Rheumatology Reports 2010; volume 2:e2

Behçet’s disease: an update on with cutaneous, musculoskeletal, vascular and nervous system manifestations.1 The etio- Correspondence: Kenneth T. Calamia, Depart- pathogenesis, diagnosis and pathogenesis of the disease remains obscure, ment of Rheumatology, Mayo Clinic Jacksonville, management of vascular although genetic predisposition, environmen- 4500 San Pablo Road, Jacksonville, Florida 32224, involvement tal factors and immunological abnormalities USA. E-mail: [email protected] have been implicated.2,3 It has recently been Key words: Behçet’s disease, vasculitis, venous Phaedon G. Kaklamanis,1 proposed that BD is an autoinflammatory dis- 4 5 thrombosis, arterial aneurysm, endothelial dys- 2 order, although there is no consensus. People Kenneth T. Calamia function, immunosuppressive agents, corticos- from the Far East, the Middle East and the 1 teroids. Emeritus Professor of Internal Medicine, Mediterranean basin are more commonly Athens Medical Center, Greece; affected than those from other parts of the 2 Contributions: PK and KC are both responsible Associate Professor of Medicine, Mayo 6 world. In Northern Europe, Central Africa and for and contributed to study conception and Clinic, Jacksonville, FL, USA the United States the disease is infrequent.7 design, and acquisition, analysis and interpreta- All ages may be affected, although the frequen- tion of data. Both authors contributed to the cy is higher in persons in the 3rd or 4th drafting of the article and revised it critically for decade. The sex predominance varies widely important intellectual content. Both authors are Abstract among the diseased population in different responsible for the final version to be published. geographical areas.6,7 Earlier studies suggested Received for publication: 22 June 2009. a male predominance in high prevalence The objective of this review is to summarize Revision received: 28 January 2010. reports of the prevalence, clinical presenta- areas, but more recent surveys indicate equal Accepted for publication: 28 January 2010. tion, diagnostic methodology and treatment of involvement of the sexes. In Western coun- vasculitic manifestations of Behçet’s disease tries, females predominate. This work is licensed under a Creative Commons (BD). We performed a literature search on vas- Behçet’s disease is included in the wide Attribution 3.0 License (by-nc 3.0). culitis in BD. Articles were selected which pro- spectrum of vasculitides.8 Vasculitis is a prin- ©Copyright P.G. Kaklamanis and K.T. Calamia, 2010 vided insight into the pathogenesis and clini- cipal pathological finding in BD and vessels of onlyLicensee PAGEPress, Italy cal aspects of vasculitis. Vasculitis underlies all sizes are involved, both in arterial and Rheumatology Reports 2010; 2:e2 many of the clinical features of BD. Small ves- venous systems. Large vessel vasculitis is not doi:10.4081/rr.2010.e2 sel vasculitis is often found in the pathology of a rare manifestation of BD and it was pro- the mucocutaneous manifestations of BD. posed that this be one of the diagnostic crite- Large vessel vasculitis has been reported in 15- ria of the disease.9 The prevalenceuse of large 40% of BD patients. Ultrasound, angiography vessel vasculitis varies according to the ing the vasculitic involvement of small vessels and tomography are applied to confirm the authors and the population. in BD. Petechiae of the nailfolds were diagnosis when venous involvement is sus- described in BD for the first time by Hashi- pected. Endothelial dysfunction plays a role in moto in 1973. The first nailfold capillaroscopic the pathogenesis of disease. Peripheral arteri- study was reported in 1984 on 30 patients with al involvement in BD occurs in the form of Materials and Methods BD.10 Periungual petechiae were recognized in arterial occlusion or aneurysms. Pulmonary 50% of patients. Pallor of the background, arterial involvement is often life-threatening. Small vessel vasculitis in in sludge, and abnormal appearance of the venous plexus with irregularly arranged The cause of cardiac vascular involvement Behçet’s disease requires an aggressive diagnostic approach. venules were also described. There was no cor- Corticosteroids and immunosuppressive In this paper, we review the prevalence, relation between the capillaroscopic findings agents have been used successfully in the clinical manifestations, diagnostic methodolo- and the disease duration. More severe damage early stage of large vessel disease and should gy, treatment and management of vasculitis in was demonstrated in patients with long dis- be used as an adjunct to surgery. An increasing BD. Specifically, we covered small vessel vas- ease duration and these findings correlated amount of data is available regarding the role culitis in BD, large vessel vasculitis, venous with skin and joint manifestations. Both stud- of anti-tumor necrosis factor (TNF) agents for involvement in BD, superficial throm- ies were open, without controls. Video capil- the treatment of BD. AnticoagulantNon-commercial therapy bophlebitis, deep vein thrombosis (DVT), infe- laroscopy, a non-invasive, reliable procedure, may be hazardous in patients with aneurysmal rior vena cava (IVC) thrombosis, Budd-Chiari may have diagnostic and prognostic value in dilatation of the pulmonary vascular tree and is Syndrome (BCS), portal vein thrombosis, the definition of the microvascular abnormali- not effective in the treatment of venous throm- superior vena cava (SVC) thrombosis, ties in patients with BD. A recent video capil- bosis. Inflammation of small and large vessels endothelium in BD, other possible contribu- laroscopic study in 15 BD patients and 16 is very frequent in BD. Both arteries and veins tions to thrombosis in BD, homocysteine, healthy subjects matched for age and sex was may be involved. Early recognition and appro- coagulation factors, peripheral arterial performed. Various nailfold abnormalities priate management of large vessel vasculitis in involvement, pulmonary manifestations, car- were found, including capillary dystrophies, BD is essential to reduce associated morbidity diac manifestations, pericarditis, myocardium numeric capillary abnormalities, sludging, and mortality. involvement, endocardium, coronary arteries, petechiae and pericapillary edema in a high cerebral vasculitis, cerebral venous thrombo- proportion of patients with BD. Similar find- sis, and cerebral arterial aneurysms. This is, ings, along with vessel microaneurysms, coil- to our knowledge, the first review which con- ing and kinking were also found in the con- Introduction siders the wide spectrum of vascular inflam- junctiva of these patients.11 In a recent study by mation found in patients with BD. stereo-microscopy, qualitative capillaroscopy Behçet’s disease (BD) is a chronic, relaps- was performed; the reported findings were ing, multisystemic disorder characterized by Results of literature review confirmed, showing high frequency of morpho- urogenital ulcers and ocular inflammation Few studies have been published concern- logical abnormalities (90%) in small vessels.

[Rheumatology Reports 2010; 2:e2] [page 13] Review

In a study of the histopathology of pathergy, around vessels and skin appendages. The aberrations observed in patients with BD.25 true vasculitis was not seen. Rather, an majority of the T lymphocytes were CD4+ and T cells play a pivotal role in the pathogene- intraepidermal pustule and polymorphonu- almost all expressed CD45RO. Neutrophils sis of BD. Several investigators have observed clear aggregates were found.12 In an electron constituted less than 5% of the infiltrating that T cells dominate in the involved tissues microscopic study, small dermal blood vessels cells.22 and their phenotypic characteristics have been were found to be filled by thrombus after stim- In Takayasu’s disease, large arteries, includ- studied. In BD uveitis, CD8+ CD56+ T cells were ulation of the skin with needle prick and in ing the aorta and its branches, and pulmonary found.26 In the histopathology of the pathergy erythema nodosum-like lesions in BD patients. arteries are affected. Transmural granuloma- reaction mononuclear cells predominate com- Excessive proliferation of endothelial cells tous inflammation and chronic intimal fibrosis posed of T lymphocytes and mononuclear caused vascular stenosis and the appearance with luminal obstruction is found. Granuloma macrophages. The majority of the T lympho- of degenerated cells.13 formation and giant cells are predominately cytes were CD4+ and almost all cells expressed On biopsy, mucous membrane and cuta- found in the media and adventia of the large CD45RO. In a recent study, the histology of neous lesions in BD patients may demonstrate elastic arteries. central nervous system lesions in BD was stud- small vessel inflammation, including lympho- In Giant Cell arteritis large arteries are also ied. In histological studies of acute neuro cytic and necrotizing vasculitis.14 Vasculitis involved, with mononuclear cells, macro- Behcet’s disease, the infiltration of mononu- and phlebitis have been found in 48% of skin phages and multinuclear giant cells. Giant clear cells around small vessels consisted of biopsies in BD patients, lymphocytic vasculitis cells are typically found at the junction CD45RO+ T lymphocytes and CD68+ monocytes, in 31% and leukocytoclastic vasculitis in 17%.15 between the intima and media. and few CD20+ B lymphocytes. Phenotypical A neutrophilic vascular reaction or lymphocyt- and functional abnormalities of ab+ and γδ T- Immunopathogenesis 24 + ic infiltrates characterize the biopsy findings cell subsets were found in BD. A reduced CD4 Multiple cell types contribute to the tissue + in other series.16,17 /CD8 T-cell ratio is found in BD patients. A damage in Behcet’s disease. Neutrophils have + + Lesions of small arteries with lymphocytic or lower frequency of CD4 CD45RA T cells were enhanced chemotaxis and phagocytosis, neutrophilic cell infiltrates have been found in found in the peripheral blood lymphocytes in induce superoxide generation and myeloper- the subcutis in nodular cutaneous lesions. active BD compared to controls, while oxidase expression and also expression of CD4+CD29+ T cells were similar in frequency.27 Kim noted vasculitis of small vessels in erythe- a 23 CD11 , CD10 and CD14 on the cell surface. only + – ma nodosum-like lesions in the majority of The proportion of CD45RA CD45RO V9νδ2 The mechanism underlying the hyperfunction patients with BD.18 Biopsy specimens from cells in peripheral blood γδ T cells increased in of neutrophils in BD is not known but it has nodular lesions in 24 patients with BD, 25 with BD patients which may not depend on the dis- been shown that heightened neutrophil 28 nodular vasculitis and 20 with erythema ease activity. In normal subsets, γδ T cells chemotaxis is related to the presence of HLA- – + nodosum (EN), were compared.19 In 42% and useusually had a phenotype of CD45RA CD45RO B51 in patients with BD. Neutrophil function + 46%, (2 observers) a neutrophilic vasculitis of Vγ9+Vδ2 . It has been demonstrated that is also regulated and maintained by cytokines + nodular lesions in subcutis of BD patients was CD45RA γδ T cells produce more TNF-α and β IL-1, IL-2, IL-6, IL-8 and TNF- and others. It noted. A neutrophil predominant inflammatory α than did CD45RO. During the active disease, a has been suggested that Th1 type cytokines cell infiltrate was seen in BD compared with subpopulation of γδ T cells in BD express acti- and chemokines including IL-17, largely pro- nodular vasculitis and erythema nodosum. vation markers including IL-2 receptors and duced by activated CD4+ and CD8+ T cells, are Septal panniculitis, lymphocyte-predominating HLA-DR. A phenotypically distinct subset of γδ involved in the recruitment of neutrophils to + – + + infiltrate, absence of vasculitis, and necrosis T cells CD45RA CD45RO Vγ9 Vδ2 may con- the site of inflammation.24 Activated neu- were features more likely found in biopsies tribute to immunological abnormalities which trophils in BD patients produce significant from patients with EN. A spectrum of play an important role in the pathogenesis of quantities of IL-12 and IL-18. Enhanced 28 histopathological findings have been observed the disease. chemotactic activity may be important in in erythema nodosum-like lesions of BD, simi- Strong polarization of the immune response pathergy hyperactivity in the skin and mucus lar to those found with EN associated with toward the Th1 pathway correlates with BD membranes. Neutrophils accumulate in other disorders.20 progression, as increased percentages of inflammatory lesions where they induce neu- CD3+/IFN γ+ and CD3+/IL-2+ cells were observed Large vessel vasculitis trophilic vasculitis. Neutrophil function and in patients with active disease compared those In Behcet’s disease, vessels of all sizes are cell surface markers were evaluated with flow with complete remission and with healthy con- involved. Arteries, veins and capillariesNon-commercial are cytometry in patients with BD compared to trols.29 Plasma levels of IFN-α and IL-12 have affected. Aortic and peripheral artery healthy and diseased controls.25 Most pheno- been found to be elevated in parallel with aneurysms, pulmonary artery occlusion and typical and functional analyses show findings increased Th1 cells. These findings suggest a aneurysms, coronary artery aneurysms, deep compatible with in vivo activation of neu- pathogenetic role of a Th1 immune response vein thrombosis, and cerebral venous throm- torophils. in active disease. bosis have been described. The pathogenesis It has been observed that epidermal In a recent review, Zierhut discussed the of the aneurysms and thrombosis is unclear. It Langerhans cells were found to be significant- role of genetics, microbial infectious, T and is suggested that an interaction of an exoge- ly increased at the site of pathergy reaction. other cells and also the role of endothelium nous agent with the mononuclear cells from a Interleukin 18, produced by antigen presenting and coagulation abnormalities in BD.24 It has genetically predisposed patient may result in cells, (APCs) contributes to Th1 polarization, been shown that Vγ9/Vδ2 T lymphocytes from damage and functional impairment. particularly in association with IL-12. patients with BD are activated and may play a Inflammatory obliterative endarteritis of the Genetically determined hyperactivity of APCs role in the pathogenesis of the disease.30 In vasa vasorum, endothelial cell swelling and might play a role in the pathogenesis of BD. unstimulated 5– day cultures, γδ+ T cells mononuclear perivascular infiltration cause APCs, either primary or secondary to their CD8+ab+, CD4+ CD56+ and CD8+ CD-11β+ T lym- destruction of media, arterial wall weakening stimulation with Th1 cytokines, cause phocyte subsets were found to be up-regulated and aneurysm formation.21 Immunohistology of enhanced production of IL-12 and IL-18. Thus, significantly in BD compared to healthy con- skin pathergy reaction demonstrated a vari- interaction of APCs, Th1 lymphocytes and trols.31 This study confirms that these cells may able dense focal mononuclear cell infiltrate neutrophils form the basis of the immune contribute to Th1 polarization of BD. CD8+

[page 14] [Rheumatology Reports 2010; 2:e2] Review

CD56+ T cells in active BD uveitis are polarized cutaneous thrombophlebitis.8 Factor analysis was found in 15.8% of patients.8 This complica- to produce large amounts of INF-γ upon stimu- clustering also reveals an association between tion should be suspected in patients with alter- lation compared with the inactive BD and nor- superficial and deep venous thrombosis36 and nating venous thrombosis of the lower limbs or mal subjects. both conditions may be connected with throm- recurrent venous thrombosis in one limb.45 Increased serum levels of Th2 type cytokines bosis at any other site. Series of IVC thrombosis have been reported including IL-4, IL-10 and IL-12 have also been The main symptom of SVT is localized by several investigators.8,38,41,47 found in patients with BD.32 This finding can extremity pain, with swelling and erythema. be explained by compensatory mechanisms in Thrombosis of superficial veins can occur after Budd-Chiari syndrome opposition to a strong Th1 type immune venipuncture and has been reported at sites of The obstruction of Budd-Chiari syndrome response. The increase in IL-12 and IFN-γ heparin infusion. The diagnosis of superficial (BCS) can be due to acute or chronic thrombo- expression within the mucocutaneous BD thrombophlebitis can be confirmed by Doppler sis,47 but clot may be associated with vessel lesions associated with the absence of typical ultrasound, which can distinguish this prob- stenosis. BCS is an uncommon but serious Th2 cytokines supports a strong polarized Th1 lem from erythema nodosum-like lesions. manifestation of BD. Hepatic vein thrombosis immune response.33 was reported in 26.4% of 53 patients in a series The role of NK cells is controversial in BD, Deep vein thrombosis of BD patients with large vessel thrombosis.47 with normal, decreased or elevated levels The incidence of DVT in BD was found to be Series of BCS cases have been reported by reported in the peripheral blood. Increased lev- 24.9% in Tunisia.40 Higher figures (38.9%) other investigators.40,48-50 This complication is els of NK cells after bacterial stimulation have were reported by other researchers 41 from the characterized by hepatome-galy, right upper been reported.31 NK and NK-T cells kill target same country. In a more recent study (2006),40 quadrant abdominal pain, ascites, and edema cells and may represent cells involved in 519 patients were studied, while in the 2001 of the lower extremities.47 The diagnosis of crosstalking between innate and aquired series 113 cases from different areas of the BCS can be established by ultrasonography, immunity by the production of IFN-γ and IL-4. country were reported. Like all large vessel angiography, vena cavography or computed Thus, it seems that NK and NK-T cells may play lesions, males are affected more frequently tomography, and typical findings may be found a role in induction and/or regulation of various than females and the problem is found more on liver biopsy. types of immune response, including several commonly in patients with a younger age at Twenty-one cases (4 reported and 17 from 42 only autoimmune diseases and in ocular inflamma- onset of BD. The highest risk of venous occlu- the literature) of hepatic vein thrombosis tion in BD. NK cells can kill target cells within sion was in the lower extremities and/or infe- caused by BD were compared to 24 cases of minutes of the first stimulation of activating rior vena cava in the report of Koç.8 hepatic vein thrombosis caused by primary receptors and respond rapidly to challenge lim- There is little consistency in reports of the myeloproliferative disorders. Five out of 20 iting capacity to an antigen load. timing of DVT in respect to the onsetuse of BD. patients with BD had acute liver failure and The complication can occur in the first years of died within the first month of the clinical Venous involvement in Behçet’s the disease. DVT is thought to be an infre- onset, while patients with myeloproliferative 51 disease quent presenting sign of BD but has been diseases had a progressive course. Rarely, reported as the initial symptom of the disease spontaneous improvement may occur but most Superficial thrombophlebitis (SVT), deep in 23 of 84 patients.43 The most critical period patients remain at risk for slowly progressive vein thrombosis, vena cava thrombosis, Budd- for the development of DVT was found to range liver failure, elevated portal pressure and Chiari syndrome, portal vein thrombosis, and from 2 to 3.2 years following the diagnosis of esophageal varices. We recommend treatment cerebral venous thrombosis are the principal BD.8,41 DVT tends to occur earlier than arterial with heparin, pulse methylprednisolone and manifestations of vasculitic involvement of the involvement. cyclophosphamide in the acute stage of the large veins. Thrombophlebitis of the lower Associations with DVT include ocular disease. extremities and of the retina in a BD patient involvement,44 erythema nodosum-like lesions, BCS without involvement of the vena cava was first recognized and described by and pathergy.8,41 has been successfully treated with early surgi- Adamantiades 16 years after his first report of Venography, venous ultrasonography, MRI, cal decompression of the portal system.52 34 the disease in 1930. Adamantiades empha- MRI venography, or CT may be sufficient diag- However, portocaval shunt is not possible in sized the frequent occurrence of throm- nostic methods for the diagnosis of DVT. the setting of inferior vena cava thrombosis bophlebitis in this disorder and suggested that Anticoagulants with anti-inflammatory drugs due to an unsuitable pressure gradient thrombophlebitis should be includedNon-commercial as the are indicated for the treatment of venous between the portal vein and the inferior vena fourth cardinal sign of the disease. thrombosis.45 However, anticoagulants for cava. The successful use of a transjugular thrombosis as monotherapy may not be suffi- intrahepatic portosystemic shunt in BD has Superficial thrombophlebitis cient, since thrombosis can occur despite anti- not yet been reported. Percutaneous translu- Subcutaneous thrombophlebitis was the coagulant therapy.38,46 The treatment of superi- minal angioplasty (PTA) was performed in a most frequent type of vascular involvement, or vena cava syndrome and extracranial arteri- 45-year old BD patient and a dramatic reduc- found in as many as 47.3% of patients with al occlusion includes a combination of immu- tion of portal venous pressure (from 24 mm Hg BD.8 The prevalence of SVT was reported as nosuppressants, glucocorticosteroids, and to 15 mm Hg) resulted. This procedure may be 26.7%,35 and a frequency of 23% in males and anticoagulants.45 In acute thrombosis of the safe and effective for BCS when caused by seg- 8% in females has also been reported from large veins, heparin infusion and corticos- mental obstruction of the IVC whether compli- Turkey.36 A prevalence of 2.2-20%, has been teroids and, possibly, fibrinolysis are cated or not by middle and left hepatic venous noted by other investigators.37-39 employed, and for maintenance treatment war- occlusion.53 The very limited experience with SVT or erythema nodosum-like lesions may farin, corticosteroids and immunosuppressant anti-TNF agents in the treatment of this syn- predict visceral involvement in BD. The risk of drugs are also recommended.38 drome has not been favorable.54 venous occlusion in the lower extremity and/or inferior vena cava was found to be 22.8% in Inferior vena cava thrombosis Portal vein thrombosis patients with subcutaneous thrombophlebitis, Inferior vena cava (IVC) thrombosis in Portal vein thrombosis is another infre- while the risk was 5% in patients without sub- patients with BD with large vessel involvement quent complication in BD.47 Patients with BD

[Rheumatology Reports 2010; 2:e2] [page 15] Review and portal vein thrombosis clinically have or ate and long-term prognosis.60 recognition of endothelial dysfunction in BD develop splenomegaly, but the clinical presen- Cerebral venous thrombosis is not rare in should lead to aggressive management of tation may be clouded if thrombosis is present BD patients; it was present in 7.8% of 820 other risk factors for atherosclerosis in BD in other large veins. patients with BD in a recent study.65 Patients patients.73 with cerebral venous thrombosis (CVT) had Multiple other factors may lead to endothe- Superior vena cava thrombosis less parenchymal central nervous system lial dysfunction and vascular disease in BD. Superior vena cava (SVC) thrombosis is yet involvement compared to those without. In this Significantly higher serum levels of vascular another vascular manifestation found in report, anticoagulation was applied which was endothelial growth factor (VEGF) were found patients with BD. The reported frequency of safe and effective. In previous studies, the in patients with BD compared to normal con- the SVC obstruction was 1.4-9.8% of cases with prevalence of CVT was 10-12% among patients trols, particularly at the active stage of the dis- venous involvement.35, 55 Other series of SVC with neuroBD.59,62 BD patients with CVT who ease75,76 and in patients with vascular manifes- thrombosis were published recently.50,56 experience a relapse may have an associated tations and ocular involvement.76 VEGF, there- In unusual cases, SVC thrombosis has prothrombotic factor.65 fore, could be a risk factor for the development resulted in blockage of the lymphatic circula- of ocular disease, contributing to poor visual tion and chylothorax.57,58 The chylous effusion The endothelium in Behçet’s disease prognosis.76 Elevated levels of endothelin-1, contains triglycerides, cholesterol, increased Disordered function of endothelial cells may homocysteine, and nitric oxide (NO) were protein and white blood cells.57 play a pivotal role in the development of found in BD patients as compared to controls. Doppler ultrasound often reveals occlusion venous and other vascular manifestations in These factors represent other substances of the SVC in affected patients. Upper extrem- BD. Measurement of vessel characteristics which may contribute to the ocular manifesta- ity venography with or without digital sub- may help to understand structural and func- tions, promoting ischemia and retinal capillary straction angiography demonstrates the tional changes in the vessel wall and possibly closure.77 obstruction of the SVC.57 provide information for the diagnosis and The production of VEGF may be subject to The suggested treatment includes corticos- treatment in patients of BD with high cardio- genetic control. The association of VEGF gene teroids, azathioprine, anticoagulants and/or vascular risk.66 polymorphism with BD was studied in patients intervention with stent placement.55,56 Flow mediated dilatation was significantly and controls.only78 Carriers of –634C and allele 1 higher in patients with BD compared to control are associated with susceptibility to develop- Cerebral venous thrombosis subjects, indicating abnormal endothelial ing BD. VEGF may also play a contributing role The main symptoms of cerebral venous function67 in active and inactive stages of the in the development of venous thrombosis in thrombosis (CVT) are a persistent headache disease. In a subsequent study, aortic elastic BD. Levels of VEGF were significantly and papilledema due to intracranial hyperten- properties were found to be impaired.68 Ause sig- increased in patients with acute thrombosis sion with elevated pressure of the cere- nificant higher pulse wave velocity has been compared to those with chronic thrombosis.79 brospinal fluid. The cerebrospinal fluid in demonstrated in BD patients and compared VEGF activates endothelial cells and causes the cases without parenchymal involvement was with matched healthy controls indicating aor- release of vasoactive substances inducing vas- usually not accompanied by elevation of pro- tic stiffness. Increased arterial stiffness may cular thrombosis and inflammation. VEGF also teins or pleocytosis.59 Symptoms of elevated relate to endothelium dysfunction and acute or up-regulates NO synthase which may induce intracranial pressure may be the presenting chronic inflammation.69,70 Significant carotid damage to host cells and tissue.76 manifestation of BD. Multiple cases and series artery intima-media thickness in patients with Asymmetric dimethylarginine (ADMA) and of patients with CVT have been reported.59-63 BD compared to control subjects has been NO levels may reflect signs of endothelial dys- The first case of CVT in BD during pregnancy found by ultrasonography.71 Increased intima- function in BD.80 The endothelial NO synthase was published in 1995.64 The presence of major media thickness and arterial distensibility are gene polymorphism Glu – 298 Asp of exon 7 is vessel disease was studied in 88 patients with related in BD patients.66 associated with BD when compared to con- CNS disease.61 Coexisting vascular problems Brachial artery flow mediated dilatation was trols.81 Other investigators have found that were identified in 15 of 77 patients with reduced in BD patients compared to normal increased plasma ADMA levels and decreased parenchymal CNS disease. Eleven of these controls.72 However, in a more recent study plasma NO levels are risk factors for cardiovas- patients also had venous involvement, one had there was no significant difference in endothe- cular events in patients with BD.80 both arterial disease and venous thrombosis,Non-commerciallial dependent and independent vasodilatation Activation of endothelial cells has been and 3 patients had coexisting arterial disease. in patients with and without vascular involve- found in a high proportion of patients with BD The majority of patients with CVT, 7 of 11 ment.73 These differences may be due to the (42%) irrespectively of current ocular disease. patients, had coexisting vascular problems. effect of immunosuppressive drugs in patients The thrombotic tendency in BD patients may Five CVT patients had venous thrombosis and with vasculitis, the small sample size, or the relate to enhanced endothelial cell activation.82 2 patients had both arterial and venous throm- exclusion of patients with active disease. Anti-endothelial cell antibodies have been bosis. In 80 controls with BD who did not have Endothelial dysfunction was shown to be found in the serum of BD patients, particular- CNS disease, 18 had major vessel involvement. associated with plasma homocysteine levels in ly during the active stage of the disease. The age of onset of CVT in men was signifi- BD,74 but the nature of this association is However, the exact role of these antibodies in cantly lower than the age of onset of parenchy- unclear. In one study, homocysteine levels the disease has not been clarified.83-85 mal disease, 23.1(8.8) vs. 32.0 (7.5) years, were higher in BD patients with vascular Endothelial cell antibodies were detected in respectively. Among the 3 women studied no involvement than in those without, but there 18-37% of patients with BD.86,87 However, others such trend could be recognized. was no correlation of homocysteine levels and have not found any statistically significant dif- The diagnosis of CVT is established by MRI endothelial dependent vasodilatation. ference between patients and controls.88 This and magnetic resonance venography of the The etiology of endothelial dysfunction in discrepancy likely reflects methodological dif- brain. Medical management of BD-associated BD is probably multifactorial and includes high ferences in ELISA assays for anti-endothelial CVT includes corticosteroids and anticoagu- homocysteine levels as well as oxidative stress, antibodies.88 The serum levels of several lants. Combination therapy with these agents although all of the mechanisms that underlie cytokines were determined in 94 BD patients, has been associated with satisfactory immedi- this dysfunction are not clearly known. The 74 with active disease, and 75 healthy individ-

[page 16] [Rheumatology Reports 2010; 2:e2] Review uals matched for age and sex who served as cysteinemia, thought not to be an independent one (6.6%) had both lupus anticoagulant and controls. Increased levels in the serum of IL-8 factor for vascular involvement.97 acl β2-GP1 antibodies.104 were found in patients with active disease Aksu93 hypothesized that homocysteine had High von Willebrand factor antigen with oral ulcers and neurological manifesta- a deleterious effect on endothelial cells, caus- (vWF:Ag) levels may be found in BD patients, tions compared to the patients with inactive ing endothelial cell damage, smooth muscle but are possibly secondary to vascular damage disease and controls. IL-8 secretion by dermal cell proliferation, and increased oxidative due to endothelial cell injury.105 More recently, microvascular endothelial cells is stimulated stress. An alternate mechanism for induction significantly higher vWF: Ag levels were report- in the presence of Behçet serum.89 It is postu- of vascular disease and thrombosis could be ed in BD patients compared to a control lated that circulating anti-endothelial cell anti- the interference with coagulation mecha- group.106 There was no statistically significant bodies may be responsible for this effect.89 nisms. Other researchers blame the genera- difference between vWF: Ag levels in patients Dyslipidemia, particularly hypertriglyc- tion of superoxide and hydrogen peroxide by with and those without organ involvement. A eridemia, might be expected to be a risk factor homocysteine for this effect, both of which significant linear correlation between high for thrombosis in BD. However, patients with may induce endothelial damage.77 According to vWF: Ag and serum ferritin levels was and without thrombosis have similar triglyc- this hypothesis, homocysteine changes coagu- observed, suggesting that vWF: Ag was related eride profiles and there were no differences in lation factor levels so as to encourage blood to disease activity.106 any of the lipid parameters that were ana- clot formation with aggregated platelets. Other BD with deep vein thrombosis and the factor lyzed.90 Leiba,91 however, reported that patients investigators suggest that homocysteine may V Leiden mutation has been reported.107 with thrombosis had significantly higher mean contribute to a decrease in serum paraoxonase However, others authors have not found any levels of factor VIII, total cholesterol, triglyc- (PON 1) activity, particularly in patients with association between three thrombogenic erides, VDRL cholesterol and apolipoprotein B- active disease.94 A current hypothesis suggests mutations (factor V gene G169IA, methylenete- 100, C-11 and C-14 than those without throm- that homocysteine may have a deleterious trahydrofolate reductase gene C677T, and pro- bosis. There were a large percentage of effect in BD by decreasing NO levels and also thrombin G →A20210 mutation) and BD patients patients with arterial events (10%) in the lat- through immune system effects. Homocy- with thrombosis.108 Heterogeneity for factor V ter series, possibly accounting for the discrep- steine activates T cells and increases the inter- gene mutation was considered to be a risk fac- ancy.90 action of monocytes and T cells with endothe- tor for venous thrombosis by others.109,110 In a lial cells.96 From these studies it is obvious that studyonly from Italy, there was no association Other possible contributions to the exact mechanism by which hyperhomocys- between deep venous thrombosis and the fac- teinemia is related to vascular disease and 111 thrombosis in Behçet’s disease tor V Leiden mutation. Factor V Leiden did venous thrombosis remains to be clarified by not correlate with retinal vascular occlusion in Several coagulability factors have been sus- further investigation. use 53 patients from the United Kingdom.112 pected to play a role in the thrombotic events However, an association was found between in BD. Hyperhomocysteinemia and decreased Coagulation factors the factor V Leiden mutation and ocular BD, levels of antithrombin III, protein C, protein S, The prevalence of antithrombin III, protein particularly for the development of vascular and the factor V Leiden mutation have been C, protein S deficiencies, the factor V Leiden occlusion.113 The prevalence of factor V Leiden investigated, with no consistency in the find- and prothrombin G→A20210 mutations, the in these Turkish patients with retinal occlu- ings and little relationship with thrombotic methylenetetrahydrofolate reductase C677T sion was 53.3%, compared to 26.7% in those episodes in the disease. polymorphism, and acquired thrombophilic without vascular occlusion. The prothrombin risk factors including anticardiolipin antibod- G→A20210 mutation was not detected in any of Homocysteine ies (ACL-Ab), lupus anticoagulant, and serum the BD patients in that study. The variable Increased levels of homocysteine were homocysteine levels have all been the subject results reported from the studies could be found in 27.6% of BD patients, compared to of recent investigations. Overall comparison of related to the methodology and/or to the differ- 6.9% in healthy controls.92 Aksu93 found mean the reported findings in patients with BD in ent populations studied. plasma concentration of homocysteine to be Spain with healthy controls showed no signifi- In a recent study from Spain, the prevalence higher in BD patients than in healthy controls cant differences.98 Nonetheless, deficiencies of of inherited and acquired thrombophilic risk (11.5±5.3 vs. 8.8±3.1 μmol/L). Hyper-homocys- the anticoagulant proteins antithrombin III, factors in 79 patients with BD and in 84 teinemia was reported to be significantly high- protein C and protein S have been implicated healthy control individuals was studied. Three er in patients with active diseaseNon-commercial than in for the thrombotic events in certain patients of 23 patients with thrombosis were carriers of patients with inactive disease and in control with BD. the prothrombin G→A20210 mutation, compared subjects.94 Moreover, high levels of homocys- Antiphospholipid antibodies may be a with none of 56 patients without thrombosis teine were reported in 64% of patients with BD marker for a risk of development of thrombo- (P = 0.022).98 In a meta-analysis, these authors with thrombosis as compared to 9% in those sis. However, several reports failed to demon- found an association with the factor V Leiden without thrombosis.93 However, in a study from strate a correlation between ACL-Ab or lupus as well as the prothrombin G→A20210 mutation Tunis,95 hyperhomocysteinemia was more fre- anticoagulant in patients with BD, but a with thrombosis in BD. A study from Italy quent in patients than in controls, but there prevalence of 0-8% has been reported.99-102 found no association with deep venous throm- was no difference in those with or without Although found in patients with BD, there has bosis, but a high frequency of the prothrombin thrombosis. Increased levels of homocysteine been no correlation with any vascular compli- G→A20210 mutation was found in a subgroup of were also found in patients with ocular cations of the disease. Circulating lupus anti- patients with posterior uveitis and retinal vas- involvement compared to those with non-ocu- coagulant or elevated levels of IgG ACL-Ab culitis, supporting the possibility that this fac- lar disease and healthy control subjects.77 In were detected in a significant number of tor may influence the development and also another recent study, hyperhomocysteinemia patients with BD without any demonstration the severity of eye involvement in BD was confirmed as a definite finding in BD of a relationship to arterial or venous throm- patients.111 patients compared to controls.96 Other bosis.103 In another study of 64 patients with Among 20 BD patients with vascular involve- researchers have found no association BD, 23.4% with vascular involvement, only 2 ment, 55% had Mediterranean fever gene between venous involvement and hyperhomo- patients (13.3%) had lupus anticoagulant and mutations compared to 11% in the non-vascu-

[Rheumatology Reports 2010; 2:e2] [page 17] Review lar group, a statistically significant differ- have been used in the treatment of large ves- vasculitis.130 Pathologically, acute inflammatory ence.114 Plasma E, L, and P selectin concentra- sel vasculitis in BD.45,116 Because rupture of destruction of elastic and muscular pulmonary tions were significantly higher in patients with these aneurysms with fatal outcome is not arteries or extensive inflammatory disruption severe BD.115 rare, physicians usually elect for urgent surgi- of alveolar capillaries is seen. It should be rec- cal intervention. Surgery should be performed ognized that anticoagulant therapy, usually Peripheral arterial involvement in a patient with a large or growing aneurysm, given for coexisting DVT or because of the Several large series and case reports of acute bleeding of the aneurysm or acute clinical suspicion of a pulmonary embolus, is patients with BD and peripheral artery abnor- ischemia.126 Various surgical procedures have extremely hazardous and may increase the malities have been reported.8,39,40,42,116-118 The fre- been employed in the treatment of aneurysms risk of extensive, fatal pulmonary hemor- quency of arterial involvement in BD ranges including bypass, ligation and tube graft inser- rhage.131,136,137 Confirmation of the cause of from 2.2-18%, with marked male predomi- tion, and aneurysmectomy but should always hemoptysis in any BD patient is essential to nance.39,42,45,119 The reason for the sex difference include simultaneous medical manage- the choice of appropriate treatment. in the prevalence of BD remains uncertain, but ment.127,128 Combined morbidity (anastomotic Associations with PAA included deep vein sex hormones and/or genetic factors have been pseudoaneurysms) and mortality of BD thrombosis of the lower extremities in 81%, implicated.118 patients after endovascular repair is consider- vena cava thrombosis in 15%, intracardiac Arterial involvement can be found in any ably lower than open surgery.129 Endovascular thrombus in 12% and arterial aneurysm at peripheral artery, particularly in femoral repair is a less invasive procedure and is more other sites in 15%.133 Pulmonary artery artery, popliteal artery, iliac artery and abdom- often successfully accomplished in BD patients aneurysms are typically confined to main pul- inal aorta, while it is infrequent in carotid compared to those with atherosclerosis monary arteries and their lobar branches.119 artery. Venous involvement is found in most because patients are younger and the Theses aneurysms can be unilateral or bilater- patients with arterial disease. Peripheral arte- aneurysm typically involves a shorter vessel al, single or multiple,138 true aneurysms.131 The rial occlusions are more frequent than arterial segment.126 However, the long-term results of occurrence of pulmonary artery aneurysms aneurysms, but the concurrent appearance of endovascular procedures remain uncertain and deep vein thrombosis is referred to as occlusions and aneurysms is not an unusual and further studies with long-term follow-up Hughes-Stovin syndrome.139,140 finding.120 Pseudoaneurysms of large or medi- are needed to determine the optimal surgical The diagnosis of pulmonary aneurysm is 126 118 only an sized arteries with occlusion or stenosis of strategy. In a study by Hosaka, the post- suspected by clinical findings and confirmed distal run off arteries in Korean patients have operative course in 10 patients (9 males), by chest X-ray, Doppler ultrasonography, heli- been reported.121 A case of pseudoaneurysm of many requiring multiple procedures, was com- cal computed tomography, pulmonary angiog- renal interlobar artery has also been report- plicated by graft occlusion in 5 patients, anas- raphy, scintigraphy, MRI angiography, and tho- ed.122 tomotic false aneurysm in 5 patients, anduse new racic computed tomography.131 FDG-PET has The clinical presentation of aneurysms aneurysms in different sites in 7 patients. Five been used successfully for the visualization of varies widely from the asymptomatic to pul- patients were alive, one patient died and 2 pulmonary artery aneurysms in one case.141 On satile mass, back pain, painful mass, were lost to follow-up. The overall cumulative chest X-ray peripheral or central pulmonary hematoma, intermittent claudication, abdomi- incidence of formation of anastomotic pseudo- nodular opacities occur and are frequently nal pain, gangrene of the forefoot, and less fre- aneurysm was 12.9% (5 of 49 anastomoses) at multiple.142 quently hemoperitoneum, anuria, or fever. five and ten years.118 Histological findings in PAA reveal a pul- Multiple aneurysms can be seen in peripheral Immunosuppressive treatment could be monary vasculitis affecting arteries, veins, arteries.123 needed together with any surgical repair venules and capillaries.143 The inflammatory Relapses of arterial involvement are very method including endovascular repair.119 process may be initiated in the vasa vaso- frequent and sudden death from aneurysm rum.119 Pathological findings can include rupture has been reported. The rate of death in Pulmonary manifestations inflammatory infiltrates with alterations of the patients with aneurysm rupture was found to Pulmonary artery aneurysms (PAA), pul- intima and elastic lamina, necrosis of the ves- be as high as 60%.124 The mortality rate in BD monary arterial and venous thrombosis, pul- sel wall, fresh thrombi and thrombotic occlu- has been studied by several authors.42,118 monary infarction, recurrent pneumonia, sions, and true and false aneurysms.144 Computed tomography, ultrasonography and bronchiolitis obliterans, organizing pneumo- The prognosis of PAA is extremely poor and MRI angiography can all be helpful for the nia and pleurisy are the major pulmonary com- requires prompt diagnosis and treatment to diagnosis of arterial aneurysms. IntravenousNon-commercialplications in BD.130,131 Thee are no prospective improve survival. In an earlier cohort of digital substraction angiography should be studies examining the true prevalence of lung Turkish patients, half of the PAA patients were considered in order to minimize the occur- involvement in BD, but the reported preva- reported to have died within ten months after rence of aneurysm formation at the site of lence ranged from 1-7.7%.132 the onset of hemoptysis.134 Ιn a more recent arterial puncture. Recently 18F-fluorodeoxyglu- The most severe complication of pulmonary report of patients with PAA, the same cose positron emission tomography (FDG- vasculitis is PAA. While uncommon, these have researchers found an overall 5-year survival PET) was used in BD with impressive results a poor prognosis and are a leading cause of rate of 63%; patients diagnosed since 1992 had for the diagnosis of arterial involvement in a death in patients with BD.42,133,134 Pulmonary a 5-year survival rate of 80%.133 The improved woman with BD.125 Histological examination of arterial vasculitis almost exclusively affects prognosis was believed to be due to earlier the aortic wall involvement shows a thinned males and has a strong association with a sys- diagnosis and rational use of immunosuppres- media and fragmentation of elastic fibers. temic pattern of vessel involvement at other sive agents. In another recent study, the cumu- Mononuclear cells and lymphocytes were sites.119,134 lative survival of patients with PAA was 57% at demonstrated, particularly in the adventitia The most frequent symptoms of PAA are one year and 39% at five years.131 where fibrosis prevailed. Thrombosis of the chest pain and hemoptysis in 80% of There are no randomized controlled studies vasa vasorum has also been described.120 patients.133 Massive hemoptysis can occur. The regarding the optimal treatment of PAA and Combination treatment with corticosteroids cause of bleeding is rupture of the aneurysm the recommendations are based on consensus and immunosuppressive drugs (azathioprine, with erosion into a bronchus or massive or observational studies.131 Spontaneous remis- cyclophosphamide) and, rarely, anticoagulants hemoptysis135 or in situ thrombosis from active sion of PAA has only rarely been reported.

[page 18] [Rheumatology Reports 2010; 2:e2] Review

Current recommendations include corticos- tion, intracardiac thrombosis, endomyocardial rin with necrosis and massive growth of gran- teroids and immunosuppressive drugs. fibrosis, coronary arteritis with or without ulation tissue have been reported.162 Dilatation Corticosteroids and immunosuppressive drugs infarction, and aneurysms of the coronary of the aortic and mitral valve with or without may be particularly beneficial especially when arteries or sinus of Valsalva. Clinical cardiac endocardiac thrombus has been demonstrat- introduced in the early stages of the develop- involvement in BD has been found in as many ed.163,164 A case reported with aortitis had vege- ment of this complication, before irreversible as 16.5% of cases in a postmortem series150 and tations of aortic and mitral valves resembling damage to the arterial wall develops. Pulse may be demonstrated in more patients if sen- aortic valve endocarditis with subaortic com- methylprednisolone and pulse cyclophos- sitive techniques are employed. plications.163 Anterior prolapse of the mitral phamide have been administered for two valve was found in 6% of BD patients and in 3% years, and then they are continued or replaced Pericarditis of healthy subjects.165 A more recent study 132,133,143 by azathioprine. Recently the anti-TNF Pericarditis may be symptomatic with chest found a prevalence of mitral valve prolapse of agent infliximab was administered to a patient pain and fever, although it can also be asymp- 25% in patients with BD, while in control sub- with life-threatening hemoptysis from pul- tomatic.151 Pericarditis may be associated with jects it was the same (3%) as in the previous 145 158 monary aneurysm with complete remission. coronary infarction, myocarditis, pleural effu- study. Dilatation of the ascending aorta was These results should be confirmed by other sion and/or obstruction of the veins of the found in 48% of BD cases and 3% in normal 165 studies. extremities. Constrictive pericarditis is a very subjects. Differences between studies may Embolization with n-butyl-cyanoacrylate rare complication.152,153 be due to different diagnostic criteria, techni- (NBCA) has been successfully used in patients The pericardial fluid in BD patients is usu- cal differences, and heterogeneity of the study with PAA presenting with life-threatening ally inflammatory, although it can rarely be population. 146 hemoptysis. Aneurysm size or vena cava chylous.57 The histology of the pericardium has In patients with BD, it may be appropriate to thrombosis may limit the use of endovascular been found to show vasculitic lesions with perform both transthoracic and trans- 119 embolization in some patients. Patients perivascular infiltration of lymphocytes and esophageal endocardiograms these being the treated with embolization, with or without plasma cells or fibrosis,57 or reactive mesothe- most sensitive tools to detect endocardiac and immunosuppression, have a better prognosis lial proliferation and fibrin exudation.152 myocardial abnormalities. than patients who underwent surgery without Pericarditis may subside with non-steroidal A serious complication in BD is the forma- immunosuppressive therapy who had the only anti-inflammatory drugs, but corticosteroids tion of an endocardial thrombus or endocar- highest mortality rate.131 Anticoagulant therapy 166-169 and immunosuppressive drugs may be diac mass. Males are affected much more may be hazardous in patients with aneurysmal required for treatment of associated frequently than females and more than half of dilatation of the pulmonary vascular tree, and lesions.153,154 Pericardial drainage may be nec- the cases were found to have intracardiac the beneficial effect of corticosteroid therapy use essary in cases of large effusions with com- thrombus at the time BD was first recog- has been discussed.142 170 pressive symptoms.57,153 nized. The principal clinical findings at the Urgent surgery was performed in 3 patients time of detection of intracardiac thrombus with pulmonary artery aneurysm due to life- Myocardium involvement were fever in 52% of patients, hemoptysis in threatening massive hemoptysis, and these 48%, dyspnea in 44%, and cough in 20%. An patients died in the post-operative period.147 Myocardial manifestations in BD include accelerated erythrocyte sedimentation rate 155 Surgical therapy should be reserved for those cardiac arrhythmias and, rarely, myocardi- was frequently found, although it was a poor 156 patients with life-threatening disease. The tis. In the first study to use pulsed wave indicator of disease activity.170 Cardiac thrombi presence of pulmonary artery aneurysms in Doppler tissue echocardiography, ventricular in BD are located in the right atrium, left atri- general confers a poor prognosis with many diastolic function was found to be abnormal in um, right ventricle and rarely in other sites of 157 BD patients as compared to control subjects. 170,171 fatalities in these young patients. Multiple the endocardium. Τhe reason for the other vascular complications may contribute to Diastolic dysfunction was reported in 37% of propensity to right-sided intracardiac throm- the prognosis. patients using transthoracic and multiplane bus in BD is unclear. BCS, PAA, and IVC throm- 158 Pulmonary embolization is rare in BD. This transesophageal echocardiography. Potential bosis are often associated with clots of the is thought to be because thrombi are adherent explanations for this dysfunction include the endocardium.172 to the vessel wall as a result of the inflamma- possibility of primary myocardial disease, dis- Transesophageal echocardiogram, enhanced tion present and do not detach easily from the turbance of the coronary microcirculation, or helical CT, and indium 111 platelet scintigra- 157 endothelium.136,148 Non-commercialthe presence of silent ischemia. In one phy have been used for the diagnosis of endo- Pleural effusion is not rare in BD patients. It recent study, no differences were found in left cardiac thrombosis. Scintigraphy can distin- may result from vasculitis of the pleura, which ventricular function in systole and diastole at guish between whether the thrombus is acute has been demonstrated by biopsy, pulmonary rest and with exercise in patients as compared or chronic. Blood fibrinolysis was impaired in 159 infarction, thrombosis of the superior vena to healthy control subjects. This discrepancy a 34-year old male with myocardial infarction cava149 or of the innominate and subclavian of the reported studies may be due to the and BD.91 veins, and may be chylous due to lymphatic patient selection or to the sensitivity of the In some individual cases, thrombophilic fac- obstruction (see above). Treatment of pleural assessment methods. tors have been present and may contribute to effusion in BD is directed to the underlying intracardiac thrombosis. Heterozygous pro- cause of the fluid and may include corticos- Endocardium thrombin G →A20210 mutation has been recog- teroids, immunosuppressive drugs and surgi- Mitral and aortic valvular insufficiency has nized in 2 patients.166,167 In most cases, pro- cal drainage. Pleurodesis with tetracycline has been observed in patients with BD.160,161 Mitral thrombotic factors are not found and the cause been employed.57 regurgitation is the most frequent valvular dis- of thrombus formation is not well under- order, reported in as many as 40% of patients stood.91,173 Cardiac manifestations of BD and in 6% in healthy controls.158 Valvulitis Anticoagulants, colchicine, thrombolytic Cardiac abnormalities in BD include peri- of mitral and aortic valves has been reported agents, corticosteroids, and immunosuppres- carditis, myocarditis with conduction system and the histological findings have been sants have been employed in the treatment of findings, endocarditis with valvular regurgita- described. Mitral valve leaflets covered by fib- intracardiac thrombus in BD patients with

[Rheumatology Reports 2010; 2:e2] [page 19] Review some success.167,168,171 The surgical removal of in-stent restenosis and aneurysm formation.178 mation in multiple clinical manifestations of thrombus was successful in a 16-year old male, The long-term results of stent placement in BD BD. The disorder is classified among the sys- followed by anticoagulant and corticosteroid patients are unknown, considering the possi- temic vasculitides. Vasculitis is believed to be treatment.169 Recurrence of the intracardiac bility of pathergy in these patients and an involved in the pathogenesis of most of the thrombus after surgical removal occurred and underlying vasculitis. Immunosuppressive problems seen in patients with the disease and azathioprine was added. In another patient, therapy should be considered in these patients it is important for the clinician to understand recurrence of the intracardiac thrombus after when progressive complications are recog- the process of vascular inflammation in order surgical removal was observed and treated nized. Aneurysmal dilatation of sinus of to best treat these patients. with prednisone and cyclophosphamide.167,168,171 Valsalva was detected by transesophageal Vasculitis may be recognized in multiple tis- We believe that this complication should be echocardiography in 28% of BD patients and in sues examined by biopsy or during the course treated with immunosuppressive agents which 3% of controls.158 These aneurysms may be of surgery, but there are no specific diagnostic are often indicated in any case because of asymptomatic, but ruptures of these findings to support the diagnosis of BD. comorbid complications. aneurysms have been reported.179 Rather, it is the expanded spectrum of blood Endomyocardial fibrosis is a rare complica- vessels involved, from the smallest vessels to tion of BD, but reported by several investiga- Cerebral vasculitis the great vessels, and the involvement of both 174,175 tors. It has been suspected that endomy- Cerebral vasculitis in BD can result in cere- arteries and veins, both in the systemic circu- ocardial fibrosis could be the result of treat- bral venous thrombosis or, less commonly, in lation as well as in the pulmonary circulation, ment with corticosteroids, anticoagulants, or intracranial aneurysms. The role of true vas- that is characteristic of BD. The term “vasculo- antiaggregants.175 More likely, this problem culitis in the pathogenesis of parenchymal Behçet” has been used to identify that sub- may be the sequela of vasculitis involving the CNS disease in BD is not well documented. group of BD patients who have a particular endocardium, myocardium or both, complicat- predilection for large vessel involvement, often ed by mural thrombus.175 Endomyocardial fibro- Cerebral arterial aneurysms with an additive, progressive course that con- sis is located in the right and left ventricles cludes with pulmonary artery aneurysm, the and only rarely in the atrium. Histologically, Cerebral aneurysms are rather infrequent complication most associated with mortality in dense fibrous tissue with neovessels, mononu- in BD but multiple case reports and case series this disorder. 180-182 clear and polymorphonuclear infiltrates and have been published. A rare case of brain Theonly pathogenesis of the vasculitis in BD calcified areas have been found. If endomy- abscess of the parietooccipital lobe with asso- continues to be studied in many centers ocardial fibrosis is complicated by cardiac fail- ciated brainstem encephalitis in a female with around the world and a clearer picture of the ure, surgical excision has been a successful BD and another patient with subarachnoid multiple contributing factors is slowly emerg- treatment in the short term.174,175 hemorrhage due to a ruptured aneurysm ofuse the ing. There has been little support for circulat- 181 superior cerebellar artery were reported. ing factors in the pathogenesis of the venous Coronary arteries Rupture of a superior cerebellar artery thrombosis associated with the disease, but aneurysm after five months of disease has also Coronary artery aneurysms in BD are rare inherited coagulation abnormalities may com- been reported,182 but this is a very rare early and few reports have been published. In one pound the problem of vascular inflammation manifestation of the disease. The clinician recent case,21 the aneurysm was associated leading to adherent clot. with an inflammatory obliterative endarteritis should be alerted to the possibility of rupture We reviewed the clinical presentation of of the vasa vasorum with endothelial cell and treatment initiated before catastrophic patients with vasculitis in various organ sys- swelling. The infiltration consisted of mononu- neurological damage results. Neurological tems and the diagnostic approach to confirm clear perivascular infiltration which caused symptoms proceeded the diagnosis of BD in the presence of disease. A discussion of the 59 destruction of media, arterial weakening and only a very few cases. The main presenting treatment of the vasculitis in BD would include aneurysm formation. The aneurysm developed symptom of a cerebral arterial aneurysm is a review of the treatment of the whole disease, in the patient during a period of apparent clin- headache, resulting from the rupture and hem- as vasculitis is usually responsible. We have 180,183 ical remission of 13 years. Conservative man- orrhage. Digital substraction angiography focused our comments on treatment to large agement with aspirin, metoprolol and atorvas- or MR angiography can be used for the detec- vessel manifestations. While recommenda- 184 tatin was elected and the patient had no chest tion of arterial aneurysms. tions for treatment are limited by the lack of pain over follow-up of one year. Coronary Treatment of cerebral aneurysms in BD is randomized controlled trials, a recent publica- angiography in another patient showedNon-commercial com- generally surgical clipping, as it is for tion by a European League Against Rheu- 180,183 plete proximal occlusion of the circumflex aneurysms in the absence of the disease. If matism subcommittee has provided guidelines artery and an aneurysmal fistula between the an unruptured aneurysm is recognized, high- based on available data as well as on expert left main branch and the pulmonary artery.176 dose corticosteroids have been recommend- opinion.186 In the area of large vessel involve- Rarely, myocardial infarction has been the ed.184 Aneurysm occlusion by an endovascular ment, the guidance statements by this group presenting symptom of BD.173 Myocardial infarc- approach can provide an equivalent therapeu- include the following: i) there is no firm evi- tion with normal coronary arteries in young tic result without the need for a cranioto- dence to guide the management of major ves- patients has been observed, presumed to be due my.183,185 This procedure can be performed in sel disease in BD. For the management of to coronary arteritis.161,177 Myocardial infarction the early stage of subarachnoid hemorrhage, acute deep vein thrombosis in BD, immuno- may be accompanied by other manifestations, particularly in those patients with poor neuro- suppressive agents like corticosteroids, aza- such as pericarditis, recurrent venous thrombo- logical status.182,183 thioprine, cyclophosphamide or cyclosporine A sis.161 In all young adults with BD and myocar- are recommended. For the management of dial infarction, non-atherosclerotic etiologies both pulmonary and peripheral arterial such as emboli, dissection, trauma, spasm or aneurysms, cyclophosphamide and corticos- arteritis should be investigated. Discussion teroids are recommended; ii) there are no con- The treatment of myocardial infarction in trolled data on, or evidence of benefit from BD is unclear. Coronary stent placement in We performed an extensive literature uncontrolled experience with: anticoagulants, one young BD patient was followed by proximal review on the participation of vascular inflam- anti-platelet or fibrinolytic agents in the man-

[page 20] [Rheumatology Reports 2010; 2:e2] Review agement of deep vein thrombosis or for the use 6. Zouboulis CC. Epidemiology of Ada- 19. Demirkesen C, Tuzuner N, Mat C, Senocak of anticoagulation for the arterial lesions of mantiades-Behcet's disease. In: Zierhut M, Buyukbabani N, Tuzun Y, et al. Clinico- BD. We believe that these statements accu- M, Ohno S, eds. Immunology of Behcet's pathologic evaluation of nodular cuta- rately describe the current status of our beliefs Disease. Amsterdam: Grafisch neous lesions of Behçet syndrome. Am J in the treatment of large vessel inflammation Produktiebedrijf Gorter 2003:1-16. Clin Pathol 2001;116:341-6. or thrombosis. Aggressive treatment of the 7. Zouboulis CC, Kotter I, Diawari D, et al. 20. Chun SI, Su WP, Lee S, Rogers RS III. inflammation in large vessel arterial and Adamantiades-Behçet’s disease: epidemi- Erythema nodosum-like lesions in venous disease with immunosuppressive ology in Germany and in Europe. In: Lee S, Behçet's syndrome: a histopathologic agents is recommended. The lack of benefit Bang D, Lee E-S, Lee S, eds. In Behçet’s study of 30 cases. J Cutan Pathol 1989; from use of anticoagulants in the treatment of disease A guide to its clinical understand- 16:259-65. these disorders should discourage the use of ing Textbook and Atlas Springer 2001:157- 21. Cevik C, Otahbachi M, Nugent K, Jenkins these agents as sole treatment of any of these 69. LA. Coronary artery aneurysms in Behçet's vascular complications. 8. Koç Y, Gullu I, Akpek G, Akpolat T, Kansu E, disease. Cardiovasc Revasculariz Med Kiraz S, et al. Vascular involvement in 2009;10:128-9. Behçet's disease. J Rheumatol 1992;19: 22. Gul A, Esin S, Dilsen N, Konice M, Wigzell 402-10. H, Biberfeld P. Immunohistology of skin Conclusions 9. Schirmer M, Calamia KT. Is there a place pathergy reaction in Behcet's disease. B J for large vessel disease in the diagnostic derm 1995;132:901-7. In conclusion, we reviewed the wide variety criteria for Behçet's disease. J Rheumatol 23. Takeno M, Kariyone A, Yamashita N, of vasculitis and vascular manifestations that 1999;26:2511-2. Takiguchi M, Mizushima Y, Kaneoka H, et can be seen in patients with BD. The vasculitis 10. Wechsler B, Le Thi Huong D, Mouthon J- al. Excessive function of peripheral blood of BD can affect vessels of all sizes, both in the M, et al. Aspects capillaroscopiques peri – neutrophils from patients with Behçet's arterial and venous circulations, including the ungueaux au cours de la maladie de disease and from HLA-B51 transgenic specialized vessels of the pulmonary circula- Behçet. A propos de 30 observations. Ann mice. Arthritis Rheum 1995;38:426-33. tion. The occurrence of multiple involvements Dermatol Venereol 1984;111:543-50. 24. Zierhut M, Mizuki N, Ohno S, Inoko H, Gul in BD is distinctive, if not unique, among the 11. Pasqui AL, Pastorelli M, Puccetti L, et al. onlyA, Onoe K, et al. Immunology and function- vasculitides, and can certainly support the Microvascular assessment in Behcet dis- al genomics of Behcet's disease. Cell Mol diagnosis of the disease when present, ease: videocapillaroscopic study. Int J Life Sci 2003;60:1903-22. although vascular involvement is not included Tissue React 2003;25:105-15. 25. Pay S, Simsek I, Erdem H, Dinc A. in the criteria of the International Study 12. Ergun T, Gurbuz O, Harvell J, etuse al. The Immunopathogenesis of Behcet's disease Group. Studies of the vasculitis in BD contin- histopathology of pathergy: a chronologic with special emphasize on the possible ue, especially with regards to the endothelial study of skin hyperreactivity in Behcet's role of antigen presenting cells. Rheuma- dysfunction and thrombosis which occurs in disease. Int J Dermatol 1998;37:929-33. tol Int 2007;27:417-24. these patients. Careful observation of BD 13. Bang D, Honma T, Saito T, et al. Ultra- 26. Ahn JK, Chung H, Lee DS, Yu YS, Yu HG. patients can lead to early diagnosis of vascular structure of vascular changes in cuta- CD8brightCD56+ T cells are cytotoxic involvement. While randomized controlled neous manifestations of Behcet's disease. effectors in patients with active Behcet's studies of the treatment of large vessel compli- Acta Derm Venereol 1988;68:33-40. uveitis. J Immunol 2005;175:6133-42. cations of the disease have not been carried 14. Balabanova M, Calamia KT, Perniciaro C, 27. Kahan A, Hamzaoui K, Ayed K. out, experience with multiple reported cases O'Duffy JD. A study of the cutaneous man- Abnormalities of T lymphocyte subsets in and the improved prognosis of affected ifestations of Behçet's disease in patients Behçet's disease demonstrated with anti- patients with aggressive treatment can guide from the United States. J Am Acad Der- CD45RA and anti-CD29 monoclonal anti- the clinician in treatment efforts. matol 1999;41:540-5. bodies. 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