Behcet’s Disease Research Committee of Japan: diagnostic criteria.
Defined as a systemic vasculitis developing in a particular genetic background, uveitis is one of the hallmarks to diagnose Behcet’s disease and also one of the important clinical criteria to start systemic treatment. Isolated anterior non granulomatous uveitis with hypopyon, even though a classic clinical picture, actually develops in a minority of cases. In most patients, uveitis is posterior, associated to small vessel occlusive retinal vasculitis, carrying a high risk of permanent retinal damage and subsequent severe visual loss. The guarded natural prognosis of the disease has positively changed in the last decennials with the introduction of biologic immunosuppressant agents in the field of uveitis. Vision can be preserved in most cases provided a prompt early diagnosis and adequate therapy. The potential role of oral bacteria as a triggering factor for autoinflammation in predisposed hosts is interesting, opening the door to prevention in this still not well-understood severe uveitis.
- hypopyon uveitis
- occlusive vasculitis
- retinal atrophy
Named after the Turkish ophthalmologist, Hulusi Behcet (who described in 1937 the classic triad of oral aphthosis, genital ulcers, and hypopyon uveitis) , Behcet’s disease (BD) is a systemic relapsing obliterative vasculitis, affecting arteries, veins, and mainly capillaries. Even though almost all organs can eventually be involved, the compromise of the central nervous system (CNS) and eye makes the disease’s prognosis guarded and usually urges to start proper treatment.
There is no specific test to diagnose Behcet’s disease: by definition, its diagnosis is a clinical one. In 1990, the International Study Group for Behcet’s disease established a set of diagnostic criteria in an attempt to unify the five different ones used by that time . They required the presence of oral ulcerations plus any two of genital ulcerations, typical defined eye lesions, typical defined skin lesions or a positive pathergy test.
Far from being solved, the debate on the diagnostic criteria is still active, and many other sets have been proposed. Among them, the Behcet’s Disease Research Committee of Japan defines the diagnosis as complete or incomplete upon the presence of major and minor symptoms (Table 1) . The Dilsen criteria (revised in 2000) seems more suitable to the European patients suffering from Behcet’s disease (Table 2) [4, 5].
|1. Major symptoms|
|Recurrent aphthous oral ulcers|
|Skin lesions: erythema nodosum-like lesions, thrombophlebitis, folliculitis, and cutaneous hypersensitivity|
|Ocular symptoms: iridocyclitis, retinitis, and sequelae of uveitis|
|2. Minor symptoms|
|Intestinal Behcet’s disease|
|Complete type: all four major symptoms present|
|Three out of the five following criteria are required to diagnose Behcet’s disease|
|1. Recurrent oral ulcers|
|2. Recurrent genital ulcers|
|3. Skin lesions|
|4. Eye lesions|
|(+) Skin pathergy test|
|Always exclude other causative factors|
2. Clinical picture
2.1 Non-ocular disease
Almost every organ and system can eventually be affected by this severe vasculitis. Painful, recurrent oral and genital ulcers are so frequent that their presence is part of the diagnostic criteria . Other skin manifestations are papulopustules, acneiform dermatitis, and erythema nodosum . Arthritis is also a common manifestation of the disease . Gastrointestinal involvement affects around 3–30% of cases with symptoms overlapping inflammatory bowel disease . Central nervous system (CNS) involvement can touch almost 31% of patients and makes the prognosis guarded . Venous thrombosis and arterial aneurysms are present in around 25% of cases .
2.2 Ocular disease
The classic clinical picture is the one of recurrent, bilateral, non-granulomatous posterior or panuveitis with retinal vasculitis. This is the case for almost 80% of patients, while in around 10% disease manifests as anterior, non-granulomatous uveitis with hypopyon and eventually synechiae (Figure 1) .
Disease seems to be more severe in males, and ocular pain, redness, photophobia, and blurred vision are almost always present.
Retinitis is also a classic and sight-threatening manifestation of posterior segment involvement, leading most of the time to retinal atrophy. Indeed, Behcet’s disease is one of the differential diagnoses of macular atrophy related to uveitis (Figure 2) .
Retinal vasculitis is the hallmark of the disease, it is obliterative in nature, it affects both arteries and veins, and, most importantly, it involves the capillaries .
Behcet’s disease is mainly a capillaropathy, being fluorescein angiography (FA) essential to its proper diagnosis and management. FA will better delineate areas of non-perfusion (Figure 3), capillary leakage (Figure 4), and vascular remodeling. The “fern-leaf”-shaped leakage pattern from capillaries, even though not pathognomonic, is highly evocative of BD (Figure 5).
Given the highly vascularized nature of choroidal tissue, it is not surprising to see choroidal involvement during active disease. Indocyanine green angiography (ICGA) shows irregular filling of the choriocapillaris, choroidal filling defects, and dye leakage from choroidal vessels . Enhanced depth imaging optical coherence tomography (EDI-OCT) shows increased subfoveal choroidal thickness even in eyes without evident uveitis activity, making this finding a possible indicator of subclinical ocular inflammation in patients with BD .
Optic neuropathy (ON), although considered a rare manifestation of Behcet´s disease, might actually be overshadowed by uveitis’ complications. It can appear during the course of already known BD (and should be considered as part of the neuro-BD disease spectrum), or it can even be the first manifestation of the disease (BD should then be kept in mind as a differential diagnosis of optic neuropathy in regions where its prevalence is high) . The prognosis of BD-associated ON seems not to be as poor as the one of BD uveitis, with excellent response to the combination of corticosteroids and immunosuppressants and recovery as the rule [18, 19]. However, the use of cyclosporine should be avoided in these cases since it could promote the development of neurologic involvement .
3. Etiology and pathogenesis
Despite years of research, BD remains idiopathic. Even though there are sporadic cases all around the world, disease is more prevalent along the ancient silk route and in countries located between 30 and 45 north latitude through the Mediterranean Basin, the Middle East, and Far East regions such as China and Japan . This particular geographic distribution points toward a genetic predisposing factor. The high frequency of HLA-B51 among a wide range of affected ethnic populations highlights the importance of a special genetic background: even though not considered as part of the diagnostic criteria, the positivity of HLA-B51 increases the risk of BD in around six times .
Besides the classic and well-known predisposition to BD associated with HLA-B51 positivity, new insights on disease’s pathogenesis came out from genome-wide association studies (GWAS). The disruption of different biological pathways might determine the intrinsic biological process in multifactorial diseases, as BD. Six biologic pathways have been recently identified as possible mechanisms in the pathogenesis of BD:focal adhesion pathway, MAPK (mitogen-activated protein kinase) signaling, TGF (transforming growth factor) beta signaling, ECM-receptor interaction, complement and coagulation cascades and proteasome pathways .
Then, on this special genetic background, environmental factors might play a role as triggers for disease development. Infectious agents have been postulated as these triggering factors. Recently, a relationship between periodontal disease and specific polymorphisms of interleukin (IL)-1alpha and (IL)-1beta in Turkish patients with BD was reported, making periodontitis-induced autoinflammatory response a candidate for the development or severity of BD via IL-1 gene alteration . Improvement of oral health among this high-risk population might affect BD course, leading to a better prognosis .
Neutrophils’ activation plays a predominant role in BD; this is evidenced through the positivity of pathergy test, one of the diagnostic criteria for the disease [2, 26]. The activation of the innate immune system against environmental and/or autoantigens in this particular genetic background is then perpetuated by the adaptive immune system .
4. Diagnosis and differential diagnosis
As it was already stated, diagnosis is clinical and based on the presence of different combinations of symptoms and signs. In the acute attack, patients usually show raised inflammatory acute reactants (sedimentation rate and C-reactive protein) and high levels of white blood cells, mainly neutrophils [28, 29].
Differential diagnosis of hypopyon uveitis encompasses HLA-B27 associated, endogenous/exogenous endophthalmitis, toxic anterior segment syndrome (TASS) after cataract surgery, and masquerade syndromes [31, 32, 33, 34, 35]. BD-associated retinal vasculitis is unique in its predilection for capillaries but a similar picture can eventually be found in cases of HLA-B27 posterior uveitis with retinal vasculitis [36, 37, 38, 39].
Topical treatment is reserved for the minority of cases in which anterior uveitis is the only ocular disease manifestation. Prednisolone acetate with or without cyclopentolate is usually enough to stop episodes of anterior non-granulomatous uveitis. However, if these attacks are frequent or inflammatory quiescence requires more than three drops per day of prednisolone acetate for long periods, systemic treatment should be initiated.
The majority of cases presenting with posterior uveitis will require systemic treatment to control the sight-threatening manifestations of the disease.
High-dose systemic corticosteroids (1 g intravenous of Solu-Medrol or 1 mg/kg/day of oral prednisone) are useful in severe acute inflammatory attacks. However, they should not be administered alone given the high risk of flare up while tapering and the side effect profile of high doses .
Azathioprine and cyclosporine have both shown to be effective in BD’s uveitis in two different randomized clinical trials (RCT) [41, 42, 43]. In many cases, a single agent is not enough to control uveitis, and a combination of them is administered. Drugs are usually well tolerated in long term, providing the proper check of their own side effects’ profile is performed (liver toxicity for azathioprine, renal toxicity for cyclosporine). The likelihood of patients on cyclosporine to develop CNS complications should be kept in mind, and the drug is not recommended in the management of BD’s associated optic neuropathy .
High levels of tumor necrosis factor (TNF) alpha are present in BD’s uveitis . The blockage of this inflammatory pathway is therefore a very effective approach to disease control. Infliximab (a chimeric monoclonal antibody against TNF alpha) and adalimumab (a fully humanized monoclonal antibody) are both widely used in the treatment of BD-associated posterior uveitis with high rates of success . Adalimumab has the advantage of subcutaneous administration, theoretically improving patients’ quality of life .
Interferon alpha-2ª is a very effective biologic treatment for BD’s associated posterior uveitis . Subcutaneously administered, it has rapid positive effect and also long relapse-free period making prophylactic maintenance treatment unnecessary [51, 52]. Drug is administered as a monotherapy after discontinuation of all previous immunosuppressive drugs (including corticosteroids). However, the associated flu-like syndrome limits the use of this important agent in the management of BD’s uveitis.
Cytotoxic agents (chlorambucil and cyclophosphamide) were in the past the drug of choice for this severe form of uveitis [53, 54]. Nowadays, however, given the more specific and less toxic agents available, they are only used in those settings
Intravitreal steroids (either triamcinolone acetonide, fluocinolone, or dexamethasone implant) are adjuvant rescue treatment in recalcitrant cases not responding to systemic medication or whenever systemic medication is contraindicated . Their effect is always transitory and associated with the risk of local complications (mainly cataract and glaucoma).
Visual prognosis is directly related to anatomical location of inflammation and rapid introduction of proper treatment. The minority of cases manifesting only by anterior uveitis usually shows excellent visual prognosis. Posterior uveitis, however, might be sight-threatening even if only one acute attack involves the macula. The development of modern biologic agents has positively changed the natural guarded prognosis of this disease even though there is still a low proportion of cases that will not respond to different combinations of treatment.
Behçet H. On relapsing, aphthous ulcers of the mouth, eye and genitalia caused by a virus. Clinical and Experimental Rheumatology. 2010. DOI: 10.1016/j.irle.2009.01.004
International Study Group for Behçet’s Disease. Criteria for diagnosis of Behcet’s disease. Lancet. 1990. DOI: 10.1016/0140-6736(90)92643-V
Davatchi F. Diagnosis/classification criteria for Behcet’s disease. Pathology Research International. 2012. DOI: 10.1155/2012/607921
Dilsen N. History and development of Behcet’s disease. Revue du Rhumatisme (English Ed.). 1996
Davatchi F, Sadeghi Abdollahi B, Chams-Davatchi C, et al. The saga of diagnostic/classification criteria in Behcet’s disease. International Journal of Rheumatic Diseases. 2015. DOI: 10.1111/1756-185X.12520
Kronborg C, Mahar PD, Kelly R. Should we keep changing the diagnostic criteria for Behçet’s disease? Dermatology. 2014. DOI: 10.1159/000355481
Scherrer MAR, Rocha VB, Garcia LC. Behçet´s disease: Review with emphasis on dermatological aspects. Anais Brasileiros de Dermatologia. 2017. DOI: 10.1590/abd1806-4841.20177359
Fatemi A, Shahram F, Akhlaghi M, Smiley A, Nadji A, Davatchi F. Prospective study of articular manifestations in Behçet’s disease: Five-year report. International Journal of Rheumatic Diseases. 2017. DOI: 10.1111/1756-185X.12633
Zhu Z, Shu X, Long S, et al. Ulcerative colitis followed by the development of typical intestinal Behçet disease. Med (United States). 2018. DOI: 10.1097/MD.0000000000009882
Akman-Demir G, Serdaroglu P, Tasçi B. Clinical patterns of neurological involvement in Behcet’s disease: Evaluation of 200 patients. Brain. 1999. DOI: 10.1093/brain/122.11.2171
Koc Y, Gullu I, Akpek G, et al. Vascular involvement in Behcet’s disease. The Journal of Rheumatology. 1992. DOI: 10.1016/j.revmed.2009.09.024
Zeghidi H, Saadoun D, Bodaghi B. Les manifestations oculaires de la maladie de Behçet. La Revue de Médecine Interne. 2014. DOI: 10.1016/j.revmed.2013.10.011
Takeuchi M, Iwasaki T, Kezuka T, et al. Functional and morphological changes in the eyes of Behçet’s patients with uveitis. Acta Ophthalmologica. 2010. DOI: 10.1111/j.1755-3768.2009.01536.x
Tugal-Tutkun I, Ozdal PC, Oray M, Onal S. Review for diagnostics of the year: Multimodal imaging in Behçet uveitis. Ocular Immunology and Inflammation. 2017. DOI: 10.1080/09273948.2016.1205100
Atmaca LS, Sonmez PA. Fluorescein and indocyanine green angiography findings in Behcet’s disease. The British Journal of Ophthalmology. 2003. DOI: 10.1136/bjo.87.12.1466
Chung Y-R, Cho EH, Jang S, Lee SY, Lee E-S, Lee K. Choroidal thickness indicates subclinical ocular and systemic inflammation in eyes with Behçet disease without active inflammation. Korean Journal of Ophthalmology. 2018. DOI: 10.3341/kjo.2017.0139
Akdal G, Toydemir HE, Saatci AO, et al. Characteristics of optic neuropathy in Behçet disease. Neurology: Neuroimmunology & Neuroinflammation. 2018. DOI: 10.1212/NXI.0000000000000490
Kidd DP. Optic neuropathy in Behçet’s syndrome. Journal of Neurology. 2013. DOI: 10.1007/s00415-013-7070-4
Khanfir MS, Belfeki N, Said F, et al. Inflammatory optic neuropathy in Behçet’s disease. Reumatismo. 2015. DOI: 10.4081/jlimnol.2014.817
Akmar-Demir G, Ayranci O, Kurtuncu M, Vanli EN, Mutlu M, Tugal-Tutkun I. Cyclosporine for Behçet’s uveitis: Is it associated with an increased risk of neurological involvement? Clinical and Experimental Rheumatology. Jul-Aug 2008; 26(4 Suppl 50):S84-S90
Alpsoy E. Behçet’s disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions. The Journal of Dermatology. 2016. DOI: 10.1111/1346-8138.13381
De Menthon M, LaValley MP, Maldini C, Guillevin L, Mahr A. HLA-B51/B5 and the risk of Behçet’s disease: A systematic review and meta-analysis of case-control genetic association studies. Arthritis Care and Research. 2009. DOI: 10.1002/art.24642
Bakir-Gungor B, Remmers EF, Meguro A, et al. Identification of possible pathogenic pathways in Behçet’s disease using genome-wide association study data from two different populations. European Journal of Human Genetics. 2015. DOI: 10.1038/ejhg.2014.158
Akman A, Ekinci NC, Kacaroglu H, Yavuzer U, Alpsoy E, Yegin O. Relationship between periodontal findings and specific polymorphisms of interleukin-1α and -1β in Turkish patients with Behçet’s disease. Archives of Dermatological Research. 2008. DOI: 10.1007/s00403-007-0794-1
Mumcu G, Ergun T, Inanc N, et al. Oral health is impaired in Behçet’s disease and is associated with disease severity. Rheumatology. 2004. DOI: 10.1093/rheumatology/keh236
Davatchi F, Chams-Davatchi C, Ghodsi Z, et al. Diagnostic value of pathergy test in Behcet’s disease according to the change of incidence over the time. Clinical Rheumatology. 2011. DOI: 10.1007/s10067-011-1694-5
Direskeneli H. Autoimmunity vs autoinflammation in Behcet’s disease: Do we oversimplify a complex disorder? Rheumatology. 2006. DOI: 10.1093/rheumatology/kel329
Fordham JN, Davies PG, Kirk A, Currey HLF. Polymorphonuclear function in Behcet’s syndrome. Annals of the Rheumatic Diseases. 1982. DOI: 10.1136/ard.41.4.421
Garcia Garcia O, Vidaller Palacin A, Munoz Sanchez J, Roca Linares G. [Granulocyte-apheresis in ocular Behcet’s disease resistant to medical treatment]. Archivos de la Sociedad Española de Oftalmología. Spanish; Jul 2004;79(7):335-340
Wallace GR, Niemczyk E. Genetics in ocular inflammation-basic principles. Ocular Immunology and Inflammation. 2011. DOI: 10.3109/09273948.2010.543306
Mamalis N, Edelhauser HF, Dawson DG, Chew J, LeBoyer RM, Werner L. Toxic anterior segment syndrome. Journal of Cataract and Refractive Surgery. 2006. DOI: 10.1016/j.jcrs.2006.01.065
Zaidi AA, Ying GS, Daniel E, et al. Hypopyon in patients with uveitis. Ophthalmology. 2010. DOI: 10.1016/j.ophtha.2009.07.025
Iannetti L, Corsi C, Iafrate F, Sammartino P, Di Giorgio A, Pezzi PP. Bilateral uveitis with hypopyon as a presenting symptom of metastatic peritoneal carcinomatosis. European Journal of Ophthalmology. 2010
Sudharshan S, Kumari A, Biswas J. Bilateral hypopyon as the presenting feature of chronic myeloid leukemia. Ocular Immunology and Inflammation. 2008. DOI: 10.1080/09273940802411437
Corriveau C, Easterbrook M, Payne D. Lymphoma simulating uveitis (masquerade syndrome). Canadian Journal of Ophthalmology. 1986
Sharma R, Randhawa S. Hemorrhagic ischemic retinal vasculitis and alopecia areata as a manifestation of HLA-B27. Ophthalmic Surg Lasers Imaging Retina. 2018. DOI: 10.3928/23258160-20171215-10
Pathanapitoon K, Dodds EM, Cunningham ET, Rothova A. Clinical spectrum of HLA-B27-associated ocular inflammation. Ocular Immunology and Inflammation. 2017. DOI: 10.1080/09273948.2016.1185527
Braakenburg AM, Rothova A. The clinical characteristics of retinal vasculitis in HLA-B27-positive patients. Ocular Immunology and Inflammation. 2014. DOI: 10.3109/09273948.2013.835429
Dodds EM, Lowder CY, Meisler DM. Posterior segment inflammation in HLA-B27+ acute anterior uveitis: Clinical characteristics. Ocular Immunology and Inflammation. 1999; 7(2):85-92. DOI: 10.1076/ocii.184.108.40.20615
Reed JB, Morse LS, Schwab IR. High-dose intravenous pulse methylprednisolone hemisuccinate in acute Behcet retinitis. American Journal of Ophthalmology. 1998. DOI: 10.1016/S0002-9394(99)80163-9
Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in Behçet’s syndrome. The New England Journal of Medicine. 1990. DOI: 10.1056/NEJM199002013220501
Saadoun D, Wechsler B, Terrada C, et al. Azathioprine in severe uveitis of Behçet’s disease. Arthritis Care & Research (Hoboken). 2010. DOI: 10.1002/acr.20308
Masuda K, Urayama A, Kogure M, Nakajima A, Nakae K, Inaba G. Double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behçet’s disease. Lancet. 1989. DOI: 10.1016/S0140-6736(89)92381-7
Kotake S, Higashi K, Yoshikawa K, Sasamoto Y, Okamoto T, Matsuda H. Central nervous system symptoms in patients with Behcet disease receiving cyclosporine therapy. Ophthalmology. 1999. DOI: 10.1016/S0161-6420(99)90120-3
Nalbant S, Sahan B, Durna M, et al. Cytokine profile in Behçet uveitis. Bratislava Med J. 2008. DOI: 10.1016/j.solmat.2011.10.028
Imrie FR, Dick AD. Biologics in the treatment of uveitis. Current Opinion in Ophthalmology. 2007. DOI: 10.1097/ICU.0b013e3282f03d42
Ramanan AV, Benton D, Compeyrot-Lacassagne S, Dawoud D, Hardwick B, Hickey H, et al. A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial). Trials. 2014. DOI: 10.1109/ICM.2008.5393823
Lopalco G, Emmi G, Gentileschi S, et al. Certolizumab Pegol treatment in Behcet’s disease with different organ involvement: A multicenter retrospective observational study. Modern Rheumatology. 2017. DOI: 10.1080/14397595.2017.1285857
Vitale A, Emmi G, Lopalco G, et al. Long-term efficacy and safety of golimumab in the treatment of multirefractory Behçet’s disease. Clinical Rheumatology. 2017. DOI: 10.1007/s10067-017-3627-4
Yalçindağ FN, Uzun A. Results of interferon alpha-2a therapy in patients with Behcet’s disease. Journal of Ocular Pharmacology and Therapeutics. 2012. DOI: 10.1089/jop.2011.0238
Diwo E, Gueudry J, Saadoun D, Weschler B, LeHoang P, Bodaghi B. Long-term efficacy of interferon in severe uveitis associated with Behçet disease. Ocular Immunology and Inflammation. 2017. DOI: 10.1080/09273948.2016.1206204
Onal S, Kazokoglu H, Koc A, et al. Long-term efficacy and safety of low-dose and dose-escalating interferon alfa-2a therapy in refractory Behçet uveitis. Archives of Ophthalmology. 2011. DOI: 10.1001/archophthalmol.2011.3
Mudun BA, Ergen A, Ipcioglu SU, Burumcek EY, Durlu Y, Arslan MO. Short-term chlorambucil for refractory uveitis in Behcet’s disease. Ocular Immunology and Inflammation. 2001. DOI: 10.1007/s00066-005-1394-7
Davatchi F, Sadeghi Abdollahi B, Shams H, et al. Combination of pulse cyclophosphamide and azathioprine in ocular manifestations of Behcet’s disease: Longitudinal study of up to 10 years. International Journal of Rheumatic Diseases. 2014. DOI: 10.1111/1756-185X.12248
Fabiani C, Emmi G, Lopalco G, et al. Intravitreal dexamethasone implant as an adjunct weapon for severe and refractory uveitis in Behçet’s disease. The Israel Medical Association Journal. 2017