Behcets disease

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Original article contributed by: Eesha Shukla
All contributors: Eesha Jayant Shukla and Russell W. Read, MD, PhD
Assigned editor:
Review: Assigned status Not reviewed by Eesha Shukla on May 26, 2015.


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Disease Entity

Behcet's disease is a chronic, relapsing, multisystem, idiopathic inflammatory disorder characterized by a triad of oral ulcers, genital ulcers, and ocular lesions. However, the spectrum of disease is even wider with the involvement of articular, intestinal, vascular, urogenital, and neurologic systems, besides the mucocutaneous and ocular findings.[1,2] 

The disease has a higher prevalence particularly in Turkey, Iraq, Iran, Korea, and Japan and accounts for up to 20% of cases of endogenous uveitis in some of these countries.[3,4] The diagnosis of Behcet's disease is based on the identification of its typical clinical features, according to the diagnostic criteria laid down by the International Study Group and the Japanese criteria for the diagnosis of Behcet's disease.[5,6]

Disease

Etiology

The etiology of Behcet's disease remains still unknown, but the most accredited hypothesis suggests a complex interaction between genetic background and environmental factors, such as microbial agents or their antigens (related to herpes simplex virus, streptococci, staphylococci, orEscherichia species) [8]. Human leukocyte antigen (HLA)-B 51, one of the numerous split antigens of HLA-B 5, is the strongest genetic marker of BD in different ethnic groups, as reported both in genome wide association [5, 6] and in meta-analysis studies [11-13]. Although HLA-B 51's mode of action is unclear, antigen presentation ability, molecular mimicry with microbial antigens, or participation in linkage disequilibrium with other genes has been suggested as potential contributive mechanisms in the pathogenesis of BD [11-13]. However, major pathogenetic mechanisms underlying BD are linked to innate immune cell activation and dysregulation, and hyperactivity of neutrophils, T-helper- (Th-) 1, and Th-17 natural killer (NK) cells, the main result of which is the critical overproduction of proinflammatory cytokines, such as tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-17 [14].☀k Factors

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General Pathology

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Pathophysiology

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Primary prevention

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Diagnosis

The International Criteria for Behcet's Disease (ICBD) was created in 2006 which underwent revision in 2011.15 ICBD are the latest diagnosis/classification criteria, created by the participation of 27 countries from different parts of the world.

They are as follows: 

  1. Oral aphthosis (OA)
  2. Genital aphthosis (GA)
  3. Skin manifestations, comprising pseudofolliculitis (PF) and erythema nodosum (EN)
  4. Ocular manifestations; anterior uveitis (AU), posterior uveitis (PU), and retinal vasculitis (RV).
  5. Presence of pathergy phenomenon (PP). It is detected by the pathergy test.
  6. Vascular Malformation (VM) is defined as superficial phlebitis, deep vein thrombosis, large vein thrombosis, arterial thrombosis, and aneurysm.


In the ICBD, genital aphthous lesions and eye lesions have more diagnostic value than the others. They get each 2 points. The other 4 items (OA, skin, VM, PP) get one point each. A patient has to get 3 or more points to be diagnosed/classified as having BD.

History

Behçet’s syndrome (BS) is a multisystemic vasculitic disorder which can affect a number of different systems. It was first described by the Turkish dermatologist, Halushi Behçet in 1937, who described a triad of oral ulceration, genital ulceration and ocular inflammation

Physical examination

Signs

Mucous Membrane involvement is in the form of apthous ulcers and genital ulcers

Dermatologic Involvement is in the form of Papulopustular lesions (Behçet’s pustulosis), erythema nodosum.

Central Nervous system involvement is in the form of Meningoencephalitis, parenchymal disease (pyramidal signs, hemiparesis, behavioral changes, sphincter disturbance), intracranial hypertension secondary to dural sinus thrombosis

Genital involvement is in the form of genital ulcers, epididymitis.

Gastrointestinal Tract Involvement is in the form of ileocecal involvement which mimics Crohn's Disease. In general, two forms of intestinal Behçet’s disease exist - neutrophilic phlebitis that leads to mucosal inflammation and ulcer formation and large vessel disease (i.e., mesenteric arteries) that results in intestinal ischemia and infarction.

Cardiac Involvement is in the form of  pericarditis, myocardial (diastolic and/or systolic) dysfunction, valvular, coronary (thrombosis, aneurysms, rupture), and intracardiac thrombus.

Ocular Behcet's:

In the anterior segment, it presents with AAU, which may be simultaneously bilateral and frequently associated with a transient mobile hypopyon in a relatively white eye (Cold Hypopuon). It usually responds well to topical steroids.

The posterior segment features may be in the form of retinitis, vitritis, or retinal vasculitis which may affect arteries as well as veins.

Retinitis may present either as a transient, white, superficial infiltrates that heal without scarring which may be seen acutely or diffuse retinitis similar in appearance to a virus-induced lesion. Retinal vasculitis may result in occlusion leading to retinal ischemia and subsequent neovascularisation. Vascular leakage may give rise to diffuse retinal edema, cystoid macular edema and disc edema. Vitritis, may be severe and persistent, is almost always seen in eyes with active disease. Optic atrophy, vascular occlusion and gliotic sheathing may all be seen in end stage disease but the vitreous is remarkably clear by this stage. Other manifestations, which are uncommon, include conjunctivitis, conjunctival ulcers, episcleritis, scleritis, internuclear ophthalmoplegia, etc.

Symptoms

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Clinical diagnosis

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Diagnostic procedures

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Laboratory test

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Differential diagnosis

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Management

It is important to address the multisystem involvement of Behcets disease . Prompt and aggressive immunosuppressive therapy may result in lasting remission and prevent vascular occlusion. Acute anterior uveitis may be managed with topical steroids alone , while the posterior segment manifestations often require a combination of steriods and immunosuppressants. Systemic steroids will shorten the duration of an inflammatory episode but an additional agent is usually required. Azathioprine does not act rapidly enough in acute disease but is suitable for long-term therapy. Ciclosporin is effective and rapidly acting but is associated with nephrotoxicity, particularly at doses higher than 5 mg/kg/day; relapses after cessation often limit its use. Subcutaneous interferon alfa is very effective for mucocutaneous lesions and may also be used to treat ocular disease resistant to high dose steroids. Side-effects are dose-dependent and include flu-like symptoms, hair loss, itching and depression. Biological blockers such as infliximab show promise in treating retinal vasculitis.18


General treatment

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Medical therapy

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Medical follow up

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Surgery

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Surgical follow up

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Complications

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Prognosis

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Additional Resources

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References

1. Sakane T, Takeno M, Suzuki N, Inaba G. Behçet's disease. N Engl J Med. 1999;341:1284–91. [PubMed]

2. Michelson JB, Chisari FV. Behçet's disease. Surv Ophthalmol. 1982;26:190–203. [PubMed]

3.Azizlerli G, Köse AA, Sarica R, Gül A, Tutkun IT, Kulaç M, et al. Prevalence of Behçet's disease in Istanbul, Turkey. Int J Dermatol. 2003;42:803–6. [PubMed]

4. Mishima S, Masuda K, Izawa Y, Mochizuki M, Namba K. The eighth Frederick H. Verhoeff Lecture. presented by saiichi mishima, MD Behçt's disease in Japan: Ophthalmologic aspects. Trans Am Ophthalmol Soc. 1979;77:225–79. [PMC free article] [PubMed]

5. Behcet's Disease Research Committee of Japan. Behcet's disease guide to the diagnosis of Behcet's disease (1972) Japanese Journal of Ophthalmology. 1974;18:291–4.

6. Criteria for diagnosis of Behçet's disease. International study group for Behçet's disease. Lancet.1990;335:1078–80. [PubMed]

7. Caso F, Costa L, Rigante D, et al. Biological Treatments in Behçet’s Disease: Beyond Anti-TNF Therapy. Mediators of Inflammation. 2014;2014:107421. doi:10.1155/2014/107421.

8. Direskeneli H. Behçet’s disease: infectious aetiology, new autoantigens, and HLA-B51. Annals of the Rheumatic Diseases. 2001;60(11):996–1002. [PMC free article] [PubMed]

9. Remmers EF, Cosan F, Kirino Y, et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s disease. Nature Genetics.2010;42(8):698–702. [PMC free article] [PubMed]

10. Kirino Y, Bertsias G, Ishigatsubo Y, et al. Genome-wide association analysis identifies new susceptibility loci for Behçet’s disease and epistasis between HLA-B∗51 and ERAP1. Nature Genetics. 2013;45(2):202–207. [PMC free article] [PubMed]

11. Maldini C, Lavalley MP, Cheminant M, de menthon M, Mahr A. Relationships of HLA-B51 or B5 genotype with Behçet’s disease clinical characteristics: systematic review and meta-analyses of observational studies. Rheumatology. 2012;51(5):887–900. [PubMed]

12. Piga M, Mathieu A. Genetic susceptibility to Behçet’s disease: role of genes belonging to the MHC region. Rheumatology. 2011;50(2):299–310.keq331 [PubMed]

13. 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;61(10):1287–1296. [PMC free article] [PubMed]

14. Pineton de Chambrun M, Wechsler B, Geri G, Cacoub P, Saadoun D. New insights into the pathogenesis of Behçet’s disease. Autoimmunity Reviews. 2012;11(10):687–698. [PubMed]

15. Davatchi F. Diagnosis/Classification Criteria for Behcet’s Disease. Pathology Research International. 2012;2012:607921. doi:10.1155/2012/607921.

16. Behçet H. Uber rezivirde, aphtose, durch virus verursachte. Geshwure am Mund, am Auge, und den Genitalien. Dermatol Wochenschr. 1937:1153–1157

17. Vaiopoulos AG, Sfikakis PP, Kanakis MA, Vaiopoulos G, Kaklamanis PG. Gastrointestinal manifestations of Behçet’s disease: advances in evaluation and management. Clin Exp Rheumatol.2014;32:S140–S148. [PubMed] 18.Jack J Kanski, et al, 7th ed Systematic Approach to clinical ophthalmology