (<25 years at disease onset) were also not predictive of eye problems in our patients.
Twenty-four patients (48%) had both orogenital ulceration and uveitis (either anterior, posterior or panuveitis). We found that often these two conditions developed within 2 years of each other (16/24 cases) (Figure 2). Nevertheless, five patients developed eye problems >2 years after the onset of orogenital ulceration, and three developed orogenital ulceration >2 years after the onset of uveitis.
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Treatments
There was a wide range of different treatments prescribed for our patient group (Figure 3
). The purpose of our multidisciplinary clinic is to advise on treatment rather than to direct it per se. The management of uveitis, however, is directed to our sister uveitis clinic. The most common treatment was oral prednisolone at a dose of at least 15 mg daily (20 patients, 40%). Thirty-five patients (70%) received systemic corticosteroids at some stage, and four patients had received intravenous methylprednisolone with cyclophosphamide. Cyclosporin A was used in 10 patients (20%). Patients had also received a variety of other `steroid-sparing agents', often as treatment for a presumed seronegative inflammatory arthropathy (such as gold, methotrexate or sulphasalazine) before the diagnosis of Behçet's syndrome had been made. Azathioprine was used in seven patients. Thalidomide and colchicine were used in three and four patients, respectively.
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Systemic immunosuppressive therapy was used in all patients with sight-threatening eye disease. Flare-ups of ocular disease occurred in 83% of these patients despite maintenance doses of oral prednisolone ranging from 2.5 to 35 mg/day. Cyclosporin A was the most commonly used second immunosuppressant in this group. Nevertheless, recurrent disease occurred in 50% of these patients despite doses of 150–500 mg/day. Methotrexate was used in 16% of these patients, but flare-ups occurred at doses of 7.5 to 15mg per week. Other agents used were cyclophosphamide and mycophenolate. Pulsed regimes of either oral or intravenous corticosteroids with oral cyclophosphamide were used in resistant cases. Other treatment modalities included orbital floor and intramuscular corticosteroid injections for recurrent cystoid macular oedema.
The prevalences of different system involvements compared to those in other studies are shown in Figure 4.
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Discussion |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix IAppendix IIAppendix IIIReferences |
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Behçet's syndrome is a multisystem disorder with a wide range of serious clinical manifestations, often over a prolonged period of time. Our clinic was established to provide an integrated multidisciplinary approach to the assessment of the syndrome. Any advice on treatment, except for the eyes, is passed on to the original referring doctor at each visit. This allows the referring doctor, regardless of discipline (e.g. rheumatologist, ophthalmologist or general practitioner) to remain primarily responsible for the patient whilst having the benefit of advice from a range of specialities. We have been able to assess patients and gather longitudinal data both on the activity of the syndrome and damage that accrues over a period of time in different organ systems.
The diagnosis of Behçet's syndrome can be difficult to establish. Although the sets of classification criteria are helpful for research, making a diagnosis remains a clinical decision. The ISG criteria require the presence of oral ulceration for the diagnosis. Nevertheless, it is recognized that 2–3% of patients with Behçet's syndrome do not have this feature.6 Therefore, we felt justified in including the four patients without oral ulceration in our study.
There was no gender predisposition for recurrent oral ulceration. In the general population, simple aphthous oral ulceration usually starts in childhood or adolescence and affects around 20% of the population. A larger proportion (52%) had suffered with recurrent oral ulceration since childhood in the study group, as might be expected. In a further 24% of patients in the study, recurrent oral ulceration did not commence until after 30 years of age, which would be unusual for simple recurrent oral ulceration. Cigarette smoking appears to protect against the development of recurrent oral ulceration in the general population (it affects 22% of non-smokers and 13.6% of smokers 9). This is perhaps secondary to an increased keratinization of the oral mucosa. In Behçet's patients with recurrent oral ulceration, 39% of were cigarette smokers, a larger proportion than is found in smokers with recurrent oral ulceration in the general population.
A prevalence of pathergy of up to 80% has been noted in Turkey and 98% in Israel, but is much less commonly found in Europeans.10–12 Pathergy was not tested formally in our clinic but only three patients (6%) reported sterile pustules on injury or venepuncture. We feel the test is of limited use in our population and the importance of pathergy is exaggerated by its inclusion in the ISG criteria.
There is a considerable variation in the pattern of system involvement in Behçet's syndrome world-wide (Figure 4
). In our study, we found a larger proportion of patients with CNS manifestations than in other parts of the world. This was also noted in other British studies.13,14 Gastrointestinal and joint involvement were also more common in our patient group than in other parts of the world. Both of these systems have previously been thought to be more prevalent in Britain and the US.15 Folliculitis is thought to be more common in the eastern countries. We found 40% of our patients had pustules, the most frequent skin manifestation in our group.
Ocular involvement is an important cause of morbidity in Behçet's syndrome. After 4 years of eye disease, a severe reduction of visual acuity has been reported in between 50 and 85% of patients (reviewed in reference 17). In a study of patients from Yorkshire of 32 cases, 25% had eye involvement.13 Four patients had recurrent conjunctivitis and four had recurrent iridocyclitis. In another British study, 10/22 patients (45%) had eye problems.14 We found a higher prevalence of ocular problems in our population than in many other studies (80%) and recognize there may be some selection bias, as our clinic is held at an Eye Hospital. Of the patients with eye disease, 35% had either sight-threatening eye disease or were blind in one eye. The development of recurrent sight-threatening eye disease was unpredictable and occurred despite aggressive immunosuppression. This highlights the variability in Behçet's syndrome, and the difficulty in adequately treating severe eye disease.15
We have found that all patients with central nervous system manifestations had eye involvement. Ocular events were not associated with young age at onset, gender, genital ulceration, skin, thromboembolism or gastrointestinal involvement. This contrasts with studies from Japan and Turkey, where young males had a poor outcomes for eye disease.20,21 Both studies found that CNS involvement predicted eye disease. We suggest these patients must be warned that any eye symptoms should be looked into immediately by an ophthalmologist.
It has been claimed that eye involvement, if it occurs, is an early feature of Behçet's syndrome.22 Nevertheless, five of our 24 patients with uveitis and orogenital ulceration (21% of this subgroup) developed the uveitis after >2 years following the onset of orogenital ulceration. In one patient, this delay was 13 years.
We routinely screen all patients with Behçet's syndrome initially and follow-up those in whom the eyes have been affected. Nevertheless, inflammatory eye symptoms were always symptomatic in our population. Therefore, we cannot recommend further ophthalmological monitoring of patients with no eye problems at initial screening. Nevertheless, these patients must be aware that they should report any ocular problems to their doctor immediately. Potentially serious eye symptoms include any visual loss, a red eye, photophobia or `floaters'.
There are few controlled trials in the treatment of Behçet's syndrome. A wide range of treatments were used in our patients. The most common therapy was oral prednisolone, in 35/50 patients (70%). Oral corticosteroids with cyclosporin was the most common combination used in the treatment of uveitis. Cyclosporin is thought to be an effective and rapidly acting drug for this complication.23,24 Azathioprine was used in seven (14%) of our group. There is some evidence for its use in preventing new eye disease and maintaining visual acuity.25 Treatment response is determined in patients with Behçet's syndrome on clinical grounds only. Unfortunately, there is no specific blood test to monitor the activity of the disease.
In our patient group, the drugs thalidomide and colchicine were rarely used. This is in contrast to the Middle East, where colchicine is more commonly used. Nevertheless, colchicine has only been demonstrated to affect erythema nodosum and arthralgia in double-blind trials.26
There are regional differences in the way in which Behçet's syndrome manifests. This may represent selection bias in the populations studied or may be a real difference. This study illustrates the limitations of strictly following the ISG classification criteria in the clinical setting.
The use of a multidisciplinary approach to the management of the condition allows us to detect involvement of different organ systems. In a syndrome that can affect all organs of the body and can have a serious prognosis, many specialties of medicine may be involved in the care of these patients often based in different hospitals. By using our approach, an integrated package of management can be formulated more easily. We feel that the centralization of the management is sensible in terms of quality of care and is also much more convenient for the patient. This is particularly the case in a relatively rare disease such as Behçet's syndrome which can have such protean manifestations. We have demonstrated the need for patient `ophthalmological awareness' due to a significant incidence of `late onset' eye disease.
Further assessment of our patient group may allow us to detect early predictors of more aggressive disease in the future. This could highlight a subgroup who require more intensive treatment. We recognize that further randomized controlled trials are required to determine those treatments that are most effective for disease control in different organ systems.
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Appendix I |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix IAppendix IIAppendix IIIReferences |
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Appendix II |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix IAppendix IIAppendix IIIReferences |
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Appendix III |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix IAppendix IIAppendix IIIReferences |
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Acknowledgments |
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We thank Mr Teifi James for allowing us to use the Behçet's syndrome eye disease activity and damage form he has developed. The validation paper has currently been submitted to the British Journal of Ophthalmology.
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References |
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TopSummaryIntroductionMethodsResultsDiscussionAppendix IAppendix IIAppendix IIIReferences |
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Chamberlain MA. Behçet's syndrome in 32 patients in Yorkshire. Ann Rheum Dis 1977; 36:491–9.
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15. O'Neill T, Rigby AS, McHugh S, et al. Regional differences in clinical manifestation of Behçet's disease. In: Wechsler B, Godean P, eds. Behçet's Disease, Excerpta Medica International congress series 1037. Amsterdam, Elsevier Science, 1993:159–63.
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