Behcet Disease

Etiology

The exact etiological basis of Behcet disease remains unknown, although genetics and environmental factors have been found to play a role.

Increased prevalence along the "Silk Route" and familial aggregation suggest a genetic element, although Behcet disease does not follow a mendelian inheritance. The most frequent association is with carriers of HLA-B51/B5, who are at high risk for developing Behcet disease compared to non-carriers.[2] HLA B51 is a common genetic factor prevalent in Japanese, middle eastern, and Turkish populations. Several other genes have been identified, including tumor necrosis factor (TNF), heat shock proteins, and major histocompatibility complex class I chain-related genes. Still, their independent contribution to the development of Behcet disease is debatable.[3]

Exposure to infectious agents, especially hypersensitivity to Streptococcus sanguinis antigens, has suggested a pathological role.[4][5] While many other infectious agents, including Staphylococcus aureus, Herpes simplex virus type 1, and Prevotella species, have been suggested as potential culprits, their direct association with the development of Behcet disease has not been confirmed.[6] The current belief is that exposure to an infectious or an external agent somehow initiates an auto-inflammatory response in genetically predisposed individuals.

Epidemiology

Behcet disease usually affects young adults 20 to 40 years of age and is also seen in children less frequently.[7][8] 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. The disease has a more severe course in males and younger populations.[9] Most cases are sporadic, although familial clusters are also reported.[10] Genetic anticipation, described as the earlier onset of disease in successive generations, has also been described.[11]

The geographic pattern of the disease suggests a distribution along the ancient "Silk Route" with the highest incidence in the Middle and the Far East. Turkey has the highest prevalence affecting 420 people per 100,000 population.[12] In the United States, the prevalence is 5.2 people per 100,000 population.[13]

Pathophysiology

Behcet disease is an auto-inflammatory vasculitis involving arteries and veins of all sizes and types. In contrast to other vasculitides, vasculitic lesions in Behcet disease lack necrotizing vasculitis or giant cell formation. Venular involvement and formation of pulmonary and arterial aneurysms are unique to Behcet disease.[14] Furthermore, patients with Behcet disease lack specific autoantibodies, as seen in other autoimmune disorders such as systemic lupus erythematosus.

Cell-mediated immunity plays a significant role in the pathogenesis of this disease. Type 1 helper T (Th1) cell activation leads to increased circulating levels of T-lymphocytes, accounting for various symptoms of Behcet disease. Pro-inflammatory cytokines, including IL-1, IL-8, IL-12, IL-17, IL-37, and TNF, are increased in Behcet disease and are thought to be involved in the pathogenesis. They may also serve as an indicator of disease severity. Increased macrophage activation, neutrophil chemotaxis, and phagocytosis have been observed in lesions of Behcet disease. Mucocutaneous lesions, including oral aphthae, skin pustules, and erythema nodosum, are thought to result from increased neutrophil activation leading to a neutrophilic vascular reaction that causes tissue injury.[15] Circulating immune complexes play a role in causing the characteristic neutrophilic vascular reaction. Anti-endothelial cell antibodies and endothelial cell dysfunction are also thought to play a role in the pathogenesis of Behcet disease.[16]

Histopathology

Histopathological features of the disease are vasculitis and thrombosis. Biopsy of the mucocutaneous lesions shows a neutrophil-predominant reaction with endothelial swelling, extravasation of RBCs, and leukocytoclastic vasculitis with fibrinoid necrosis of the blood vessel walls. The presence of lymphocytic vasculitis represents older lesions, and a neutrophilic vascular reaction is considered the most predominant reaction in Behcet disease. The involvement of vasa vasorum (vasculitis) may result in the formation of aneurysms in the large arteries.[17] Synovial fluid analysis in Behcet disease reveals neutrophil-predominant leucocyte counts varying from 300 cells/mm^3 to more than 30,000 cells/mm^3.[18]

History and Physical

While mucocutaneous lesions are the hallmark of Behcet disease, the most severe manifestations are uveitis, large vessel, and neurological involvement.

Aphthae

Oral ulcers occur in 97% to 99% of patients with Behcet disease, often representing the initial clinical feature. Lesions are usually painful, recurrent, and multiple and may involve the soft palate, hard palate, buccal mucosa, tongue, gingiva, lips, and tonsils. More than 90% of oral ulcers heal without scarring.

Genital lesions are seen in more than 80% of patients with Behcet disease. These lesions are also recurrent, although, in contrast to oral lesions, more than 70% of genital lesions heal with scarring. Genital ulcers occur on the scrotum (90%) in males and the vulva or vagina in females.

Cutaneous Manifestations

 Several cutaneous manifestations of Behcet disease have been described. Erythema nodosum-like lesions on the lower extremity are common. Behcet disease-related erythema nodosum lesions show a more vasculitic component compared to erythema nodosum, which is idiopathic or from other causes.[19] Superficial thrombophlebitis appearing as nodular lesions may be associated with deep vein thrombosis. Acneiform or pseudofolliculitis lesions are common but are non-specific and may be indistinguishable from ordinary acne.[17] Other cutaneous manifestations that have been described include pyoderma gangrenosum-like lesions, pustular vasculitic lesions, cutaneous small-vessel vasculitis, and Sweet syndrome-like lesions.

A positive pathergy reaction characterized by the formation of erythematous papules or pustules 24 to 48 hours after needle insertion is thought to be very specific for Behcet disease.[20] While it is seen in 60% to 70% of patients from Turkey and Japan, a positive pathergy reaction is rarely observed in patients with Behcet disease who are from Northern Europe or the United States.[21]

Ocular Manifestations

More than 50% of patients with Behcet disease have eye involvement, although it is much more common in males and younger patients. Eye involvement is usually not the presenting feature of Behcet disease but usually occurs within the initial few years of diagnosis and is rare to occur late in the disease if not present earlier.[22]

Uveitis that is relapsing, chronic, bilateral, and involves both anterior and posterior uveal tracts is common. Anterior uveitis causes erythema and photophobia, while posterior uveitis causes vision loss. Hypopyon-related uveitis is less common but very severe, as it almost always accompanies severe retinal disease. Retinal involvement with retinal vasculitis can be seen as a cause of blindness in these patients. Conjunctivitis and isolated anterior uveitis are rare. 

Musculoskeletal Manifestations

Inflammatory, non-erosive, non-deforming arthritis is seen in 50% of patients with Behcet disease, more common in patients with acneiform lesions.[23] It is usually oligoarthritis that is symmetric or asymmetric, but polyarthritis and monoarthritis can also be seen. Joint involvement is peripheral, and spine involvement or sacroiliitis is not usually seen, differentiating it from HLA-B27-associated erosive sacroiliitis. The knees are the most commonly involved joint, followed by ankles, wrists, and elbows.[24]

Vascular Manifestations

The involvement of arterial and venous tracts of all sizes is a hallmark of Behcet disease and can be seen in 25% of patients, more commonly in males. The most common vascular manifestation is superficial and deep thrombophlebitis of the lower extremities. Rarely, Budd-Chiari syndrome or vena cava obstruction may be seen. Embolism of these thrombi is rare as the inflammatory thrombi tightly adhere to the diseased endothelium. Arterial vasculitis may involve any sized artery and be accompanied by aneurysms or occlusions. Aortitis and vasculitis of the carotid, femoral, and popliteal arteries can be seen. Pulmonary artery involvement with aneurysm formation is unique to Behcet disease and is the leading cause of death in these patients.[25] 

Neurological Manifestations

Central nervous system involvement is seen in 5% to 10% of patients with Behcet disease, and 80% of it is parenchymal involvement, most commonly of the brainstem, that leads to cerebellar, pyramidal, and sensory signs and symptoms. The cerebrospinal fluid examination is sterile but may reveal elevated protein and/or cell count. Nonparenchymal involvement characterized by dural sinus thrombi is seen in 20% and leads to headaches and papilledema. Simultaneous parenchymal and nonparenchymal involvement, isolated cerebellar involvement, and cranial and peripheral nerve involvement are rare.[26]

Gastrointestinal Manifestations

Mucosal ulcerations resembling the orogenital aphthae can be seen in the terminal ileum, cecum, colon, and esophagus. Extensive ulcerations, especially ileocecal lesions, may lead to perforation. Inflammatory bowel disease can present with similar gastrointestinal features in addition to extragastrointestinal features, including uveitis, erythema nodosum, oral ulcers, inflammatory arthritis, and pyoderma gangrenosum; and needs to be ruled out before confirming a diagnosis of Behcet disease.

Other Systemic Manifestations

Cardiac involvement has been reported, including pericarditis, myocarditis, endocarditis, coronary artery vasculitis, and coronary aneurysms. Renal involvement is rare and may include AA-amyloidosis and glomerulonephritis. Epididymitis can also be seen.

Evaluation

Diagnosis of Behcet is clinical and can be difficult due to the lack of any pathognomic laboratory findings. Laboratory findings are usually non-specific, including anemia of chronic disease, leukocytosis, and elevation in markers of inflammation. Imaging studies shall be directed at the organ involved and may include X-rays and arthrocentesis to assess arthritis, CT-scan to assess for bleeding, thrombosis, and ischemia, angiography to look for aneurysms and lumbar puncture to evaluate meningitis. The rationale for carrying out these investigations is to rule out other causes of the clinical presentation. A careful ophthalmologic examination to evaluate ocular involvement shall be pursued at the initial presentation, and cutaneous lesions shall be biopsied to confirm the cutaneous diagnosis.

Although several classification criteria have been published, they shall be used cautiously in the clinical setting to make a diagnosis. The International Team for the Revision of International Criteria for Behçet Disease (ITR-ICBD) revised the established criteria in 2008. The revised criteria are point-based and give 1 point each to oral aphthosis, skin manifestations (pseudofolliculitis, skin aphthosis), vascular lesions (phlebitis, large vein thrombosis, aneurysm, arterial thrombosis), positive pathergy test and 2 points each to genital aphthosis and ocular lesions. Three or more points are needed for the diagnosis of Behcet disease. Similar to previous classification criteria, there are also some pitfalls with this criteria.

Patients with inflammatory bowel disease, systemic lupus erythematosus, reactive arthritis, and herpetic infections can mimic Behcet disease and shall be ruled out first.

Treatment / Management

Mucocutaneous Manifestations

Isolated oral and genital aphthae:

• Initial treatment with topical triamcinolone acetonide cream 3 to 4 times a day until the pain from the ulcer is relieved[27]
• Topical sucralfate 1g/5mL four times daily with or as an alternative to topical corticosteroids[28]
• Topical anesthetics, generally not as effective as steroids or sucralfate, can also provide temporary relief
(A1)

 Prevention of recurrent oral and genital ulcers:

• Colchicine 1 to 2 mg/day in divided doses
  • First-line drug 
  • Doses in the range of 1.2 to 1.8 mg can be used when 0.5 mg tablets are unavailable.[29]
  • More effective in genital ulcers.
  • Has a narrow therapeutic index.
  • Cytopenias are a significant side effect.
• Apremilast is titrated at a rate of 10 mg daily over six days to attain a maintenance dose of 30 mg twice daily.[30]
  • More effective in oral ulcers.
  • Adverse events include nausea, diarrhea, and headache.
(A1)

Multiple lesions or isolated oral aphthae or genital ulcers are refractory to the therapy mentioned above:

• Prednisone 15 mg/day, tapering to 10 mg/day after one week and completing the course over a two- to three-week period
  • Low-dose prednisone (e.g., 5 mg/day) with a prolonged course may be used in case of recurrent oral aphthae

When all the treatment mentioned above fails:

• Azathioprine
  • The initial dose of azathioprine is 50 mg daily.
  • As tolerated, increase the daily dose by 50 mg every four weeks.
  • The target dose is 2.5 mg/kg/day.
  • Complete blood count (CBC) is monitored every two weeks initially till the maximum required dose is achieved and then every 6 to 12 weeks.
  • A lower dose is used in case of renal compromise.
  • Genetic testing for thiopurine methyltransferase is advised before starting therapy. A deficiency of thiopurine methyltransferase can cause an increased risk of developing severe, potentially life-threatening bone marrow toxicity with conventional doses of azathioprine or mercaptopurine.[31]
  • It can be combined with tumor necrosis factor (TNF)-alpha inhibitors (infliximab, adalimumab, etanercept)[32]
• Interferon
  • Interferon alfa-2a and Interferon alfa-2b (generally given 3 to 6 million units three times weekly)[33][34]
(A1)

Cutaneous lesions (except erythema nodosum and pyoderma gangrenosum):

• Mild:
  • Colchicine 1 to 2 mg daily in divided dose
• Lesions unresponsive to colchicine:
  • Prednisolone up to 40 mg/day initially and a maintenance dose of 5 and 10 mg/day

Erythema nodosum:

• Initial therapy is a combination of oral prednisone  (40 to 60 mg daily) and azathioprine.
  • The initial dose of azathioprine is 50 mg daily.
  • As tolerated, increase the daily dose by 50 mg every four weeks.
  • The target dose is 2.5 mg/kg/day.
  • Complete blood count (CBC) is monitored every two weeks initially till the maximum required dose is achieved and then every 6 to 12 weeks.
  • The initial prednisone dose is administered for one month and then tapered gradually to complete the course over three to four months.

Pyoderma gangrenosum (PG):

• Extensive debridement is discouraged.
• Sterile saline or a mild antiseptic for wound care
  •  Mild, localized PG:
    • Topical corticosteroid (high potency or superpotent) or topical tacrolimus (0.03% to 0.3%)[35]
  • More extensive or rapidly progressing PG:
    • Systemic glucocorticoids
      • Oral prednisolone (0.5 to 1.5 mg/kg per day) or its equivalent is started initially, with a maximum daily dose of 60 mg.
      • Intravenous pulse therapy with 1 g methylprednisolone daily for one to five days can be started initially for very aggressive or painful disease.[36]
      • Taper off glucocorticoids within 4 to 10 weeks and monitor closely for continued improvement or adverse effects.
    • Systemic cyclosporine
      • Alternative for glucocorticoid intolerant or glucocorticoid unresponsive cases.[37]
      • Initiated at a dose of 4 to 5 mg/kg and subsequently tapered as tolerated
      • Treatment is limited to less than one year due to side effects, such as hypertension and renal toxicity
(B2)

Arthritis

• Initial treatment:
  • Colchicine 1 to 2 mg/day in divided doses[38]
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) for symptomatic pain relief
• Uncontrolled with colchicine:
  • Prednisone 10 mg/day is initiated.
  • Low-dose prednisone (e.g., 5 mg/day or lower) when a prolonged course may be required
• Refractory or persistent arthritis:
  • Azathioprine and/or TNF-alpha inhibitors
• Refractory to the therapy mentioned above:
  • Interferon alfa or methotrexate[39]
  • Apremilast[40][41]
(A1)

Gastrointestinal Disease

Gastrointestinal ulceration:

• Glucocorticoids plus azathioprine
  • Starting dose of prednisone 0.5 to 1 mg/kg daily[42]
    • Given for at least one month or until the resolution of symptoms improve
    • Decrease the daily dose to 10 mg/day over two to three months.
  • Azathioprine started at the same time as prednisone
    • The initial dose of azathioprine is 50 mg daily.
    • As tolerated, increase the daily dose by 50 mg every four weeks.
    • The target dose is 2.5 mg/kg/day.
    • Complete blood count (CBC) is monitored every two weeks initially till the maximum required dose is achieved and then every 6 to 12 weeks.
• TNF-alpha inhibitors[43]
  • Used when patients do not respond to glucocorticoids plus azathioprine
  • Infliximab and adalimumab have been used successfully.
(A1)

Renal disease

Minimal or mild nephritis:

• No specific therapy is indicated

Secondary amyloidosis:

•  Colchicine 1 to 1.2 mg daily

Ocular Involvement

Anterior uveitis:

• Initial therapy:
  • Topical corticosteroids (scopolamine 0.25% or cyclopentolate 1%
• Unresponsive to initial therapy:
  • Prednisone at a starting dose of 40 mg and may be tapered to discontinuation over one month.[44]
(B3)

Posterior uveitis:

• Initial therapy:
  •  Combination of oral prednisone and azathioprine
    • Starting dose of prednisone 1 mg/kg per day for one month and tapering as tolerated
    • Methylprednisolone as pulse therapy at a dose of 1 g/day for three days may be used empirically to save the sight.
    • The initial dose of azathioprine is 50 mg daily.
    • As tolerated, increase the daily dose by 50 mg every four weeks.
    • The target dose is 2.5 mg/kg/day.
    • Complete blood count (CBC) is monitored every two weeks initially till the maximum required dose is achieved and then every 6 to 12 weeks.
• Severe or refractory disease:
  • Infliximab and adalimumab have been used successfully.[45]
  • The initial dose of infliximab is 5 mg/kg at 0, 4, 8, 16, and 24 weeks or 0, 2, 6, and every eight weeks.
  • Adalimumab is given at a loading dose of 80 mg, followed by 40 mg one week later and 40 mg every two weeks thereafter.[46]
(B2)

Vascular Disease

Large artery disease:

• High-dose glucocorticoids and cyclophosphamide
• Interventions or surgeries should preferably be done when the disease is not active.

Venous thrombosis:

• Data does not support using anticoagulant, antiplatelet, or fibrinolytic agents in patients with thrombosis.
• Anticoagulation may be recommended case by case bases in patients with Behçet-associated dural sinus thrombi.[47]
• Treatment includes glucocorticoids with another immunosuppressive agent as prescribed for posterior uveitis.
(B3)

Neurologic Disease

• Treatment includes high-dose glucocorticoids with another immunosuppressive agent as prescribed for posterior uveitis.

Differential Diagnosis

Behcet disease is a clinical diagnosis. However, the other diseases can mimic clinical features seen in Behcet disease, all of which should be ruled out before confirming a diagnosis of Behcet disease.

1. Inflammatory bowel disease (IBD): In addition to gastrointestinal involvement, IBD and Behcet disease share several similar clinical features, which include oral ulcers, uveitis, inflammatory arthritis, erythema nodosum, and pyoderma gangrenosum. Colon biopsies may not be adequate in differentiating these diseases. However, sacroiliitis and axial inflammatory arthritis can be seen in IBD but not in Behcet disease. Posterior uveitis and panuveitis are rare in IBD. Vascular inflammation leading to aneurysms, venous thrombosis, CNS involvement, and pathergy test are also features of IBD. Without these other extra-gastrointestinal clinical features, it is challenging to differentiate these two conditions. 
2. Seronegative arthritis: Reactive arthritis is another major differential diagnosis, as it can also cause peripheral inflammatory arthritis, ocular inflammation, and skin disease. As in IBD, posterior uveitis and panuveitis are rare in reactive arthritis, and vascular or CNS involvement is also rare. Sacroiliitis and axial involvement are common in reactive arthritis, while not in Behcet disease. Urethritis, penile lesions on the glans penis, and conjunctivitis, which are features of reactive arthritis, are not usually seen in Behcet disease.
3. Systemic lupus erythematosus (SLE): SLE can have a very similar presentation to Behcet disease and can involve all the organs similarly involved in Behcet disease. However, inflammatory thrombi are not usually seen in SLE; the SLE-specific autoantibodies can help differentiate these two conditions.
4. Herpetic infections: Oral and genital lesions can be seen in herpetic infections, and when appropriate, a culture shall be done from the lesion to rule out herpes before considering Behcet.
5. Behçet-type disease manifests in patients treated with interleukin (IL) 17 inhibitors.[48]

Other differential diagnoses that shall be considered (depending on organ involvement) include sarcoidosis, other systemic vasculitides, relapsing polychondritis, and multiple sclerosis.

Prognosis

Behcet disease has no cure and is associated with significant morbidity and mortality. Poor prognosis and higher mortality are related to the male sex and younger age of onset. Major causes of mortality include ruptured pulmonary and peripheral aneurysms and neurologic and gastrointestinal involvement. Renal involvement, especially amyloidosis, also carries a poor prognosis. However, more than 60% of patients go into remission after passing the initial years when the disease is most active. In addition, most patients eventually show improvement in disease flares, morbidity, and mortality.

Complications

• Besides increased mortality, Behcet disease is associated with several potential lifelong complications, most of which result from ocular or neurologic involvement. Patients with hypopyon-related uveitis and retinal involvement are at a high risk of blindness.
• Coronary or pulmonary arterial aneurysmal rupture is also associated with Behcet disease, which carries a high mortality risk.
• Centraal nervous involvement can lead to significant morbidity, permanent deficits, and death. Ocular involvement as anterior and posterior uveitis may result in permanent blindness.
• Another complication of Behcet disease is an increased incidence of miscarriages due to the vasculitis of the placenta.