Behçet Syndrome: to Anticoagulate or Not to Anticoagulate?

We posted a poll on twitter on 2/13/24 asking the following question:

• Most respondents chose to anticoagulate.
• Although evidence is scant regarding the best approach to managing patients with Behçet syndrome complicated by thrombosis, expert opinion and clinical guideline recommendations stress the importance of immunosuppressives and in some cases argue against the use of anticoagulation.
• That being said, a 2012 survey study found that anticoagulation was preferred by 87% among physicians from USA/Israel and 40% in Turkey.
• Decision-making may take into account the following considerations/hypotheticals:
  • In favor of anticoagulation:
    • Prevent propagation of clot.
    • Promote recanalization of the vessel.
  • In favor of no anticoagulation:
    • Thrombi are formed as a result of inflammation, and therapy should be aimed at the inflammatory axis.
    • Clots are believed to stick to the blood vessel wall and are therefore less likely to embolize.
    • Anticoagulation may lead to life-threatening hemorrhage related to rupture of arterial aneurysms (present in many patients with BS).

Below, we will:

• Provide an overview of Behçet syndrome.
• Review the literature concerning anticoagulation.

The bottom line is that the risks-benefits of anticoagulation in Behçet syndrome remain unknown!

Description:

• Behçet syndrome is a chronic inflammatory disease classified as one of the systemic vasculitides; it was initially described as a triad of manifestations:¹
  • Oral aphthosis
  • Genital aphthosis
  • Non-granulomatous uveitis
• However, Behçet syndrome can affect almost any organ, including:²
  • Skin
  • Mucosa
  • Joints
  • Eyes
  • Blood vessels³
    • Arteries
    • Veins
  • Nervous system (neuro-Behçet’s disease)
  • GI system
• Behçet syndrome typically follows a relapsing and remitting course.
• Goal of treatment is to promptly suppress inflammatory exacerbations and recurrences to prevent irreversible organ damage.⁴
• A multidisciplinary approach is necessary for optimal care.⁵

History:

Behçet syndrome is named after the Turkish physician professor Hulusi Behçet, who, in 1937, described the classic symptom complex of hypopyon, iritis, and orogenital aphthosis in 3 patients.⁶

Epidemiology:

• Countries and regions with the highest risk of Behçet syndrome are Turkey and the Asian (Japan, China, and Korea), Middle Eastern, and North African countries.⁷
• Average age at diagnosis is approximately 30 years; most diagnoses are made in patients between 15 and 45 years old.⁸
• Men and women equally affected, but most severe disease occurs in young adult men.

Pathogenesis:

• Pathogenesis of Behçet syndrome is poorly defined but may involve infection-related, genetic, epigenetic and immunological factors.⁹
• Vascular manifestations in Behçet syndrome are induced by an impaired inflammatory response, and Behçet syndrome has been defined as a natural model of thrombo-inflammation (inflammation-induced thrombosis).¹⁰
  • Neutrophils promote thrombo-inflammation¹¹ via different mechanisms of damage, which ultimately lead to platelet activation, endothelial dysfunction and impaired fibrinolysis.¹²
  • Several clinical features indirectly point to the inflammatory nature of vascular involvement:¹³
    • Vascular manifestations (both venous and arterial) are associated with signs of inflammatory activity, such as fever, constitutional symptoms and an increased acute phase response.
    • FDG-PET scans reveal a significant uptake in the arterial vessel wall, mainly of aneurysmatic and pseudoaneurysmatic lesions.
  • Most studies have described normal levels of the anticoagulant factors protein C, protein S and antithrombin in Behçet syndrome.¹⁴
  • A meta-analysis showed a significantly higher prevalence of aPL antibodies in patients with Behçet syndrome than in healthy controls, but this was not correlated with an increased risk of thrombosis.¹⁵
  • Venous disease:¹⁶
    • Believed to result from endothelial inflammation leading to thrombosis, which is the rationale for controlling systemic inflammation rather than administering primary anticoagulation.
    • In deep vein thrombosis, the clot adheres tightly to the vessel wall.¹⁷
    • Pulmonary artery occlusion differs from classic VTE, most commonly representing in situ thrombi complicating an underlying vasculitis rather than embolus.
    • The main histopathological features of venous disease in Behçet syndrome include:¹⁸
      • Thickened vein walls
      • Lumen occluded with an organized thrombus that usually sticks to the vessel wall
      • Presence of inflammatory cells
  • Arterial disease:¹⁹
    • The histopathological features of arterial disease in Behçet syndrome include:
      • Arterial aneurysms:
        • Indicative of obliterative endarteritis
        • Filled with a thick thrombus
        • Prone to life-threatening rupture/bleeding in setting of anticoagulation treatment
      • Disrupted medial elastic fibers (in most cases)
      • Inflammatory cell infiltration, particularly around the vasa vasorum

Clinical Presentation:

• Vascular Behçet:²⁰
  • Vascular events occur in ~15–50% of patients.
  • More frequent/severe in young adults, particularly males.²¹
  • Almost any vessel can be affected, although veins are more commonly affected than arteries.
  • Vascular involvement occurs early in the disease course with 75% of patients experiencing their first event within 5 years of disease onset.
  • Vascular involvement can develop before or simultaneously with the skin–mucosa lesions characteristic of Behçet syndrome in about one-third of patients.
  • The vascular phenotype almost always includes fever, a high acute phase response and constitutional symptoms.
  • Vascular disease is invariably relapsing. Approximately 30–50% of patients with vascular Behçet syndrome have recurrent vascular episodes, with a mean of 1.1–2.2 episodes per patient.
• Venous involvement:
  • Around 20–40% of patients with Behçet syndrome develop venous thrombosis (14-fold increased risk vs. those without Behçet syndrome).²²
  • Superficial vein thrombosis (SVT) and deep vein thrombosis (DVT): ²³
    • The most common vascular manifestation in Behçet syndrome, accounting for up to 70% of vascular Behçet.
    • Can affect upper or, most commonly, lower limbs.
    • SVT and DVT may coexist in the same patient.
    • Venous involvement may be multiple and associated with arterial involvement.
    • Compared to those without Behçet syndrome:
      • Complete or partial recanalization is much less frequent.
      • Collateral formation more common.
      • Higher rates of:
        • Severe post-thrombotic syndrome (PTS) (50% of cases)
        • Claudication (33% of cases)
    • Major predictors of relapse:
      • Poor recanalization
      • Lack of immunosuppressant use
    • Successful control of Behçet syndrome disease activity with immunosuppressants may:
      • Decrease the development of PTS
      • Improve venous disease-specific quality of life
      • Prevent relapses in vascular Behçet syndrome
  • Thromboses in atypical sites include:
    • Inferior vena cava (IVC)
    • Superior vena cava (SVC)
    • Hepatic and portal veins
    • Cerebral venous sinus
    • Right heart
  • Hughes–Stovin syndrome (association of deep vein thrombosis with arterial pulmonary aneurysms) includes a high risk of hemoptysis.²⁴
  • Behçet syndrome must be considered in the presence of unexplained thrombosis in a young adult, without other vascular risk factors or evidence of thrombophilia.²⁵
• Arterial involvement:²⁶
  • Occurs in 3–5% of patients.
  • Arterial disease manifests commonly with aneurysms and less frequently with in situ thrombosis.
  • Pulmonary artery involvement:
    • Occurs earlier than lesions in other arteries.
    • Characterized by aneurysms (in 72% of cases) and in situ thrombosis (in 28% of cases).
    • Typically bilateral, multiple and mostly located on the lower lobe arteries.
    • Aneurysmal pulmonary artery damage is rare, serious, and marked by sometimes massive hemoptysis.
  • Non-pulmonary artery involvement:
    • All arteries may be affected, especially:
      • Aorta
      • Peripheral arteries:
        • Usually in the lower limbs than in the upper limbs.
    • A late event that develops on average 10 years after disease onset.
    • Common sites include the abdominal aorta and iliac, femoral, popliteal and carotid arteries
    • Adjacent veins may also be involved

Diagnosis

• There are several classification criteria for Behçet syndrome:
  • These are primarily for research purposes.
  • Classification criteria may help even though they cannot rule out a diagnosis of Behçet syndrome.
• The most frequently used international classification criteria are those of the International Criteria for the Classification of Behçet’s syndrome revised in 2013:

Treatment other than anticoagulation:

• Mucocutaneous involvement:²⁷
  • Topical measures such as steroids should be used for the treatment of oral and genital ulcers.
  • Colchicine should be tried first for the prevention of recurrent mucocutaneous lesions especially when the dominant lesion is erythema nodosum or genital ulcer.
• Eye involvement:²⁸
  • inflammatory eye disease affecting the posterior segment, treatment regime may include systemic glucocorticoids and one of the following agents:
    • Azathioprine
    • Cyclosporine-A
    • Interferon-alpha
    • Monoclonal anti-TNF antibodies
  • acute sight-threatening uveitis should be treated with high-dose glucocorticoids, infliximab or interferon-alpha.
• Nervous system involvement:²⁹
  • Acute attacks of parenchymal involvement should be treated with high-dose glucocorticoids followed by slow tapering, together with immunosuppressives such as azathioprine. Cyclosporine should be avoided. Monoclonal anti-TNF antibodies should be considered in severe disease as first-line or in refractory patients.

Anticoagulation:

Expert opinion:

• According to Nair and Moots:
  • We strongly advocate intense immunosuppression, which is required to reduce the stimulus for thrombosis and do not recommend anticoagulation.
• According to Toledo-Samaniego et al:
  • DVT in Behçet syndrome should be treated with glucocorticoids and immunosuppressants (IS) as azathioprine, cyclophosphamide or cyclosporine A, with no data to mandate the preference of one IS agent over the other.
  • DVT in Behçet syndrome is the result of inflammation of the vessel wall rather than hypercoagulability, which questions the role of anticoagulation in these patients.
  • If anticoagulation is initiated in Behçet syndrome patients, a thoracic computed tomography should be performed to rule out pulmonary artery aneurysms due to the high risk of bleeding.
• According to Becatti et al:

• According to Karadag and Bolek:

• According to Bettiol et al:
  • The role of anticoagulants for the treatment of venous thrombosis in patients with Behçet syndrome is controversial. Anticoagulant treatment does not seem to affect the relapse rate, presence or severity of PTS or decrease residual thrombosis. However, according to local clinical practice, anticoagulation is prescribed in addition to immunosuppressants in some centers, whereas in others anticoagulants are administered only in selected patients with additional Behçet syndrome-unrelated cardiovascular risk factors.
  • Recurrence rates of up to 36% are reported at 5 years, regardless of whether immunosuppressants are used with or without anticoagulation.
  • A meta-analysis of retrospective studies exploring the effect of treatment modalities on thrombotic relapse risk showed that immunosuppressant use is associated with reduced risk of relapse (relative risk (RR) 0.17; 95% CI 0.08–0.35), whereas anticoagulant use is not (RR 0.75; 95% CI 0.48–1.17)
  • The use of anticoagulants for the treatment of vena cava thrombosis and Budd–Chiari syndrome is controversial.
  • CVST is usually manageable with short-term corticosteroids and immunosuppressants and the outcome is usually good.

What do the guidelines say?

• 2018 update of the EULAR recommendations for the management of Behçet’s syndrome
  • Acute deep vein thrombosis:
    • Deep vein thrombosis is thought to result from inflammation of the vessel wall rather than hypercoagulability.
    • Post-thrombotic syndrome is frequent especially with recurrent episodes of deep vein thrombosis and may result in leg ulcers that are very difficult to treat.
    • One of the most controversial issues regarding the management of BS is whether deep vein thrombosis should be treated with immunosuppressives, anticoagulants or both.
    • The authors performed a meta-analysis of the three retrospective studies that reported on the efficacy of immunosuppressives and/ or anticoagulants for preventing recurrences of deep vein thrombosis in patients with BS. A pooled estimate of the relapse risk of deep vein thrombosis in patients with BS treated with immunosuppressives and anticoagulants compared with those treated with only anticoagulants favored the use of immunosuppressives with an relative risk (RR) of 0.17 (95% CI 0.08 to 0.35). On the other hand, treatment with anticoagulants and immunosuppressives compared with immunosuppressives alone did not provide a significant benefit in preventing relapses.”
    • There were no data to mandate the preference of one immunosuppressive agent over the others. Azathioprine, cyclophosphamide or cyclosporine-A are agents that can be preferred in such patients. Cyclophosphamide may be reserved for patients with extensive thrombosis of larger veins such as vena cava due to its potential adverse events.
  • Refractory venous thrombosis:
    • There were no data to guide the management of patients with refractory venous thrombosis. Monoclonal anti-TNF antibodies may be used since beneficial results have been obtained in BS patients with refractory arterial involvement. Interferon-alpha may be tried in selected cases.
    • Although their meta-analysis indicated that adding anticoagulants to immunosuppressives did not decrease the relapse risk, there is a retrospective study suggesting that not using anticoagulants may increase the risk of post-thrombotic syndrome.
    • The task force felt that no recommendation against anticoagulant use can be made because of the lack of prospective controlled trial data demonstrating that anticoagulants do not decrease the relapse risk and the frequency of post-thrombotic syndrome in patients with BS.
    • However, great caution is required with respect to bleeding in anticoagulated patients with BS. This is especially important since arterial aneurysms are closely associated with deep vein thrombosis in BS. Patients need to be scrutinized for aneurysms when starting anticoagulants and physicians should be alert about the risk of developing aneurysms during the course of treatment since almost all BS patients with aneurysms have a history of deep vein thrombosis.

• French recommendations for the management of Behçet’s disease:
  • In those with vascular involvement, It is currently clearly established that immunosuppressant treatment is the cornerstone of the therapeutic strategy in these severe forms of BD. It is based on the fact that inflammation of the vascular wall probably plays a preponderant role in the occurrence of thrombotic vascular lesions.
  • Although no pro-thrombotic factor has been identified in BD and the pathogenesis of thrombosis is linked to endothelial inflammatory disease, the experts recommend the use of curative anticoagulation for deep vein thrombosis. Curative anticoagulation is recommended in venous thromboses after evaluation of the risk of hemorrhage and verification of possible aneurysmal arterial lesions. The duration of anticoagulant treatment will be from 3 to 6 months, except in serious forms, such as thromboses of the supra-hepatic veins and/or of the vena cava, which require extended anticoagulation.

• Up-to-Date
  • Venous disease in Behçet syndrome is believed to result from endothelial inflammation leading to thrombosis.
  • The approach to preventing venous thrombotic events in Behçet syndrome is control of systemic inflammation rather than the institution of primary anticoagulation. Treatment should include glucocorticoids in combination with another immunosuppressive agent used in the same manner as for posterior uveitis.
  • However, if venous thrombotic events occur, they should be treated with anticoagulation using standard approaches.
  • Complicated venous thrombotic events such as cerebral sinus thrombosis and pulmonary vein thrombosis can occur in Behçet syndrome. The management of these conditions must be handled on a case-by-case basis, through consultation with appropriate subspecialists:
    • Treatment with systemic glucocorticoids with or without another immune-modulating treatment is indicated to reduce the inflammation that drives Behçet-associated thrombosis.
    • There is no consensus whether anticoagulation is beneficial in patients with Behçet-associated dural sinus thrombi, and, if patients have Behçet-associated aneurysms, anticoagulation increases the risks of hemorrhage.

• Primary data:
  • Retrospective study of 766 patients from China with Behçet syndrome:
    • 93 patients developed thrombosis.
    • Vascular thrombosis occurred more often in male patients (16.3% vs 5.4%)
    • Ages at diagnosis of Behçet syndrome were 32 +/- 11 years.
    • interval between Behçet syndrome diagnosis and emergence of first thrombotic events was 0-15 years.
    • Among the 93 Behçet syndrome patients with thrombosis, thrombosis developed after the diagnosis of BD in 30 cases; the median interval was 2 years.
    • There were 12 patients who developed thrombosis prior to the diagnosis of Behçet syndrome with the average interval from 4 months to 4 years.
    • For location of thrombi see Table 1 below.
    • Among these cases, venous thrombosis was more common than arterial involvement, and most of patients (88/93, 94.6%) had multiple sites of thrombosis.
    • Systemic manifestations:
      • Oral ulceration was present in all patients
      • Genital ulcers in 68 cases (73.1%)
      • Skin lesions in 67 cases (72.0%)
      • Positive pathergy test in 46 cases (49.5%)
      • Ocular involvement in 26 cases (28.0%)
      • Arthritis in 10 cases (10.8%)
      • Gastrointestinal involvement in 9 cases (9.7%)
      • Non-thrombotic neurologic involvement in 6 cases (6.5%)
      • Non-thrombotic cardiac involvement in 5 cases (5.4%)
    • Treatment:
      • All patients received glucocorticosteroids and immunosuppressive agents. Forty-nine patients received two or more immunosuppressants.
      • Anticoagulants were used in 76 patients.
      • After a median follow-up of 14 months (3–63 months):
        • 89 patients improved as measured by decreased ESR and CRP levels (in 40 patients)
        • 4 patients died:
          • One patient with DVT died from myocardial infarction despite of aggressive treatment of the underlying Behçet syndrome, anticoagulants and anti-infection therapy.
          • One patient with vena cava thrombosis and multiple aneurysms received steroids and immunosuppressive agents and died from aneurysm rupture.
          • One patient with Budd–Chiari syndrome died from hepatic failure.
          • One patient with septic shock.
    • Conclusions: The management of venous thrombosis in Behçet syndrome has remained controversial. In 2008, the European League Against Rheumatism published recommendations that endorsed the use of glucocorticoids and immunosuppressants (azathioprine, cyclophosphamide, and cyclosporine A) in the management of acute deep venous thrombosis in Behçet syndrome, while discouraging the use of antiplatelet, anticoagulant, and antifibrinolytic agents, due to the fact that tight adhesions of a peripheral thrombosis to venous walls rarely results in emboli in the lungs. In addition, anticoagulants could increase the risk of rupturing aneurysms which could cause fatal bleeding. Recently, a French study including 807 Behçet syndrome patients found that the use of immunosuppressants significantly reduced the risk of recurrent DVT. In our study, aspirin and/or anticoagulants were used in thrombotic patients who did not have pulmonary artery aneurysms.

• Primary data (cont’d):
  • Retrospective study of 936 patients from Turkey with:
    • VBD developed in 27.7%
    • 86.2% of those with vascular Behçet syndrome were male
    • Mean age was 32.3 years
    • In 57.3% of the vascular Behçet syndrome patients vascular involvement was the presenting sign of the disease
    • A second vascular event was observed in 9.2%
    • Subtypes of vascular Behçet syndrome:
      • 84.6% of vascular Behçet syndrome patients had only venous disease
        • deep venous thrombosis of the lower extremities (70.5%)
        • vena cava superior or inferior thrombosis in 8.5%
        • Budd–Chiari syndrome in 1.2%
      • 8.1% had only arterial disease
      • 4.2% had both venous and arterial diseases.
    • Treatment:
      • After the first vascular event:
        • Corticosteroid therapy was given to all patients with vascular Behçet syndrome.
        • Immunosuppressive treatment was given to 88.8%:
          • Median duration of IS treatment was 22 months
        • Anticoagulation treatment to 59.8% of the patients:
          • Median duration of anticoagulation was 13 months.
          • Minor hemorrhage was observed in 4.7%:
            • 4 gastrointestinal bleeding
            • 1 epistaxis
            • 2 subcutaneous hematoma
    • Vascular relapse:
      • developed in 32.9% of vascular Behçet syndrome patients.
      • The time interval between the first and second vascular events was 25.5 (1–252) months.
      • When this first relapse developed, 16.3% of the patients were only on anticoagulation treatment and 32.6% were untreated.
      • Relapse was:
        • Significantly lower in patients taking immunosuppressives 25.3% vs 85.7%, P< 0.001
        • Significantly higher in the group taking only anticoagulants (91.6% vs 29.1%, P< 0.001).
      • The rate of new vascular event development was similar between the patients taking only immunosuppressives and anticoagulant + immunosuppressive treatments (29.1% vs 22.4%)
    • Conclusions: In the present study, we did not observe any additional positive effect of anticoagulation treatment (added on to immunosuppressive treatments) to prevent relapses in the course of vascular involvement… Although not supported in this analysis, the exact role of anticoagulation treatment in the long-term course of vascular Behçet syndrome can only be clarified with randomized, controlled, prospective studies investigating course of vascular insufficiency and vascular quality of life in addition to relapses. Until then, long-term immunosuppressives should stay as the main treatment option in vascular Behçet syndrome.
  • Retrospective study of 807 patients from France with Behçet syndrome:
    • 36.7% of patients had venous involvement.
    • 18.6% of patients had arterial involvement.
    • 73.3% were male.
    • Median age was 30 years.
    • Compared to patients without venous involvement vs. those with venous thrombosis:
      • More frequently male.
      • More arterial, cardiac, and neurologic involvement.
    • For location of thrombi see Table 2 below.
    • Treatment:
      • Anticoagulation in 98.6% of patients:
        • The median duration of anticoagulation was 10 months.
        • Bleeding complications occurred in 7 patients treated with anticoagulation (2.4%).
      • Immunosuppressive agents in 46.8%:
        • Median duration of therapy with immunosuppressives was 3.1 years
      • Glucocorticoids in 62.7%.
    • Outcomes:
      • The mortality rate was 6.4% (19 of 296 patients with venous thrombosis) after a median followup of 4.75 years.
      • The mortality rate tended to be higher in BD patients with venous thrombosis than in those without (4.1%).
      • The causes of death included:
        • Budd-Chiari syndrome n=4 [21.1%]
        • Neurologic involvement n=4 [21.1%]
        • Cardiovascular involvement n=4 [21.1%]:
          • 2 ruptured aneurysms
          • 1 endocarditis
          • myocardial infarction
        • Pulmonary embolism n=3 [15.8%]
        • Sepsis n=2 [10.5%]
        • Cancer n=1
        • Unknown etiology n=1
    • Venous thrombosis relapse:
      • The incidence of first relapse was:
        • 36.5% at 5 years
        • 46.4% at 10 years
        • 55.3% at 20 years
      • 33.8% of patients experienced at least 1 relapse of venous thrombosis.
      • Relapses of thrombosis occurred in 8 patients treated with immunosuppressive agents (20%) compared to 68 not treated with immunosuppressive agents (56%).
      • In multivariate analysis, the use of immunosuppressive agents was found to prevent relapse of venous thrombosis (HR 0.27 [95% CI 0.14–0.52],P<0.00021), and there was a trend toward prevention of relapse with the use of glucocorticoids.
    • Conclusions:
      • The most important conclusions that we can draw from this study are that immunosuppressive agents improve prognosis by decreasing the odds of venous thrombosis relapse in BD by 4-fold.
      • Regarding anticoagulation, there are neither con-trolled data nor evidence of benefit from uncontrolled studies of anticoagulants in the management of deep vein thrombosis in BD. Some authors recommend anti-coagulants for major vein thrombosis, while others suggest that they be avoided owing to the increased risk of fatal bleeding from coexisting pulmonary arterial aneurysm, and owing to the estimated low risk of pulmonary embolism in BD.
      • In our study, almost all BD patients with deep vein thrombosis received anticoagulation therapy despite a high number of associated arterial aneurysms (n=44 [14.9%]), 8 of which were pulmonary arterial aneurysms. The tolerance was satisfactory, with only 2% of patients having hemorrhagic complications. On the other hand, pulmonary embolism accounted for10% of all cases of thrombosis and 15.8% of deaths

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