Ocular and Systemic Manifestations of Behçet’s Disease: Exploring Pathogenesis and Therapeutic Modalities

Abstract

Behçet’s disease (BD) is a rare, chronic, relapsing multi-system inflammatory disorder, first described by Hulusi Behçet in 1937, and classically characterized by ocular inflammation, recurrent oral ulcers & genital ulcers. It is presently identified as a variable-vessel vasculitis affecting arteries and veins irrespective of size,thereby contributing to widespread organ involvement. Bilateral occlusive retinal vasculitis and recurrent uveitis are the primary ocular manifestations associated with BD, representing the major sight-threatening complications that can lead to severe visual impairment or blindness if untreated. BD is more prevalent along the historic Silk Road, including Iran, Korea, Japan, and Turkey, despite being observed globally.The etiology remains unknown, but multifaceted interactions between genetic predisposition, especially HLA-B51, & environmental or infectious inducers lead to pathogenesis, facilitated largely by imbalanced Th1 and Th17 immune responses. Diagnosis is based on clinical criteria, as disrupted biomarker exists, with ocular involvement, oral and genital ulcers, cutaneous lesions, and a positive pathergy test being significant features. Therapeutic approach requires a combination of corticosteroids for acute flares and immuno-suppressive for chronic disease control. Azathioprine, cyclosporine, and methotrexate are commonly used conventional treatment, although cyclosporine is contraindicated in neuro-Behçet’s disease. Among biologic therapies, interferon-? remains effective in stimulating sustained remission, while TNF-? inhibitors have shown high efficacy in refractory systemic and ocular disease. Timely diagnosis, early immunosuppression, and cautious biologic use are necessary to minimize relapses, resist irreversible tissue damage, and induce long-term prognosis in BD, as discussed in this review article.

Keywords

Introduction

Behcet’s disease is an idiopathic multisystem disease named for the Turkish dermatologist Hulusi Behcet who in 1937 described it as a triad of oral ulcers, genital ulcers, skin lesions and uveitis.[ ] BD is also known as Adamantiades – Behcet’s  disease, rare but serious systemic inflammatory condition which is characterized by a relapsing & remitting course of unknown pathogenesis. It is classified as vasculitis, meaning it causes inflammation of blood vessels, which can lead to occlusion (blockage) of the vessels.[ ] Uveitis is by far the most frequent & most common ocular manifestation. It is most often acute, recurrent, non-granulomatous, panuveitis associated with retinal vasculitis which may induce severe ocular tissue damage (70% of patients) & subsequent blindness.[ ] BD has a higher prevalence in the countries along the ‘Silk Road’, an ancient trading route, & also widespread presence particularly in Turkey, Iran, Korea & Japan, it affects individuals worldwide but is more common in these regions, which has led to speculation that genetic and environmental factors may play a role and accounts for up to 20% of cases of endogenous uveitis in some of these countries.[ , ]  The report on Behcet’s disease among Indian patient’s  highlight the fact that BD, as well as ocular involvement, is significantly less common in our population.[ , , , ] The age at onset of the disease is most often between 25 & 30 years. BD is considered to be more frequent & more serious in young males 7 diminishing activity with age.3  In most patients with Behçet’s disease, ocular involvement is bilateral, and visual loss typically follows one of three patterns: (1) a slowly progressive, insidious decline in vision; (2) progressive visual loss with partial recovery; or (3) rapid, irreversible loss of vision in one eye, followed shortly by involvement of the other eye.[ ] Recent reports indicate that patients with Behçet’s disease have higher levels of antibodies against complement C1q compared to healthy controls, with the highest levels observed in those with vascular involvement.[ ] As there is a lack of universally recognized pathogenic test, BD diagnosis is based on clinical criteria. Oral aphthosis (OA), genital aphthosis (GA), cutaneous lesions (such as inflammatory papulopustular lesion, erythema nodosum & skin ulcers) & positive pathergy (PP) reaction as well as uveitis /retinitis/hypopyon-iritis have been used in several sets of diagnostic criteria. Interestingly, rates of PP reaction not only vary widely in different population but also there are indications that its sensitivity is declining over time.[ ] Though the exact pathogenesis of BD remains unclear, a relationship between BD & complex genetic factors perpetuating inflammation, such as presence of HLA B-51 haplotype, have been reported.[ ]

CLINICAL MANIFESTATION:

Behcet’s disease is a chronic immune-mediated disorder with wide range of clinical manifestation which affect various organs, including the eyes, mucosa, skin, vascular systems, joints, gastrointestinal tract & central nervous system. Among the most serious and vision threatening complications is ocular involvement, particularly bilateral occlusive retinal vasculitis, which accounts for significant morbidity in BD.

Ocular involvement carries one of the most serious implications of BD occurs in 50-70% of patients ,with the predominant features of uveitis & bilateral occlusive retinal vasculitis.[   ] In obstructive retinal vasculitis, the occlusions typically occur in the branch retinal veins. However, central artery or vein occlusion is uncommon and usually leads to a rapid deterioration or complete loss of vision, often with a poor visual prognosis.[ , ]  In Behçet’s disease, uveitis can affect the anterior, posterior, or peripheral parts of the retina. Anterior segment involvement typically presents as nongranulomatous uveitis, with hypopyon being the most frequent feature. Posterior segment involvement often leads to vitreous haze, retinal lesions, vascular sheathing, vessel occlusion, macular edema, and various other inflammatory signs.[ ] The anterior uveitis generally regresses in 2 to 3 weeks.One feature of this uveitis is that it may recur very suddenly and rapidly.[19]  The presence of diffuse vitritis is an important clinical indicator in cases of acute anterior uveitis, with or without hypopyon, and helps differentiate Behçet’s uveitis from HLA-B27-associated anterior uveitis. In Behçet’s disease, the vitritis typically involves widespread cellular and protein infiltration throughout the vitreous body. Within a few days of the inflammatory episode, vitreous precipitates may form on the surface of the inferior peripheral retina. These deposits are found in approximately 30% of patients and often accumulate along the posterior border of the vitreous base in a string-of-pearls pattern, though they can also be scattered across the inferior peripheral retina.  Optic nerve involvement is a frequent ocular manifestation of Behçet’s disease, appearing either as visible disc edema on examination or as disc hyperfluorescence seen on fluorescein angiography.[ ]

Hemorrhagic occlusive vasculitis in Behçet’s Disease. Wide angle fundus photos (Optos, Marlborough, MA) of the right (A) and left eye (B) demonstrating innumerable intraretinal hemorrhages concentrated in the macula and midperiphery, multiple sclerotic vessels and retinal soft exudates indicative ischemia, more prominent in the left than right eye.[ ] Systemic manifestation of BD includes oral or genital ulcers, skin lesions (cutaneous lesion), gastrointestinal, arthritis & neurological involvement ( neuro-behcet). The symptoms follow a relapsing-remitting pattern, are more pronounced in young males, and generally lessen with advancing age.[ , , ] Oral ulcers in Behçet’s disease are typically painful, 1 to 3 cm in diameter, shallow or deep with a yellow fibrinous base, and may be single or multiple, lasting between 1 and 4 weeks, most commonly occurring on the buccal mucosa, gums, tongue, lips, and pharynx.[ ] Ulcers may be herpetiform, presenting as pinpoint lesions that occur in coalescing clusters. Aphthae in Behçet’s disease and complex aphthosis usually resolve without leaving scars, unlike Sutton’s ulcers, which are large necrotic lesions around salivary glands and often heal with scar formation.[ ] Genital aphthae usually begin as tender nodules that become deep and painful, often interfering with sitting, walking, and normal function. They typically heal slowly and often leave behind scarring.[ ] In females, they are most commonly located on the labia majora, labia minora, vulva, perineum, or perianal skin. In males, the ulcers are primarily found on the scrotum, less commonly on the shaft, and occasionally on the tip of the penis.[12]  Genital ulceration in Behçet’s disease is not contagious and cannot be transmitted through sexual intercourse; however, bacterial colonization of the ulcers may pose a risk for transmitting secondary infections to a sexual partner.[ ] In the early presentation of oral, and particularly genital ulcers, herpes simplex virus (HSV) should be considered as a potential differential diagnosis. It can be ruled out through diagnostic methods such as viral culture or PCR testing.

A variety of cutaneous lesions can be seen in BD, including erythema nodosum (EN)-like lesions, papulopustular eruptions, abscesses, acne-like lesions.[3, ] EN Like lesions are common in BD, occurring in approximately 45% of people.3  A recent study of 42 people with Behçet’s disease revealed that 48% with cutaneous lesions had either a lymphocytic or leukocytoclastic vasculitis.[ ]

Gastrointestinal involvement in Behçet’s disease is characterized by ulceration throughout the gastrointestinal tract, including the esophagus, with the terminal ileum and cecum being the most commonly affected sites.[ , ,  ] These ulcers may be ovoid or geographic in shape, often deep, and tend to appear large when visualized using double contrast barium enema.[ ] Arthritis affects up to 50% of individuals with Behçet’s disease, typically presenting as an inflammatory but non-erosive type. It most commonly involves arthralgia, erythema, and swelling. The knees, wrists, elbows, and ankles are the joints most frequently affected.[ , ] Destruction and atrophy of bone & cartilage can occur occasionally.[ ]

Approximately 5% of people with BD have neurological involvement, which is the serious manifestation of the disease.[ ,  ] Japanese and Turkish researchers have reported that migraine-like headaches may occur in up to 50% of individuals with Behçet’s disease.[ ] Neuro-Behçet’s disease (NBD) is subdivided into non parenchymal and parenchymal disease, although overlap can occur. Acute parenchymal disease is the more common presentation of NBD, typically affecting the brainstem and leading to cranial nerve palsies and motor symptoms due to basal ganglia involvement.[ , ,  ] NBD lesions typically appear hyperintense on T2-weighted images and are distributed across both periventricular and non-periventricular areas, including the spinal cord, representing features of NBD-associated meningoencephalitis. A key diagnostic challenge is that isolated periventricular and/or subcortical cerebral hemispheric white-matter lesions in NBD cannot be reliably distinguished from those seen in multiple sclerosis.[43]

PATHOGENESIS:

The etiology of Behcet’s disease is still unknown. It appears to be an autoinflammatory process triggered by infectious or environmental factors in a genetically predisposed individual.[ , ] Several studies from Great Britain, Korea, Japan, and the Middle East have shown a strong association between HLA-B51 and Behçet’s disease.[ ] The human leukocyte antigen (HLA)-B51 is considered the strongest genetic risk factor for BD.[ ] The development of BD is thought to be influenced by multiple endogenous and exogenous factors, as many HLA-B51–positive individuals never develop BD, while nearly half of BD patients are HLA-B51–negative.[ , ]  According to the environmental trigger hypothesis, in genetically susceptible individuals BD develops through activation of the innate immune system, which is further sustained by the adaptive T-cell response to infectious antigens or autoantigens.[13] Several immune cell abnormalities contribute to the immunopathology of Behçet’s disease. A predominant Th1 and Th17 lymphocytic response leads to activation of neutrophils and endothelial cells, resulting in elevated levels of TNF-α and interleukins IL-6, IL-17, IL-1β, IL-21, and IL-23, along with reduced levels of the anti-inflammatory cytokine IL-10.[43,44, ] The basic histopathologic lesion of Behçet’s disease is a non-granulomatous occlusive vasculitis, characterized by chronic perivascular infiltration of T lymphocytes and neutrophils.[ ] Lymphocytes from patients with Behçet’s disease exhibit cytotoxicity against homogenates of oral mucosa, and significant lymphocyte transformation is induced by homogenates of fetal oral epithelium in cases of recurrent oral ulceration.[ ,  ]  Heavy metals, such as zinc, and toxic agents, including organophosphate pesticides, have been implicated in the etiology of Behçet’s disease.[36, ]

TREATMENT:

Treatment of ocular involvement in Behçet’s disease typically involves corticosteroids, which provide rapid anti-inflammatory effects during acute flare-ups, along with immunosuppressive agents (conventional or biologic) for long-term control of inflammation.[ , , , ] To minimize or prevent complications associated with systemic corticosteroid therapy, patients should be closely monitored and advised to follow specific dietary measures, including a normocaloric diet rich in proteins, low in carbohydrates, salt-free, and supplemented with vitamin D, potassium, and antacids.[ ] Cyclophosphamide, usually administered in combination with corticosteroids, is reserved for the treatment of life-threatening manifestations of Behçet’s disease, such as pulmonary artery aneurysms or central nervous system involvement.[ ] The combination of azathioprine and cyclosporine has proven effective as either first- or second-line therapy. However, cyclosporine A carries risks of nephrotoxicity and hypertension, necessitating regular monitoring of serum creatinine and blood pressure. Importantly, cyclosporine A is contraindicated in neuro-Behçet’s disease due to its potential neurotoxic effects.[58,  ]  Thalidomide 100 mg daily is effective in treating oral and genital ulcers as well as follicular lesions in Behçet’s syndrome; however, relapses are common once treatment is discontinued.[ ] Low-dose oral methotrexate (7.5–20 mg/week) can be effective for severe mucocutaneous involvement in patients without liver disease, but requires regular monitoring for hepatic cirrhosis and renal insufficiency.[ ] Oral tetracycline, used for decades in the treatment of oral ulceration, is thought to exert its effects through antibacterial and antichemotactic properties.[ ] IFN-α, which was the first biologic agent introduced for the treatment of Behçet’s disease before the development of anti-TNF therapies, is currently available in two recombinant forms, IFN-α-2a and IFN-α-2b. It has demonstrated significant efficacy by inducing long-lasting remission in patients, during which no additional medications are required, thereby greatly improving the overall prognosis and quality of life in BD.[ ,  ] Long-term follow-up studies have confirmed the efficacy and safety of IFN-α in refractory ocular disease, while clinical evidence also supports the effectiveness of TNF-α inhibitors in refractory major organ involvement, with IL-1 inhibitors and tocilizumab serving as promising alternatives for patients with persistent ocular manifestations.[ ] Adalimumab (Humira®) is a fully human monoclonal IgG1 antibody that specifically inhibits TNF-α and neutralizes its biological activity; administered subcutaneously at a dose of 40 mg every 1–2 weeks, it is indicated for the management of severe, refractory uveitis.[ , ,  , ]  Despite treatment, legal blindness (BCVA ≤6/60) develops in about 13% of eyes in patients with Behçet’s disease, most often as a result of ischemic maculopathy.[ ]

CONCLUSION:

Optimal management of BD requires a patient-centered and integrated approach that goes apart from treating isolated symptoms. Because the disease usually follows a relapsing–remitting pattern, continuous monitoring is vital to diagnose early flares, especially ocular or neurological events, which can quickly contribute to permanent damage.  Multidisciplinary care among ophthalmologists, dermatologists, rheumatologists, gastroenterologists, and neurologists enhances address the distinct systemic manifestations efficiently. Similarly important is patient education, assuring individuals are attentive to warning signs, stick with prescribed therapies, and follow lifestyle measures that decrease complications and boost overall quality of life.

While corticosteroids continue to be invaluable for quick intervention of acute inflammation, long-term reliance can lead to significant adverse effects. Early adoption of immunosuppressants like cyclosporine, azathioprine, or methotrexate is hence advised for sustained disease control. Developments in biologic therapy have additional transformed outcomes, with interferon-α offering durable remission in ocular disease & TNF-α inhibitors attesting highly efficient at  ocular involvement and refractory systemic. Advanced therapies, such as IL-1 inhibitors and tocilizumab, carry promise for patients immobile to established treatments, extending the range of therapeutic options. Close supervision for drug toxicity and modifying therapy to each patient’s risk profile remain vital for safe and effective care.

Developing the prognosis of BD based on early recognition, timely administration of advanced therapies, and organized long-term follow-up. Through integrated collaboration, close monitoring, and patient empowerment, it is possible to lower relapses, retain vision, and avoid life-altering undesirable outcomes, ultimately improving both survival and quality of life.

REFERENCES

1. Behcet H. Uber rezidivierende Aphthose durch ein virus verusaente grschware am Mund am Auge und an de Cranitalien. Dermatol wochenschr 1937;105:1152-1157.
2. Chen K, Kawahara Y, Miyakawa S, Nishikawa T. Cutaneous vasculitis in Behçet’s disease: a clinical and histopathologic study of 20 patients. J Am Acad Dermatol. 1997;36:689–96.
3. Sakane T, Takeno M, Suzuki N, Inaba G. Behçet’s disease. N Engl J Med. 1999;341:1284–91.
4. Azizlerli G, Kose AA, Sarica R, Gul A, Tutkun IT, Kulac M, Tunc R, Urgancioglu M, Disci R. Prevalence of Behçet’s disease in Istanbul, Turkey. Int J Dermatol. 2003;42:803–6.
5. Mishima S, Masuda K, Izawa Y, Mochizuki M, Namba K. The eighth Frederick H. Verhoeff lecture presented by Saiichi Mishima, MD: Behçet’s disease in Japan—ophthalmologic aspects. Trans Am Ophthalmol Soc. 1979;77:225–79.
6. Singal A. Ocular manifestations of Behçet’s disease in India. J Ophthalmol. 2003;51:309–13.
7. Kunjuraman G, Joseph PP, Philip J. Behçet’s syndrome: a report of cases with review of the literature. J Assoc Physicians India. 1980;28:195–8.
8. Singh RR, Malaviya AN. Behçet’s syndrome in North India. J Assoc Physicians India. 1988;36:238.
9. Pande I, Uppal SS, Kailash S, Kumar A, Malaviya AN. Behçet’s disease in India: a clinical, immunological, immunogenetic, and outcome study. Br J Rheumatol. 1995;34:825–30.
10. BenEzra D. The ocular viewpoint of Behçet’s disease. In: O’Duffy JD, Kokmen E, editors. Behçet’s disease: basic and clinical concepts. New York: Marcel Dekker; 1991. p. 93–7.
11. Bassyouni IH, Gamal S, Talaat RM, Siam I. Autoantibodies against complement C1q in patients with Behçet’s disease: association with vascular involvement. Mod Rheumatol. 2014;24(2):316–20.
12. Davatchi F, Chams-Davatchi C, Ghodsi Z, et al. Diagnostic value of pathergy test in Behçet’s disease according to the change of incidence over time. Clin Rheumatol. 2011;30:1151–5.
13. Deuter CM, Kotter I, Wallace GR, Murray PI, Stubiger N, Zierhut M. Behçet’s disease: ocular effects and treatment. Prog Retin Eye Res. 2008;27:111–36.
14. Kitaichi N, Miyazaki A, Iwata D, Ohno S, Stanford MR, Chams H. Ocular features of Behçet’s disease: an international collaborative study. Br J Ophthalmol. 2007;91(12):1579–82.
15. Levy-Clarke G, Jabs DA, Read RW, Rosenbaum JT, Vitale A, Van Gelder RN. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology. 2014;121(3):785–96.
16. Tugal-Tutkun I, Gupta V, Cunningham ET. Differential diagnosis of Behçet uveitis. Ocul Immunol Inflamm. 2013;21:337–50.
17. Kolar P. Risk factors for central and branch retinal vein occlusion: a meta-analysis of published clinical data. J Ophthalmol. 2014;2014:724780.
18. Shulman S, Kramer M, Amer R, et al. Characteristics and long-term outcome of patients with noninfectious retinal vasculitis. Retina. 2015;35:2633–40.
19. Tugal-Tutkun I. Behçet’s disease. In: Gupta A, Gupta V, Herbort CP, Khairallah M, editors. Uveitis: text and imaging. 1st ed. New Delhi: Jaypee Brothers Medical Publishers Ltd; 2009. p. 397–413.
20. Zafirakis P, Foster CS. Adamantiades–Behçet disease. In: Foster CS, Vitale A, editors. Diagnosis and treatment of uveitis. Philadelphia, PA: WB Saunders; 2002. p. 632–52.
21. Gasparian SA, Barrett D, Sierpina D, Chalam KV. Successful repair of combined tractional and rhegmatogenous retinal detachment with pars plana vitrectomy without scleral buckle in severe Behçet’s disease. J Surg Case Rep. 2020;2020(11):1–4.
22. Tugal-Tutkun I. Behçet’s uveitis. Middle East Afr J Ophthalmol. 2009;16:219–24.
23. Kural-Seyahi E, Fresko I, Seyahi N, et al. Mortality and morbidity of Behçet syndrome. Medicine (Baltimore). 2003;82:60–76.
24. Kerstens FG, Turkstra F, Atalay S, van Vugt RM, Swearingen CJ, Yazici Y. Adherence to guidelines for the treatment of Behçet’s syndrome in New York and Amsterdam. Clin Exp Rheumatol. 2017;35(108):55–9.
25. Chajek T, Fainaru M. Behçet’s disease: report of 41 cases and a review of the literature. Medicine. 1975;54:179–96.
26. Rogers RS. Recurrent aphthous stomatitis: clinical characteristics and evidence for an immunopathogenesis. J Invest Dermatol. 1977;69:499–509.
27. Alpsoy E, Zouboulis C, Ehrlich G. Mucocutaneous lesions of Behçet’s disease. Yonsei Med J. 2007;48(4):573–85.
28. Ghate J, Jorizzo J. Behçet’s disease and complex aphthosis. J Am Acad Dermatol. 1999;40(1):1.
29. Alpsoy E, Donmez L, Onder M, Gunasti S, Usta A, Karincaoglu Y, et al. Clinical features and natural course of Behçet's disease in 661 cases: a multicentre study. Br J Dermatol. 2007;157:901–6.
30. Chen K-R, Kawahara Y, Miyakawa S, Nishikawa T. Cutaneous vasculitis in Behçet’s disease: a clinical and histopathological study of 20 patients. J Am Acad Dermatol. 1997;36:689–96.
31. Kasahara Y, Tanaka S, Nihino M, et al. Intestinal involvement in Behçet’s disease: review of 136 surgical cases in the Japanese literature. Dis Colon Rectum. 1981;24:103–6.
32. Lockhart JM, McIntyre W, Caperton EM. Esophageal ulceration in Behçet’s syndrome. Ann Intern Med. 1976;84:572–3.
33. Yashiro K, Nagasako N, Hasegawa K, et al. Esophageal lesions in intestinal Behçet’s disease. Endoscopy. 1986;18:57–60.
34. Kim JH, Choi BI, Han JK, et al. Colitis in Behçet’s disease: characteristics on double-contrast barium enema examination in 20 patients. Abdom Imaging. 1994;19:132–6.
35. Chajek T, Fainaru M. Behçet’s disease: report of 41 cases and a review of the literature. Medicine. 1975;54:179–96.
36. O’Duffy JD, Carney JA, Deodhar S. Behçet’s disease: report of 10 cases, three with new manifestations. Ann Intern Med. 1971;75:561–70.
37. Shimizu T, Ehrlich GE, Inaba G, et al. Behçet disease (Behçet syndrome). Semin Arthritis Rheum. 1979;8:223.
38. Akman-Demir G, et al. Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients. Brain. 1999;122:2171–82.
39. Siva A, et al. Behçet’s disease: diagnostic and prognostic aspects of neurological involvement. J Neurol. 2001;248:95–103.
40. Jorizzo JL. Behçet’s disease: an update based on the 1985 international conference in London. Arch Dermatol. 1986;122:556–8.
41.   Peño IC, De Las Heras Revilla V, Carbonell BP, et al. Neurobehçet disease: clinical and demographic characteristics. Eur J Neurol. 2012;19:1224–7.
42. Çoban O, Bahar S, Akman-Demir G, et al. Masked assessment of MRI findings: is it possible to differentiate neuro-Behçet’s disease from other central nervous system disorders? Neuroradiology. 1999;41:255–60.
43. Al-Araji A, Kidd DP. Neuro-Behçet’s disease: epidemiology, clinical characteristics, and management. Lancet Neurol. 2009;8:192–204.
44. Park UC, Kim TW, Yu HG. Immunopathogenesis of ocular Behçet’s disease. J Immunol Res. 2014;2014:653539.
45. Morton LT, Situnayake D, Wallace GR. Genetics of Behçet’s disease. Curr Opin Rheumatol. 2016;28:39–44.
46. Yazici H, Chamberlain MA, et al. HLA antigens in Behçet’s disease: a reappraisal by a comparative study of Turkish and British patients. Ann Rheum Dis. 1980;39:344–8.
47. Kirino Y, Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, et al. Genome-wide association analysis identifies new susceptibility loci for Behçet’s disease and epistasis between HLA-B51 and ERAP1. Nat Genet. 2013;45(2):202–7.
48. Takeuchi M, Mizuki N, Meguro A, Ombrello MJ, Kirino Y, Satorius C, et al. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet’s disease susceptibility. Nat Genet. 2017;49(3):438–43.
49. Kirino Y, Ideguchi H, Takeno M, Suda A, Higashitani K, Kunishita Y, et al. Continuous evolution of clinical phenotype in 578 Japanese patients with Behçet’s disease: a retrospective observational study. Arthritis Res Ther. 2016;18(1):217.
50. Greco A, De Virgilio A, Ralli M, Ciofalo A, Mancini P, Attanasio G, et al. Behçet’s disease: new insights into pathophysiology, clinical features and treatment options. Autoimmun Rev. 2018;17:567–75.
51. Melikoglu M, Kural-Seyahi E, Tascilar K, Yazici H. The unique features of vasculitis in Behçet’s syndrome. Clin Rev Allergy Immunol. 2008;35:40–6.
52. Rogers RS, Sams WM, Shorter RC. Lymphocytotoxicity for oral epithelial cells in recurrent aphthous stomatitis and Behçet’s syndrome. Arch Dermatol. 1974;109:361.
53.  Lehner T. Stimulation of lymphocyte transformation by tissue homogenates in recurrent oral ulceration. Immunology. 1967;13:159.
54. Callen IP. Behçet’s syndrome. In: Callen JP, editor. Cutaneous aspects of internal medicine. Chicago: Year Book Medical Publishers; 1981. p. 93.
55. Tugal-Tutkun I. Behçet’s disease. In: Gupta A, Gupta V, Herbort CP, Khairallah M, editors. Uveitis: text and imaging. 1st ed. New Delhi: Jaypee Brothers Medical Publishers Ltd; 2009. p. 397–413.
56. Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain AM, Gul A, et al. EULAR recommendations for the management of Behçet’s disease. Ann Rheum Dis. 2008;67:1656–62.
57. Evereklioglu C. Ocular Behçet disease: current therapeutic approaches. Curr Opin Ophthalmol. 2011;22:508–16.
58. Benitah NR, Sobrin L, Papaliodis GN. The use of biologic agents in the treatment of ocular manifestations of Behçet’s disease. Semin Ophthalmol. 2011;26:295–303.
59. Saadoun D, Wechsler B, Terrada C, Hajage D, Le Thi Huong D, Resche-Rigon M, et al. Azathioprine in severe uveitis of Behçet’s disease. Arthritis Care Res (Hoboken). 2010;62:1733–8.
60. Hamuryudan V, et al. Pulmonary artery aneurysms in Behçet syndrome. Am J Med. 2004;117:867–70.
61. Kato Y, Numaga J, Kato S, Kaburaki T, Kawashima H, Fujino Y. Central nervous system symptoms in a population of Behçet’s disease patients with refractory uveitis treated with cyclosporine A. Clin Exp Ophthalmol. 2001;29:335–6.
62. Hamuryudan V, et al. Thalidomide in the treatment of the mucocutaneous lesions of Behçet syndrome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1998;128:443–50.
63. Jorizzo JL, White WL, Wise CM, et al. Low-dose weekly methotrexate for unusual vascular reactions: cutaneous polyarteritis nodosa and Behçet’s disease. J Am Acad Dermatol. 1991;24:973–8.
64. Lehner T. Oral ulceration and Behçet’s syndrome. Gut. 1977;18:491–511.
65. Yalcindag FN, Uzun A. Results of interferon alpha-2a therapy in patients with Behçet’s disease. J Ocul Pharmacol Ther. 2012;28:439–43.
66. Aydinoglu-Candan O, Araz-Ersan B, Gul A, Badur S, Tugal-Tutkun I. Anti-interferon alpha antibodies and autoantibodies in patients with Behçet’s disease uveitis treated with recombinant human interferon alpha-2a. Graefes Arch Clin Exp Ophthalmol. 2015;253:457–65.
67. Alibaz-Oner F, Sawalha AH, Direskeneli H. Management of Behçet’s disease. Curr Opin Rheumatol. 2018;30:238–42.
68. Interlandi E, Leccese P, Olivieri I, Latanza L. Adalimumab for treatment of severe Behçet’s uveitis: a retrospective long-term follow-up study. Clin Exp Rheumatol. 2014;32:S58–62.
69. Levy-Clarke G, Jabs DA, Read RW, Rosenbaum JT, Vitale A, Van Gelder RN. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology. 2014;121:785–96.e3.
70. Vallet H, Seve P, Biard L, Baptiste Fraison J, Bielefeld P, Perard L, et al. Infliximab versus adalimumab in the treatment of refractory inflammatory uveitis: a multicenter study from the French Uveitis Network. Arthritis Rheumatol. 2016;68:1522–30.
71. Leccese P, Latanza L, D’Angelo S, Padula A, Olivieri I. Efficacy of switching to adalimumab in a patient with refractory uveitis of Behçet’s disease to infliximab. Clin Exp Rheumatol. 2011;29:S93.
72. Taylor SRJ, Singh J, Menezo V, et al. Behçet disease: visual prognosis and factors influencing the development of visual loss. Am J Ophthalmol. 2011;152:1059–66.