Behçet’s Disease

Robert B. Nussenblatt

Key concepts

•This is a multisystem disease, with the posterior ocular complications potentially being devastating.

•The posterior pole disease should not be treated with corticosteroid alone.

•Newer approaches, such as IFN therapy and biologics such as infliximab, have been suggested as  

being effective for the ocular manifestations, but randomized studies still need to be done.

Retinal vascular involvement is a common finding in many patients with posterior and intermediate uveitis. Behçet’s disease may be the best example of a disorder characterized mainly by its retinal vascular involvement, often with devastating effects on the patient’s eyesight.

Behçet’s disease is a multisystem disorder named after the Turkish dermatologist, Hulusi Behçet (1889–1948),1 who in 1937 recognized and reported a triad of symptoms: recurrent intraocular inflammatory episodes with oral and mucosal ulcerations. These observations were based on three patients, two of whom had ocular symptoms atypical of the disorder we recognize today. It should be noted that in the 20th century at least two other clinicians reported cases with similar findings earlier than did Behçet: Adamantiades in 1931 (publishing in the French literature)2 and Shigeta from Japan in 1924.3 However, their reports did not stimulate the universal interest that Behçet’s did. The disease was known in ancient times, with Hippocrates probably being the first to describe an association between ocular inflammation and oral and genital lesions.4 Familial occurrence is seen in 8–18% of Turkish patients with the disease, 15% of Koreans, and 13% of Jews, but much less in a Chinese population (2.6%).5,6 In a more recent study reviewing 761 patients in Turkey, almost 57% of patients with an identifiable diagnosis had Behçet’s disease, with 10.4% being juvenile onset.7 The prevalence has been calculated to be 80–370/100 000.6 It is interesting to note that the frequency of the disease is 18 times less in Turks living in Germany than in those in Anatolia. In one center in the United States Behçet’s disease constituted 2.5% of uveitis referrals.8 One report from Iran9 put at 8.6% the number of patients seen in a uveitis clinic in Teheran having Behçet’s disease, with more cases of ocular toxoplasmosis being seen. The complete form of Behçet’s disease is rare in Northern Italy, with a prevalence calculated at 3.8/100 000 (incidence of 0.24/100 000).10 The disease has been noted to be

especially common in the Far East and in the Mediterranean basin, and is very frequently noted between 30° and 45° north latitude in Asian and European populations.11 This corresponds to the old Silk Route used for centuries by traders making the dangerous passage from the East to the West (Fig. 26-1). It appears that the disease is changing in character, severity and prevalence. About 40 years ago Japan appeared to have the greatest frequency of this disorder,12 with an overall prevalence of 70–85 cases/1 000 000 population, as calculated in the late 1970s.13 In the early 1990s it was estimated that the total number of patients with this disease in Japan was 16 570, with a prevalence of 135 cases/1 000 000 population.14 However, the northern portions of Japan have a higher incidence than do the southern areas. Of the estimated 15 000 patients in Japan with Behçet’s disease in 1986, 11 000 were under treatment.15 This diagnosis was applied to more than 20% of the patients with uveitis seen in the uveitis clinic of the University of Tokyo’s Department of Ophthalmology from 1965 through 1977.13 Other studies have suggested a lower prevalence of 13.5–20/100 000 in Japan and Korea.6

This disorder may have devastating consequences for the eyes, and has therefore attracted a great deal of attention. Insight into its mechanisms has led to an improvement in our treatment of this disorder.

Clinical manifestations

The diagnosis of Behçet’s disease is based firmly on the presence of a constellation of clinical findings. Therefore, clinical criteria have been established that help the clinician decide whether a patient has the disease. Numerous sets of clinical criteria have been proposed for the diagnosis of Behçet’s disease.16,17 For our service we have adapted the criteria established by the Behçet’s Disease Research Committee of Japan (Box 26-1). As can be seen, these criteria add an additional major finding to the original three: skin lesions. Further, the presence of ocular inflammatory disease is given greater weight in the diagnosis. It should also be noted that the minor criteria are not considered in this grading system. The Behçet’s Disease Research Committee of Japan recognizes three special cases: intestinal Behçet’s, vasculo-Behçet’s, and neuro-Behçet’s (essentially the minor criteria). It has also specifically included three laboratory tests: a pathergy test (a skin-prick test), HLA testing for HLA-B51, and screening for nonspecific factors indicative of immune system activation, such as an elevated erythrocyte sedimentation rate, positive results for C-reactive protein, and an increase in the number of peripheral blood leukocytes.

Box 26-1  Criteria for diagnosis of Behçet’s disease

MAJOR CRITERIA

Recurrent aphthous ulcers of oral mucosa Skin lesions

Erythema nodosum, acne, cutaneous hypersensitivity thrombophlebitis

Genital ulcers

Ocular inflammatory disease Recurrent anterior and posterior

MINOR CRITERIA

Arthritis Intestinal ulcers Epididymitis Vascular disease

Obliteration, occlusion, aneurysm Neuropsychiatric symptoms

Complete type

Four major symptoms simultaneously or at different times

Incomplete type

Three major symptoms simultaneously or at different times or

Typical recurrent ocular disease with one other major criterion

Suspect type

Two major symptoms, excluding ocular Possible type

One main symptom

Modified from Behçet’s Disease Research Committee: Clinical research section recommendations, Jpn J Ophthalmol 1974; 18: 291–294.

Country with high incidence of Behçet's disease

Figure 26-1.  Map of a broad band through Asia and Europe where Behçet’s disease is common. This coincides with the old Silk Route. (Courtesy of S. Ohno, MD.)

Another system that the reader should be familiar with is the one suggested by the International Study Group for Behçet’s Disease,18,19 which requires the presence of oral aphthous ulcers for the diagnosis in all patients (Box 26-2). These investigators emphasize the importance of oral aphthous ulcers as a sign of this disease on the basis of data collection from a large number of patients and control subjects, in which they found that 97% of patients with Behçet’s disease had oral aphthae.19

Other systems have used the minor criteria by equating two of those to one major criterion. Others have tried to

Clinical manifestations

Box 26-2  Diagnostic criteria of international study

group for Behçet’s disease

RECURRENT ORAL ULCERATION

Minor or major aphthous lesions or herpetiform-like lesions need to have been observed by the physician or patient at least three times within a 12-month period.

PRESENCE OF TWO OTHER CRITERIA

Recurrent genital ulceration

Observation by the physician or patient of the aphthous ulceration or scar is required.

Eye lesions

The ocular disease can include anterior and/or posterior uveitis, cells in the vitreous, or the presence of a retinal vasculitis.

Skin lesions

These changes, noted by the physician or patient, include erythema nodosum, pseudofolliculitis, and papulopustular lesions. In addition, lesions would include an acneiform nodule in postadolescent patients not receiving corticosteroid therapy.

Positive pathergy test result

Read by physician at 24–48 hours.

Modified from International Study Group for Behçet’s Disease: Criteria for diagnosis of Behçet’s disease, Lancet 1990; 335: 1078–1080.

introduce a standardized scoring system for all parts of the disease.20 There is no question that some degree of uncertainty is built into any system, because the various criteria may manifest at different times during the clinical course. Until we have a better way to diagnose this disease, we have favored a strict adherence to the Japanese criteria, as the patients in whom we have diagnosed Behçet’s disease have fairly homogeneous clinical findings.

In a 1991 survey of 3316 patients with Behçet’s disease in Japan, oral aphtha was the most frequently seen major criterion, occurring in 97.7%.21 Other commonly seen problems were skin lesions (90.4%), with genital ulcers and ocular attacks having a similar incidence (79.8% and 78.6%, respectively)13 (Table 26-1). Oral aphthae are by far the most common major criterion at presentation13 (Table 26-2). After the oral aphthae, the order of appearance of the major criteria is skin lesions, ocular symptoms (25.4% in males), genital ulceration in males, and ocular lesions in females (8.6%). Of the minor criteria the most frequently seen in Japan was arthritis (see Table 26-1). The ratio of males to females with this disease in Japan was 1.2 : 1 in 1972, whereas in 1981 it had changed to 0.77 : 1.15 A study involving 25 eye centers and 14 countries identified 1465 patients with ocular lesions. In those patients 94.5% had oral ulcers, with skin lesions and genital ulcers found in over 60%. Differences over 20 years have been noted in the various aspects of the disease and their presence in men and women (Table 26-3). In Israel, Krause and colleagues22 evaluated 100 patients with Behçet’s disease, 66 of whom were Jewish (with origins from Iran, Turkey, and North Africa) and 34 of whom were Arab. The expression of the disease seemed to be the same, but the patients of Arab ethnicity appeared to have more serious eye disease. In Turkey, however, the male-to-female ratio is 3.3 : 1.15 More males have the complete form of the disease than do females. Although it is a disease with onset during early adulthood, childhood onset

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Table 26-1  Percentage of patients manifesting criteria for Behçet’s disease*. (Data from Mishima S, Masuda K, Izawa Y et al. Behçet disease in Japan: ophthalmologic aspects. Trans Am Ophthalmol Soc 1979; 76: 225–229.)

*At least 1700 patients were analyzed for each criterion.

Table 26-2  Incidence (%) of major criteria as initial manifestation

*Data from Mishima S, Masuda K, Izawa Y et al.: Behçet disease in Japan: ophthalmologic aspects, Trans Am Ophthalmol Soc 1979; 76: 225–229.

†Data from Chajek T, Fairanu M: Behçet’s disease: report of 41 cases and a review of the literature, Medicine (Baltimore) 1975; 54: 179–196.

has been reported to occur in rare cases.23,24 Laghmari and associates25 studied 13 patients with childhood Behçet’s disease and found that familial Behçet’s disease as well as articular and digestive manifestations were more commonly seen in younger children, whereas neurologic and vascular involvement, including panuveitis, seemed to occur more frequently in the older children. Ando and colleagues26 compared patients seen in a Tokyo eye clinic from 1974 to 1983 with those seen from 1984 to 1993. The number of women presenting with the disease increased to about one-quarter of the patients. Initially 70% of patients manifested ocular symptoms (in the third and fourth decades), and by 1993 almost two-thirds of the patients seen had the incomplete form of the disease. What was striking was the observation that the patients seen between 1984 and 1993 had a much better visual course, ascribed by the authors to better therapy (see below). In one study of 520 patients with Behçet’s disease in North Africa,27 83% were male and patients had a mean age of 20 years, which is very young based on our experience. Eighty percent of the patients had ophthalmic involvement, with one-quarter being blind because of their

Table 26-3  Epidemiologic changes in Behçet’s disease in Japan from 1972 to1991. (Reproduced with permission from Nakae K, Masaki F, Hashimoto T et al. Recent epidemiological features of Behcet’s disease in Japan. in Godeau P, Wechster B, Behcet’s disease. Copyright 1993 Elsevier.)

disease. Being male, presenting initially with poor visual acuity to the eye clinic, and posterior or panuveitis were all associated with a poor visual outcome.28,29 Being female and having the disease at a young age were associated with nonrecurrence of ocular inolvement.30

The majority of our patients with Behçet’s disease are male. We recently reviewed 120 Behçet’s disease patients seen at the National Eye Institute31 and compared those we have seen over several decades (late 1960s to the early 2000s). Over the three decades the majority (68%) were Caucasian, and the median age at diagnosis was remarkably similar over the three decades (Table 26-4); 95% of the patients had bilateral disease. All the patients presented with oral ulcers, with genital and skin lesions being next most common. Over the three decades 8–22% of patients had central nervous system disease (Table 26-5). The reader can compare these extraocular findings with the frequency of clinical findings and onset of manifestations reported in 661 Turkish patients (Table 26-6).32 Table 26-7 compares the therapies used over the three decades. We have seen a marked improvment in the initial visual acuity in those patients treated in the 1990s and 2000s as compared to earlier groups. The mean inflammation score decreased as well.

Barra and colleagues33 from Brazil reviewed 49 patients with Behçet’s disease, representing 2% of the total number of patients with uveitis they saw over a 16-year period. Of their patients 71% were male, and more than three-quarters of all patients were white; in 34.5% the ocular attack was the first symptom of their disease, whereas on the whole it took a little more than 3 years for the ocular symptoms to appear after the first manifestation of disease. In a review of 31

Table 26-4  Comparison of demographic characteristics and follow-up duration of patients with ocular Behçet’s disease. (Reproduced with permission from Kump et al. Behcet’s disease: Comparing 3 decades of treatment response at the National Eye Institute. Can J Opthalmol 2008;43:468.)

Table 26-5  Comparison of extraocular manifestations of Behçet’s disease over three decades*. (Reproduced with permission from Kump et al. Behcet’s disease: Comparing 3 decades of treatment response at the National Eye Institute. Can J Opthalmol 2008;43:468.)

*No significant difference among decades, Fisher’s exact test.

French patients, an ocular manifestation was the first symptom in 29%.34

How similar is the presentation of the ocular complications of Behçet’s disease in various parts of the world? It would appear that there are more similarities than differences. Muhaya and colleagues35 compared 19 patients with

Clinical manifestations

TABLE 26-6  The frequency of clinical findings and onset manifestations. (Reproduced with permission from Alpsoy et al. Clinical features and natural course of Behcet’s disease in 661 cases: a multicentre study. British Journal of Dermatology 2007;157:901.)

the disease seen at Moorfields Hospital in London with 35 patients seen at the Kurume University Eye Clinic in southern Japan over the same period. The Japanese patients were older (43 years) than those seen in London (35 years). No significant differences were noted in extraocular findings. More of the Japanese patients had acute uveitis and posterior pole disease and received treatment with topical steroids. Those in London were more often treated with systemic steroids.

Oral aphthous ulcers

An almost universal finding in Behçet’s disease is the amount of discomfort the oral lesions can cause. The number of patients with oral aphthae in the general population is quite high. However, in our experience the lesions in patients with Behçet’s disease can occur in clusters and may be found not only on the gums but also on the lips, posterior pharynx, uvula, palate, and tongue. They can be small but painful, and they recur (Fig. 26-2). They usually heal in 7–10 days without scarring, but scarring occurs when a particularly large ulcer heals. It has been suggested that in contrast to the regular flat borders of the aphthae seen in this disorder, the lesions in the Stevens–Johnson syndrome tend to be irregular, whereas in

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