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Behçet’s syndrome 

Behçet’s syndrome
Chapter:
Behçet’s syndrome
Author(s):

Hasan Yazici

, Sebahattin Yurdakul

, and Izzet Fresko

DOI:
10.1093/med/9780199204854.003.191105_update_002

Update:

Aetiology—description of new susceptibility loci.

Updated on 27 February 2014. The previous version of this content can be found here.
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Essentials

Behçet’s syndrome is an inflammatory disorder of unknown aetiology that involves arteries and veins of all sizes. Most cases are from the countries around the Mediterranean basin, the Middle East and east Asia, with the highest prevalence in Turkey.

Clinical features—the disease typically presents in the second and third decades with recurrent oral ulcers (98% of cases), genital ulcers (85%), acneiform lesions (85%), pathergy reaction (60% in some countries), erythema nodosum (50%), uveitis (50%), arthritis (50%), thrombophlebitis (30%), and less commonly with arterial occlusion/aneurysm, central nervous system involvement or gastrointestinal lesions. A relapsing/remitting course is usual. Disease is more severe and mortality is higher in men. The diagnosis is clinical, laboratory findings are nonspecific and there is no specific diagnostic test for Behçet’s syndrome.

Management and prognosis—elderly people, and women with mild mucocutaneous lesions, can be managed symptomatically. Young people and men need a more aggressive treatment approach, typically as follows (1) mucocutaneous lesions—can be helped by colchicine, thalidomide, and local ointments (i.e. corticosteroids); (2) acute severe eye involvement—ciclosporin with or without steroids, an anti-TNF agent, or solo interferon is the first agent to use, often replaced by azathioprine to maintain remission; (3) thrombophlebitis—typically managed with aspirin and azathioprine; (4) severe vascular disease—cyclophosphamide and steroids is the preferred treatment; (5) parenchymal central nervous system disease—management remains problematic: steroids, immunosuppressives, interferon-α‎, and tumour necrosis factor α‎ antagonists have all been tried. Major vessel disease and neurological involvement are the main causes of death. About 10–15% of male patients who have eye disease lose useful vision despite treatment.

Introduction

Hulusi Behçet, a Turkish dermatologist working in Istanbul, described three patients with oral and genital ulceration and uveitis with hypopyon in 1937; it soon became apparent that many other organ systems were involved and that the condition was a widespread vasculitis.

Aetiology, genetics, pathogenesis, and pathology

Behçet’s syndromeBehçet’s syndrome is an inflammatory disorder of unknown aetiology. HLA B51 is the genetic marker which had consistently been shown to be associated with the condition. This is now confirmed in several whole-genome studies. However, non-HLA loci may also be operative, such as IL-10, IL-23R IL-12RB2, CCR1, STAT4 and KLRC4. An interaction between ERAP1 and HLA-B51 has also been suggested.

Behçet’s syndromeBoth the adaptive and innate immune systems are activated in Behcet’s syndrome. The evidence for the former is the Th1 predominant cytokine profile, a Th1 type tissue infiltration in cutaneous and intestinal tissues, and elevated IL-17 levels; the evidence for the latter is the primed state of neutrophils and the presence of polyclonal γδ‎ T cells in the sera. The absence of classical autoimmune features such as specific antibodies and the intermittent nature of the clinical findings have led some to include Behçet’s syndrome among the autoinflammatory syndromes. However, this generalization is certainly not true when one considers the monogenic auto-inflammatory disorders (see Chapter 12.12.2), but can be more justified when one compares Crohn’s disease with patients with Behçet’s syndrome with mainly intestinal inflammation.

In considering the pathogenesis of Behçet’s syndrome it might prove useful to consider particular variants of disease expression. One notable cluster of patients is those with acne and arthritis; another is those with superficial and deep vein thrombosis, and a propensity to dural sinus thrombi. These differing manifestations of what we now regard as Behçet’s syndrome might indicate more than one disease mechanism.

Behçet’s syndrome involves arteries and veins of all sizes, but there are some lesions where direct evidence of injury to the vessel wall cannot be demonstrated. Among these are the acne lesions of the skin, where histology is no different from ordinary acne, and, in the brain, where evidence for direct vessel wall injury is difficult to find. There is no specific cell type that dominates in vasculitic lesions and immune complex deposition can be seen only in some. Thrombophilic factors seem not to be the primary event in explaining the hypercoagulability of Behçet’s syndrome: hypertriglyceridaemia might be a risk factor.

Epidemiology

Behçet’s syndrome has a distinct geographical distribution, with most cases being from the countries around the Mediterranean basin, the Middle East, and east Asia. The prevalence ranges from 0.07/104 in Spain to 8 to 42/104 in Turkey. The Silk Route has been suggested as the mechanism through which an aetiological agent (genetic or environmental) was spread. A recent study performed in North African and Asian immigrants in Paris showed that (by contrast with the native population) Behçet’s syndrome was nearly as frequent as the primary vasculitides among them, and the increased prevalence was not related to the age of immigration, suggesting a genetic rather than environmental explanation. The condition can affect every age group, but onset before puberty or after the sixth decade is relatively rare.

Clinical findings

Clinical manifestations are protean (Table 19.11.5.1) and the disease course is characterized by unpredictable periods of recurrences and remissions. Although skin and mucosal lesions are most common, the ocular, central nervous system (CNS), and large-vessel manifestations are more serious.

Table 19.11.5.1 Clinical manifestations of Behçet’s syndrome

Manifestation

Features

Recurrent oral ulcers (97–99%)

  • Usually the first and most recurrent manifestation

  • Mostly minor ulcers; heal without scarring

  • Usually indistinguishable in appearance and histology from recurrent aphthae

Genital ulcers (c.85%)

  • Mostly on the scrotum or both labiae

  • Less frequent on the penis

  • Large ulcers (>1 cm) heal with a scar

Papulopustular lesions (c.85%)

  • Indistinguishable from ordinary acne

  • On face and back as well as unusual acne sites (extremities)

Erythema nodosum (c.50%)

  • Mostly on lower extremities

  • Similar to primary erythema nodosum

  • Confused with superficial thrombophlebitis.

Pathergy reaction (60%)

  • 60–70% positivity in Turkey or Japan

  • Rarely positive in northern Europe or the USA

Uveitis (c.50%)

  • Chronic, relapsing, bilateral panuveitis

  • Hypopyon indicates a grave prognosis

Joints (50%)

  • Mono- or oligoarticular yet symmetrical

  • Nondeforming, nonerosive, and self-limited

  • Mostly knees, ankles, elbows, and wrists

Thrombophlebitis (30%)

  • Frequently superficial or deep veins of the legs

  • Thromboembolism is rare

Arterial occlusion/aneurysm (c.4%)

  • Entire arterial tree

  • Pulmonary artery aneurysms present with haemoptyses

CNS involvement (5–10%)

  • Parenchymal (80%) and dural sinus thrombi (20%)

  • Peripheral neuropathy uncommon.

Gastrointestinal lesions (1–30%)

  • Rare in Turkey and 30% in Japan

  • Mimicking inflammatory bowel diseases

Mucocutaneous

Oral ulceration is generally the first, as well as the most frequent, manifestation of Behçet’s syndrome. Smoking may decrease the frequency.

Genital ulcers cause pain and discomfort (Fig. 19.11.5.1), with the presence of genital scarring being quite useful for diagnosis. Urethritis is not observed, in contrast to that seen in Reiter’s disease or sexually transmitted infections.

Fig. 19.11.5.1 Genital ulcers in a patient with Behçet’s syndrome.

Fig. 19.11.5.1
Genital ulcers in a patient with Behçet’s syndrome.

Papulopustular or acneiform lesions are usually indistinguishable from ordinary acne vulgaris, both in appearance and in histology. They are usually seen on the face, upper chest, and back, but they can also affect sites not typically affected by acne vulgaris, such as the arms and legs. The lesions of erythema nodosum can be difficult to differentiate from superficial thrombophlebitis using the naked eye: ultrasound examination may obviate the need for a biopsy. Less common forms of skin lesions are papules, palpable purpura, skin ulcers, Sweet’s syndrome, and pyoderma gangrenosum.

The pathergy phenomenon is defined as a nonspecific hyperreactivity to simple trauma. Typically, a papule or a pustule forms in 24 to 48 h after skin puncture with a needle (Fig. 19.11.5.2). This is quite specific for Behçet’s syndrome, but although found in 60 to 70% of patients in Turkey or Japan, it is rarely observed in northern Europe or the United States of America. It can be observed in organs other than the skin, such as attacks of uveitis after eye surgery, synovitis after arthrocentesis, or development of an aneurysm after puncture of an artery. However, wound healing is normal.

Fig. 19.11.5.2 The pathergy reaction induced by needle pricks to the forearms.

Fig. 19.11.5.2
The pathergy reaction induced by needle pricks to the forearms.

Ocular

Eye involvement takes the form of a relapsing panuveitis that generally starts within the first 2 years of disease onset. It is more frequent (70%) and has a more severe course in men, and in young people (aged less than 25 years). Hypopyon uveitis, an intense inflammation in the anterior chamber that can be seen by the physician without any ophthalmological aids in 20% of patients with ocular disease, is associated with severe retinal disease.

Posterior uveal inflammation with retinal vasculitis causes retinal exudates, haemorrhages, venous thrombosis, papilloedema, and macular disease. Recurrent attacks of eye inflammation lead to structural changes such as synechiae and retinal scars, which are the main determinants of eye prognosis. Episcleritis, conjunctivitis, corneal ulcerations, and lid lesions are occasionally seen.

Musculoskeletal

Arthritis is mono- or oligoarticular, usually resolves in a few weeks, and is associated with acneiform lesions. A subgroup with acne and arthritis has increased enthesopathy when examined by ultrasonography. Chronic synovitis with erosions and deformity can be seen, but is rare. Back pain and sacroiliac joint involvement are not part of the clinical picture. Synovial fluid is commonly inflammatory, with a predominance of neutrophils, but it has a good mucin clot formation. Local myositis of the legs, or generalized similar to polymyositis, is infrequently seen, as is osteonecrosis.

Vascular

Behçet’s syndrome involves both veins and arteries. Around a third of patients have thrombophlebitis, most frequently in the superficial or deep veins of the legs. Venous claudication is occasionally observed. Obstruction of the superior and/or inferior vena cava (SVC and IVC) are less frequent, and occlusion of the suprahepatic veins (Budd–Chiari syndrome) is rare but carries a high mortality. Thromboembolism is rare, most probably due to the tight adherence of thrombi to the diseased vein.

The entire arterial tree can be affected by arterial aneurysms and/or occlusion: the abdominal aorta is the most frequent site, followed by the iliac, femoral, popliteal, carotid, and subclavian vessels. Pulmonary artery aneurysms are associated with thrombophlebitis of leg veins and IVC in 90% of patients. They present with haemoptyses, which can be fatal, with the typical finding on chest radiography being noncavitating single or multiple shadows (Fig. 19.11.5.3). CT scans confirm the diagnosis.

Fig. 19.11.5.3 Chest radiograph showing pulmonary artery aneurysms in a patient with Behçet’s syndrome.

Fig. 19.11.5.3
Chest radiograph showing pulmonary artery aneurysms in a patient with Behçet’s syndrome.

Neurological

Disease of the CNS is also more common and more severe in male patients. Most of those affected (80%) have parenchymal disease, which causes pyramidal, cerebellar, and sensory signs and symptoms, sphincter disturbances, and behavioural changes. The remaining 20% have nonparenchymal involvement in the form of intracranial hypertension due to dural sinus thrombosis presenting with headaches and papilloedema. Both types of involvement rarely occur in the same patient. Cerebrospinal fluid examination shows nonspecific findings, but a high protein or cell count implies a grave prognosis in the long run. Peripheral neuropathy, which is frequently seen in other vasculitides, is uncommon in Behçet’s syndrome.

Gastrointestinal

Gastrointestinal involvement shows geographical variation, being rare among people who live in the Mediterranean countries although frequent among those in Japan. Mucosal ulceration, primarily in the ileum and colon, presents with colicky abdominal pain and diarrhoea that mimic inflammatory bowel diseases. It usually follows a fluctuating course, with exacerbations and remissions, and it tends to perforate.

Hepatic involvement is uncommon except for the rare Budd–Chiari syndrome. A slightly enlarged spleen can be found in men.

Cardiac

There have been sporadic reports of many types of conduction problem, valvular disease, and aortitis, as well as ventricular aneurysms and coronary vasculitis, and endomyocardial fibrosis with intracardiac thrombi. However, the overall frequency of cardiac disease was no different from that seen in controls in a prospective controlled study.

Other features

Renal involvement, seen infrequently, ranges from IgA nephropathy to rapidly progressive glomerulonephritis. Immune complexes are not usually found in the kidneys. Amyloidosis of the AA type occasionally occurs, as observed in other chronic inflammatory states, usually presenting in men with a nephrotic syndrome, which has a grave prognosis.

Epididymitis is a well-recognized feature, reported in up to 20% of cases. Voiding disturbances have also been described.

Differential diagnosis

The two conditions that most commonly cause problems in diagnosis are inflammatory bowel disease, especially Crohn’s disease, and multiple sclerosis. Intestinal and especially ileocaecal ulcers are both observed in Crohn’s disease and Behçet’s syndrome, but fistulization and perianal ulcerations are rare in the latter. Furthermore, the eye inflammation of Behçet’s syndrome is most often a panuveitis, compared with the anterior chamber disease seen in Crohn’s disease. With regard to multiple sclerosis, optic neuritis is rare in Behçet’s syndrome, and the characteristic MRI lesions of Behçet’s syndrome are situated in the basal ganglia and diencephalon, whereas those in multiple sclerosis are usually seen as white matter lesions in the periventricular areas.

Clinical investigation

Laboratory findings are nonspecific. A mild anaemia of chronic disease and leucocytosis are seen in some patients. The erythrocyte sedimentation (ESR) rate and C-reactive protein (CRP) may be moderately elevated, and the latter may correlate with erythema nodosum and acute thrombophlebitis, although these inflammatory markers generally do not mirror clinical activity. Autoantibodies such as rheumatoid factors and antinuclear antibodies are absent and tests for antineutrophil cytoplasmic antibodies (ANCA) and anticardiolipin antibodies are usually negative.

Criteria for classification

In 1990 the International Study Group for Behçet’s syndrome proposed a set of classification criteria that are sensitive (95%) and specific (98%) (Box 19.11.5.1).

Reprinted from The Lancet, 335, International Study Group for Behçet’s Disease, Criteria for diagnosis of Behcet’s disease, 1070–80, 1990, with permission from Elsevier

Management

Treatment depends on the type and severity of symptoms, disease duration, and the age and sex of the patient. Those who are elderly, and women with mild mucocutaneous lesions, can be managed symptomatically, while young people and men need a more aggressive approach. A EULAR based recommendation concerning management has recently been published (Table 19.11.5.2).

Table 19.11.5.2 EULAR recommendations for the management of Behçet’s syndrome

Manifestation

Recommendation

Eye disease

  • Any patient with inflammatory eye disease affecting the posterior segment should be on a treatment regimen that includes azathioprine and systemic corticosteroids.

  • Severe eye disease—defined as >2 lines of drop in visual acuity on a 10/10 scale and/or retinal disease (retinal vasculitis or macular involvement)—should be treated with either ciclosporin A or infliximab in combination with azathioprine and corticosteroids; or with IFNα‎ with or without corticosteroids.

Arterial and/or venous disease

  • There is no firm evidence to guide the management of major vessel disease. For acute deep vein thrombosis, immunosuppressive agents such as corticosteroids, azathioprine, cyclophosphamide, or ciclosporin A are recommended. For pulmonary and peripheral arterial aneurysms, cyclophosphamide and corticosteroids are recommended.

  • There are no controlled data on, or evidence of benefit from uncontrolled experience with anticoagulants, antiplatelet or antifibrinolytic agents in the management of deep vein thrombosis, or for the use of anticoagulation for arterial lesions.

Gastrointestinal disease

  • There is no evidence-based treatment that can be recommended for the management of gastrointestinal involvement. Agents such as sulfasalazine, corticosteroids, azathioprine, TNFα‎ antagonists and thalidomide should be tried before surgery, excepting in emergencies.

Arthritis

  • Can be managed with colchicine in most cases.

CNS disease

  • There are no controlled data to guide management. For parenchymal involvement agents to be tried include corticosteroids, IFNα‎, azathioprine, cyclophosphamide, methotrexate and TNFα‎ antagonists. For dural sinus thrombosis corticosteroids are recommended.

  • Ciclosporin A should not be used in central nervous system involvement unless necessary for intraocular inflammation.

Skin and mucosal disease

  • The decision to treat will depend on the perceived severity by the doctor and the patient. Mucocutaneous involvement should be treated according to the dominant or co-dominant lesions present.

  • Topical measures (i.e. local corticosteroids) should be the first line of treatment for isolated oral and genital ulcers. Acne-like lesions are usually of cosmetic concern only, hence topical measures as used in acne vulgaris are usually sufficient. Colchicine should be preferred when the dominant lesion is erythema nodosum. Azathioprine, IFNα‎ and TNFα‎ antagonists may be considered in resistant mucocutaneous disease.

  • Leg ulcers may not be caused by Behçet’s disease, in which case treatment should be planned accordingly.

Controlled trials show that colchicine 1 to 2 mg/day is effective for genital ulcers, erythema nodosum, and arthritis in women. It is beneficial only for arthritis in males. Thalidomide at 100 mg/day is effective for orogenital ulceration, but its well-known adverse effects, in particular as a teratogen, hinder its more widespread use. Dapsone 100 mg/day is also beneficial in mucocutaneous lesions.

Azathioprine (2.5 mg/kg per day) helps preserve visual acuity in established eye disease and prevents the emergence of new eye disease. It also has salutary effects on oral–genital ulcers and arthritis, and its use early in the course of disease is associated with a more favourable outcome. A drawback is its slow onset of action—usually taking 4 to 6 months for full effect. Ciclosporin 3 to 5 mg/kg per day acts within weeks and is the first agent to use in acute and severe eye involvement. It decreases the frequency of mucocutaneous lesions as well. Adverse effects are hypertension, renal impairment, and neurotoxicity, which require close monitoring. Ciclosporin and azathioprine are frequently combined, with the former used to induce remission and the latter as a remission-maintaining agent.

Corticosteroids are widely used in managing Behçet’s syndrome, but in the only controlled study methylprednisolone acetate (40 mg intramuscularly every 3 weeks) was useful only in controlling erythema nodosum lesions in women. Cyclophosphamide (2 to 2.5 mg/kg per day orally, or 500 to 1500 mg as monthly intravenous boluses) is the preferred treatment for severe vascular disease, with steroids usually added for the initial few months.

The management of the parenchymal type of CNS disease is problematic: steroids, immunosuppressives, interferon-α‎, and tumour necrosis factor (TNF)-α‎ antagonists have all been tried. Dural sinus thrombosis is managed with brief courses of steroids.

Gastrointestinal involvement is initially managed by sulfasalazine at a dose of 2 to 6 g/day, but sometimes bowel resection is required.

There is debate about whether or not to use heparin or oral anticoagulants for the thrombophlebitis of Behçet’s syndrome. As stated previously, pulmonary embolism is seldom observed, so antiplatelet drugs (i.e. aspirin) are probably sufficient. We also use azathioprine to generally suppress disease activity in the thrombophlebitis of Behçet’s syndrome.

Surgical correction of peripheral arterial aneurysms is usually successful (in appropriate cases), with immunosuppressives given before surgical intervention to prevent recurrence. However, surgical correction of pulmonary arterial aneurysms should not be attempted because of high surgical mortality.

Data on α‎-interferon and the TNF-α‎ blockers from open studies have shown that they are also beneficial in patients who are resistant to conventional treatments. Interferon-α‎ (3 to 6 MU/day) was reported to cause a partial or complete response in patients with resistant posterior uveitis. Side effects such as flu-like symptoms were frequent and dose dependent. The TNF-α‎ blocker infliximab 5 mg/ kg was useful in controlling severe and resistant uveitis, and other severe manifestations such as gastrointestinal and neurological Behçet’s syndrome, but relapses were common after discontinuation. A double-blind, placebo-controlled study with the TNF-α‎ blocker etanercept found it to be useful in controlling most mucocutaneous lesions of Behçet’s syndrome when used at 25 mg twice a week for a period of 4 weeks.

Prognosis

Young men have the highest morbidity and mortality. Women have less severe disease than men. Major vessel disease and neurological involvement are the main causes of death. Eye inflammation and its greatest damage occur during the first 2 years. The disease tends to abate after 40 years of age, but CNS involvement and major vessel disease may have a late onset (5 to 10 years after diagnosis). Loss of useful vision ensues in about 10–15% of male patients with eye disease despite therapy.

Mortality attributable to Behçet’s syndrome decreases with time after diagnosis, which is the opposite of the situation in rheumatoid arthritis and systemic lupus erythematosus. This may be due both to self-abating disease activity, and to the fact that atherosclerosis is not accelerated in Behçet’s syndrome in the same way that it is in rheumatoid arthritis and systemic lupus erythematosus. A recent study of pulmonary arterial aneurysms has shown that the related mortality rate has decreased from 50% to around 20% in the last decade, due to either earlier recognition or more rational use of immunosuppressives.

Overall, the outlook for patients with eye disease and the mucocutaneous manifestations of Behçet’s syndrome is considerably better than it was in the past, but management of CNS disease and thrombophilia/major vascular complications, including thrombotic events, remains problematic.

Further reading

Akman-Demir G, Serdaroglu P, Tasci B (1999). Clinical patterns of neurological involvement in Behcet’s disease: evaluation of 200 patients. Brain, 122, 2171–82.Find this resource:

    Direskeneli H (2006). Autoimmunity vs. autoinflammation in Behcet’s disease: do we oversimplify a complex disorder? Rheumatology (Oxford), 45, 1461–5.Find this resource:

      Frassanito MA, et al. (1999). Th1 polarization of the immune response in Behcet’s disease: a putative pathogenetic role of interleukin-12. Arthritis Rheum, 42, 1967–74.Find this resource:

        Gul A, et al. (2000). Familial aggregation of Behcet’s disease in Turkey, Ann Rheum Dis, 59, 622–5.Find this resource:

          Hamuryudan V, et al. (1998). Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med, 128, 443–50.Find this resource:

            Hatemi G, et al. (2009). Management of Behcet’s disease: a systematic literature review for the European League Against Rheumatism: evidence based recommendations for the management of Behcet’s disease. Ann Rheum Dis, 68(10), 1528–34.Find this resource:

              Ideguchi H, et al. (2011). Behçet disease: evolution of clinical manifestations. Medicine, 90, 125–32.Find this resource:

                International Study Group for Behçet’s disease (1990). Criteria for diagnosis of Behçet’s disease. Lancet, 335, 1078.Find this resource:

                  Kirino Y, et al. (2013). Genome-wide association analysis identifies new susceptibility loci for Behçet’s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet, 45, 202–7.Find this resource:

                    Kötter, et al. (2004). The use of interferon alfa in Behcet’s disease: A review of the literature. Semin Arthritis Rheum, 33, 320–35.Find this resource:

                      Kural-Seyahi E, et al. (2003). The long-term mortality and morbidity of Behçet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center. Medicine (Baltimore), 82, 60–76.Find this resource:

                        Leiba M, et al. (2004). Thrombophilic factors are not the leading cause of thrombosis in Behçet’s disease. Ann Rheum Dis, 63, 1445–9.Find this resource:

                          Mahr A, et al. (2008). Population-based prevalence study of Behçet’s disease: differences by ethnic origin and low variation by age at immigration. Arthritis Rheum, 58, 3951–9.Find this resource:

                            Matsumoto T, et al. (1991). Vasculo-Behçet’s disease: a pathologic study of eight cases. Human Pathol, 22, 45–51.Find this resource:

                              Melikoglu M, et al. (2005). Short term trial of etanercept in Behcet’s disease: a double blind, placebo controlled study. J Rheumatol, 32, 98–105.Find this resource:

                                Melikoglu M, et al. (2006). Characterization of the divergent wound-healing responses occurring in the pathergy reaction and normal healthy volunteers. J Immunol, 177, 6415–21.Find this resource:

                                  Mizuki N, et al. (2011). Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci. Nat Genet, 42, 703–6.Find this resource:

                                    Remmer EF, et al. (2010). Genome wide association studies identifies variants in the MHC Class I, Il 10 and IL23R-IL12RB2 regions associated with Behcet’s disease. Nat Genet, 42, 698–702.Find this resource:

                                      Tugal-Tutkun I, et al. (2004). Uveitis in Behçet disease: an analysis of 880 patients. Am J Ophthalmol, 138, 373–80.Find this resource:

                                        Ugurlu S, et al. (2008). Prevalence of angina, myocardial infarction and intermittent claudication assessed by Rose Questionnaire among patients with Behcet’s syndrome. Rheumatology (Oxford), 47, 472–5.Find this resource:

                                          Yazici H, et al. (2007). Behcet’s syndrome; disease manifestations, management and advances in treatment. Nat Clin Pract Rheumatol, 3(3), 148–55.Find this resource:

                                            Yazici Y, Yazici H (eds) (2010). Behcet’s syndrome, 1st edition. Springer, New York.Find this resource:

                                              Yurdakul S, et al. (2001). A double-blind trial of colchicine in Behçet’s syndrome. Arthritis and Rheumatism, 44, 2686–92.Find this resource: