Does Extended Vascular Screening Be Performed in All Asymptomatic Behçet's Disease Patients With Previously Diagnosed Vascular Involvement or Unexplained Inflammatory Response?

Abstract

Behçet's disease (BD) usually start with mucocutaneous symptoms such as orogenital ulcers and later on develop ocular, vascular, gastrointestinal, and neurological manifestations [1]. Oral ulcers are the first manifestation in up to two thirds, whereas ocular manifestations (~50%) are usually observed in the first few years and vascular disease in 5–10 years of follow-up [2, 3]. However, as major organ manifestations can be the first manifestation without orogenital ulcers, the hallmark of the disease, diagnosis can be delayed [4]. Recently, efforts to increase diagnostic tools in BD has shown “femoral vein wall assessment” with Doppler US as a useful diagnostic test for BD [5].

Disease monitoring in early Behçet's disease is usually limited to multi-systemic assessment of symptoms or signs with laboratory tests to detect systemic inflammation (with routinely available acute-phase reactant biomarkers C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) or necessary for drug monitorization. As most patients with early disease has mainly mucocutaneous manifestations, this approach is usually sufficient. However, in centers experienced in severe BD and working with ethnicities with a high-risk of major organ involvement, all patients are seen by ophthalmologists for early asymptomatic disease. In a recent study, Uçar et al. observed that BD patients without uveitis but with cellular debris in the anterior vitreous have a higher risk of clinically significant ocular disease (22% vs. 1%) during follow-up [6]. Therefore, subclinical ocular findings might have prognostic implications in patients with BD screened for ocular involvement.

Vascular disease in BD is reported to be 15%–50% in different series with the highest prevalence around the Mediterranean basin [2, 3, 7]. In addition to genetic factors, follow-up of patients in different specialties such as dermatology or ophthalmology can also explain different prevalences, as guidelines for systemic disease monitoring is not established.

Vascular disease in BD has characteristics of a variable-vessel vasculitis involving both venous and arterial systems [2, 8]. Patients are usually young males in the third/fourth decades and present most frequently (up to 70%) with superficial thrombophlebitis or deep vein thrombosis of the lower extremities (DVT) [9, 10]. Any male, physically active young patient presenting with DVT without traditional risk factors (immobility, surgery, etc.) should lead an experienced clinician to a search for the diagnosis of BD, at least in regions with a high prevalence of vascular-BD. About 10% of the cases with a further diagnosis of BD can have a vascular event as the first manifestation without mucocutaneous features [10]. In patients without immune-suppressive treatment after the first attack, relapses are observed in up to 50% in a distinct manner [2]. Venous disease is observed to relapse upwards more frequently in upper lower extremity, vena cavas and as cerebral vein thrombosis [2, 10]. Budd–Chiari syndrome (BCS) and arterial thrombosis/aneurysms are also observed during further relapses of patients with vascular BD with a high morbidity/mortality [11, 12].

This interesting question is not clearly answered in Behçet's literature until now with limited prospective data. Asymptomatic vascular disease is systematically investigated only for DVT in BD patients. In a cumulative analysis of the studies done with Doppler US in patients without vascular BD, asymptomatic DVT is observed in only one study with 6% prevalence [13-15]. This data suggests that clinical relevance of the assessment for DVT in asymptomatic patients is low and possibly not required.

Assessment of further asymptomatic venous disease which might affect vena cavas, hepatic artery or pulmonary system is a more clinically relevant question, as involvement of these vascular structures is a major cause of morbidity and mortality in BD [1, 2]. Although a systematic, prospective assessment with imaging is not performed until now, current retrospective data provide important clues.

The highest mortality for venous disease in BD is due to BCS. Among two recent series of BCS from Turkey, 21% in one and 74% in the other series, diagnosis of BCS was done when patients were present with features of previous lower extremity/caval thrombosis without hepatic failure [11, 12]. Survival was much better in these groups compared to patients presenting with hepatic failure and the authors suggest that early diagnosis of BCS is crucial for improved prognosis. Similarly, evaluation for vascular involvement in other regions is also suggested in patients with cerebral sinus thrombosis [16].

Although rare, arterial aneurysms/thrombosis is one of most feared complications of vascular BD with the highest mortality. Systematic assessment of arterial disease is currently not suggested in any management recommendation. Part of this approach comes from the expert opinion that clinically important arterial disease will be either manifest symptomatically or too rare to justify screening. However, one crucial recommendation is present in EULAR 2018 guideline for the management of Behçet's syndrome (BS) for the “anti-coagulation of venous vascular disease” suggested as “anti-coagulation may be chosen in refractory venous disease when the risk of bleeding is thought to be low and coexistent pulmonary aneurysms are ruled out” [17]. This approach stems from the observation of rare fatal bleedings of pulmonary aneurysm ruptures under anti-coagulation treatment in Behçet's patients. However, in fact, the number of bleedings reported in two published multi-center vascular-BD series from Turkey and France are very low, together with the literature search of ‘Japanese guidelines for BD’ reporting serious bleeding to be very rare [3, 18, 19]. More than 50% of DVT patients with BD are given anti-coagulation with expert opinion in BD, but whether in routine practice all patients using anti-coagulation is having a screening for pulmonary aneurysms is not clear [20].

A typical example of the role of timing in vascular assessment is possibly associated with the changing spectrum of pulmonary involvement in BD. Although most early series suggest that pulmonary disease is commonly an aneurysm in BD, recent series with more regular CT-angiography (CTA) use suggest that pulmonary thrombi is more common in BD patients with a less severe vascular disease course [21, 22].

Recently, we analyzed our vascular Behçet's series for pulmonary artery involvement (PAI) [23]. In this series of 1350 patients with BD, 30% (n = 402) had vascular disease with 8% (n = 110) PAI. Pulmonary arterial thrombosis (PAT) was seen in 104 (94.5%) and aneurysms in 9 (6.6%) patients. Eight patients were newly diagnosed with BD when they had presented with PAI. At the time of the first PAI, 48 (43.7%) patients already had a history of vascular involvement other than PAI, 37 (33.6%) of which were DVT.

Among the PAI group, 28% (n = 31) had asymptomatic disease. These patients had pulmonary CTA for either anti-coagulation pre-screening or investigation of unexplained systemic inflammatory response with elevated CRP levels. When symptomatic vs. asymptomatic patients were compared, asymptomatic patients had a shorter disease duration (70 vs. 95 months), less main/lobar artery involvement (12.5% vs. 27.1%) and lower rate of relapses (12.5% vs. 34.7%) suggesting earlier and milder disease in asymptomatic patients.

As all other multi-systemic inflammatory disorders, systemic inflammatory response is assessed during the initial diagnosis phase and also during follow-up for disease activity in patients with BD. Although, CRP or ESR are higher during disease relapses in most studies, it is usually a modest elevation, especially in limited mucocutaneous disease course such as oro-genital ulcers. Muftuoglu et al. first showed that significant systemic inflammatory response is observed mainly in nodular skin lesions, arthritis, and vascular involvement [24]. Lack of correlation of ESR and CRP levels with ocular, gastrointestinal, and central nervous system manifestations is also shown [25]. However, recently, CRP is shown to be the highest predictor among different laboratory parameters for vascular BD [26].

Patients with unexplained fever of unknown origin or only with systemic inflammatory response is a clinical problem in routine practice, with BD as an uncommon diagnosis [27, 28]. These patients with or without fever, usually get an extensive investigation for subclinical infections or malignancies. However, especially in young, male BD patients with a high-risk of vascular disease, screening for asymptomatic intra-abdominal (vena cava thrombosis, BCS) venous disease or pulmonary thrombosis/aneurysms should be high on the list and possibly a more cost-effective approach compared to malignancy screening in these young patients.

Retrospective data suggests that full vascular screening for venous and arterial disease in asymptomatic BD patients is possibly not feasible with current literature. However, certain patient subsets have a higher vascular involvement risk which might modify this approach. Young (< 30 years old) male BD patients from endemic regions with a severe mucocutaneous course can be candidates for close follow-up and early screening for suspected symptoms.

On the other hand, all patients with a history of vascular BD including superficial thrombophlebitis, deep vein thrombosis, dural sinus thrombosis, or pulmonary/extrapulmonary aneurysms should be screened for other vascular regions. This might include Doppler US assessment of the abdomen for vena cava and hepatic vein assessment and a pulmonary CTA for pulmonary thrombosis/aneurysms.

Approach to fever/inflammation of unknown cause is also not clearly defined for BD. However, when obvious causes such as infection are ruled out and nodular lesions or arthritis are not present, any (especially young) patient with fever or persistent high CRP or ESR should be screened for occult vascular disease in BD.

Finally, our editorial depends mostly on our interpretation of the retrospective literature with our “expert-opinion” formed in a 25-year-old expert, multi-disciplinary Behçet's Clinic. Our approach can be further refined with prospective studies on the assessment of vascular BD in asymptomatic patients.

H.D., K.Y.A. and F.A.-O. all contributed to the preparation of the manuscript.

The authors declare no conflicts of interest.