Behcet Disease

Article Author:
Abdullah Adil
Article Editor:
Jessilin Quint
Updated:
11/7/2019 4:14:17 PM
PubMed Link:
Behcet Disease

Introduction

Behcet’s disease, also known as an oculo-orogenital syndrome, is a chronic remitting and relapsing inflammatory disorder characterized by recurrent oral aphthous ulcers, genital ulcerations, ocular manifestations (e.g., uveitis, conjunctivitis) and other systemic involvement. It is also known as Behcet syndrome and Malignant aphthosis.[1][2][3][4]

Etiology

The exact etiological basis of Behcet’s disease is unknown. It is considered to be an autoimmune disease triggered by infections like herpes simplex virus (HSV), Streptococcus, and Staphylococcus in genetically predisposed individuals. Genetic predisposition to develop this syndrome has been found in HLA-B51 carriers. The current belief is that exposure to an infectious agent or an external agent somehow initiates an autoimmune response.

Behcet disease tends to occur sporadically but familial aggregation is also known to occur. Carriers of HLA-B51 are at high risk for developing Behcet disease compared to non-carriers. HLA B51 is a common genetic factor prevalent in Japanese, middle eastern and turkish populations.

Epidemiology

The incidence and prevalence of this disease are high amongst the Far Eastern and Mediterranean ancestries. Turkey has the highest prevalence affecting 420 people per 100,000 population.

It affects patients in their twenties and thirties; however early and late onsets have been reported. Both genders are equally affected by the disease; a male predominance is observed in Arab populations while female predominance is evident in Korea, China, the United States, and some northern European countries.

Behcet disease is more common in males than in females. The more severe disease also tends to occur in males. Females, on the other hand, are more likely to develop skin manifestations including erythema nodosum. Behcet disease tends to be common in between the 2-4 decades of life. If the disorder develops before age 25, the individual is more likely to have severe disease with eye involvement.

Pathophysiology

Behcet’s disease is characterized by vasculitis of all sized vessels that involves both arterial and venous sides of the circulation. Cell-mediated immunity plays a major role in the pathogenesis of this disease. Helper T- cells type-1 activation leads to increased circulating levels of CD-4 positive and cytotoxic (CD8 positive) lymphocytes in the peripheral blood which target the oral mucosa, skin and other systems of the body. There are a number of immunological findings in Behcet's disease;

  • Autoantibodies are circulating in patients' blood against different components like intermediate filaments found in mucous membranes etc.
  • Immune complexes circulating in the blood and their deposition at the involved sites.
  • Decreased complement levels in patients' blood
  • Immunoglobulin and complement deposition within and around blood vessels.
  • Evidence of the decreased ratio of CD4+ to CD8+ cells has also been observed.

However, the common pathogenic denominator is leukocytoclastic vasculitis which is considered to be pathognomonic for the disease. Due to the involvement of immune complexes, the disease shares a number of common features to other diseases (e.g., SLE)  which have similar pathogenesis. An example of this is erythema nodosum commonly manifested in these disease.[4][5][6][7]

Histopathology

Histopathological features of the disease are vasculitis and thrombosis. Mucocutaneous lesions biopsies show a neutrophil-predominant reaction with endothelial swelling, extravasation of RBCs and leukocytoclastic vasculitis (suggestive sign of the disease) with fibrinoid necrosis of the blood vessel walls. Some older lesions show lymphocytic perivasculitis. However, a neutrophilic vascular reaction is considered to be the most predominant reaction in Behcet's disease. The involvement of vasa vasorum (vasculitis) may result in the formation of aneurysms in the large arteries.

History and Physical

Typically patients have a history of recurrent painful oral lesions (aphthous ulcers) with odynophagia, foul-smelling breath, photophobia, vision loss, joint pains, and painful genital lesions.

Multiple aphthous ulcers in the oral cavity involving the soft palate, hard palate, buccal mucosa, and tonsils, having a sharp regular border with a grayish base and surrounding bright red halo. Genital lesions may occur on the scrotum in males and vulva and vagina in females.

Ocular manifestations may include conjunctivitis, uveitis, and hypopyon. Retinal vasculitis or posterior uveitis is the most classic ocular sign and an important cause of blindness in these patients. Other secondary ocular complications are cataract, glaucoma and neovascular lesions. Retinal inflammation can lead to vascular occlusion and ultimately results in tractional retinal detachment. Recurrent vasculitic changes can ultimately result in ischemic optic nerve atrophy and can cause blindness.

Non-deforming arthritis of medium and large joints is seen in many patients. The characteristic arthritis is non-erosive, asymmetrical, sterile and seronegative; however symmetrical polyarticular involvement is comm in Behcet's disease. Joint manifestations frequently occur in one knee or ankle and then other as a migratory monoarthritis, then in both joints simultaneously and finally affecting nearly all joints of the body. An important differential to be excluded is an HLA-B27-positive erosive sacroiliitis.

Neurological and gastrointestinal manifestations may also be seen. Neurological manifestations include meningoencephalitis, cerebral venous thrombosis, benign intracranial hypertension, cranial nerve palsies, and various pyramidal and extrapyramidal lesions.

Behcet’s disease is characterized by both arterial and venous thrombosis; however arterial involvement is rare. A swollen tender calf (due to deep venous thrombosis) in a patient with orogenital ulcers and eye involvement is highly suggestive of Behcet’s disease.

Gi involvement occurs in 10% of patients and may affect the esophagus and terminal ileum. Ulceration is common resulting in Gi bleeding.

Renal involvement may include amyloidosis, proteinuria, and even glomerulonephritis.

Cardiac features may include pericarditis, myocarditis, endocarditis, valvular regurgitation, and coronary artery vasculitis

Criteria for Diagnosis

Must have at least three episodes of aphthous or herpetiform ulcers within a 12 month period.  In addition, two of the following need to be present:

  1. Ophthalmic lesions including hypopyon, uveitis or retinal vasculitis
  2. Skin lesions- erythema nodosum
  3. Recurrent painful ulcers in the genital area
  4. Positive pathergy skin testing
  5. Age of onset between 25-35
  6. Multiple organ involvement
  7. Relapsing and remitting course

Evaluation

Diagnosis is mainly clinical, and the diagnostic criteria consist of recurrent oral aphthous stomatitis with two or more of the following clinical findings in the absence of other systemic diseases:

  1. Recurrent painful genital lesions
  2. Ocular lesions; retinal vasculitis or uveitis
  3. Skin lesions (e.g., erythema nodosum, papulopustular lesions)or a positive Pathergy test (a sterile pustule that appears after local trauma to the skin)
  4. Central nervous system (CNS) lesions (e.g., cerebral infarction, meningoencephalitis).

Depending on the organ involved, imaging studies are necessary. This may involve x-rays to assess the joint, CT brain to assess for bleeding, thrombosis, and ischemia. Angiography is done to look for coronary artery aneurysms. Lumbar puncture and arthrocentesis are often done to rule out other disorders.

Laboratory findings are usually non-specific.

Treatment / Management

Medical Intervention

Treatment is aimed at preventing the recurrence of the disease. Treatment strategy depends on the site and severity of the disease. Following order shows the treatment plan according to involvement sites and severity:

  • Mucocutaneous involvement: Topical antibiotics, topical corticosteroids, sucralfate
  • Ocular disease: topical corticosteroids+mydriatics or cycloplegics
  • Articular involvement (arthritis): Colchicine, NSAIDs, Benzathine penicillins
  • Vascular involvement: Systemic corticosteroids
  • CNS involvement: Systemic corticosteroids
  • GIT involvement: Sulfasalazine, corticosteroids

In pregnancy, prednisolone is the systemic drug of choice without potential side effects related to pregnancy.

For refractory cases, the following drugs are being used as second and third-line therapies:

  • Immunomodulators (e.g., azathioprine, cyclosporine)
  • Immunosuppressive drugs (methotrexate, cyclophosphamide)
  • Anti-Tumor Necrosis Factor-alpha (e.g., infliximab). These agents are increasingly used and have become the standard of therapy. Adalimumab has been shown to suppress the skin features of the disorder.

Surgical Intervention

Surgical interventions are used at the last resort if all the medical interventions failed. It is mostly used in extensive vascular involvement refractory to medical management. Surgery is also used to manage fistulas, intestinal stenosis, perforation, pulmonary artery aneurysms, glaucoma, cataracts, and CNS aneurysms.[8][9][10]

Differential Diagnosis

Differential diagnoses include:

  • Sweet syndrome
  • Erythema multiforme
  • Pemphigus

Prognosis

Behcet disease has no cure and is associated with enormous morbidity and mortality. Most data indicate that the death rate varies from 5-20% at 7 years. These patients are prone to developing coronary and pulmonary artery aneurysms. In addition, CNS involvement is also associated with high mortality. When the eye is involved, vision loss and permanent blindness also occur.

Complications

Morbidity

Ophthalmic and neurological complications are the leading causes of morbidity in these patients. Others are severe vascular and extensive gastrointestinal involvement.

Pearls and Other Issues

Prevention

Severe or progressive recurrent aphthous stomatitis in patients should raise suspicion of the disease, and they should be followed for up to years as potential candidates for Behcet's disease. Especially those with a strong family history.

Patients who are suspected to have this disease should be referred for specialty consultation.

Patients (especially males) who present with systemic involvement as a presenting sign should be treated with systemic drugs.

Patients who have early onset of the disease have a poor prognosis.

Enhancing Healthcare Team Outcomes

Because of the diverse presentation of Behcet disease, it is best managed by an interprofessional team that consists of an ophthalmologist, rheumatologist, internist, cardiologist, neurologist, dermatologist, vascular surgeon, and a gastroenterologist. There is no cure for the disease and all treatments are aimed at preventing a recurrence. The disorder is not easy to diagnose and often requires consultation from the rheumatologist.

Besides corticosteroids, the patients are treated with newer biological therapies. The pharmacist should educate the patient on the importance of medication compliance. In addition, a wound care nurse should be involved as these patients develop skin ulcers, fistulas, and rashes. Surgery is sometimes required when the peripheral vessels are involved.  Because the condition is rare in North America, the team should have weekly meetings and decide on the steps to treatment. Close communication between the members is vital to prevent complications.

The disease is progressive and patients need life long monitoring. Family members have to be screened early on to prevent the high morbidity. Overall, the prognosis for most patients with Behcet disease is poor. [11](Level V)


References

[1] Dal NE,Cerci P,Olmez U,Keskin G, The role of vitamin D receptor gene polymorphisms in the pathogenesis of Behçet's disease: A case-control study in Turkish population. Annals of human genetics. 2019 Feb 7;     [PubMed PMID: 30730049]
[2] Emre S,Güven-Yılmaz S,Ulusoy MO,Ateş H, Optical coherence tomography angiography findings in Behcet patients. International ophthalmology. 2019 Feb 1;     [PubMed PMID: 30710254]
[3] Hamza N,Ben Sassi S,Nabli F,Nagi S,Mahmoud M,Ben Abdelaziz I,Hentati F, Stroke revealing Neuro-Behçet's disease with parenchymal and extensive vascular involvement. Journal of the neurological sciences. 2019 Jan 26;     [PubMed PMID: 30708211]
[4] Çalık AN,Özcan KS,Mesci B,Çınar T,Çanga Y,Güngör B,Kavala M,Oğuz A,Bolca O,Kozan Ö, The association of inflammatory markers and echocardiographic parameters in Behçet's disease. Acta cardiologica. 2019 Jan 28;     [PubMed PMID: 30689956]
[5] Kechida M,Salah S,Kahloun R,Klii R,Hammami S,Khochtali I, Cardiac and vascular complications of Behçet disease in the Tunisian context: clinical characteristics and predictive factors. Advances in rheumatology (London, England). 2018 Oct 1;     [PubMed PMID: 30657088]
[6] Koca TT, Clinical Significance of Serum Bilirubin in Behçet's Disease. Journal of translational internal medicine. 2018 Dec;     [PubMed PMID: 30637206]
[7] Kötter I,Reinhold-Keller E, [Vasculitis mimics]. Zeitschrift fur Rheumatologie. 2019 Feb;     [PubMed PMID: 30627843]
[8] Kirino Y,Nakajima H, Clinical and Genetic Aspects of Behçet's Disease in Japan. Internal medicine (Tokyo, Japan). 2019 Jan 10;     [PubMed PMID: 30626832]
[9] Albayrak O,Oray M,Can F,Uludag Kirimli G,Gul A,Tugal-Tutkun I,Onal S, Effect of Interferon alfa-2a Treatment on Adaptive and Innate Immune Systems in Patients With Behçet Disease Uveitis. Investigative ophthalmology     [PubMed PMID: 30601931]
[10] Emmi G,Bettiol A,Silvestri E,Di Scala G,Becatti M,Fiorillo C,Prisco D, Vascular Behçet's syndrome: an update. Internal and emergency medicine. 2018 Nov 29;     [PubMed PMID: 30499073]
[11] Barešić M,Reihl M,Habek M,Vukojević N,Anić B, Improvement of neurological and ocular symptoms of Behçet's disease after the introduction of infliximab. Rheumatology international. 2018 Jul;     [PubMed PMID: 29777341]