Background: Vasculitis damage index (VDI) is a validated damage index for systemic vasculitis, and as Behçet’s disease is considered one of systemic vascular disease we aimed to study the relationship of the vasculitis damage index to clinical manifestations and comorbidity in patients with Behçet’s disease (BD) to determine if VDI could be used to assess damage in patients with BD. Methods: A total of 109 patients with BD were recruited from the Rheumatology Department (outpatient and inpatient clinic), Cairo University Hospitals. All patients were subjected to full history taking, clinical examination, and routine laboratory investigations. Disease activity was assessed by the BD current activity form, and the VDI was calculated in all patients. The relationship of the VDI to the disease clinical manifestations was studied. Mann– Whitney and Kruskal Wallis tests were used to estimate differences in quantitative variables. Spearman correlation test was used to test for correlation between quantitative variables. Results: In the current study, the VDI ranged from 1 to 10, with a mean of 3.5 ± 1.8. It was significantly associated with total thrombosis (P = 0.022); total neurological manifestations (P = 0.000), especially stroke and cranial nerve affection; uveitis (P = 0.005); avascular necrosis (AVN) (P = 0.015); osteoporosis (P = 0.01); impaired vision (P < 0.0001); cataract (P < 0.0001); and diabetes (P = 0.012). Generally, immunosuppressive treatment was significantly associated with VDI (P = 0.039), especially cyclophosphamide (P < 0.0001), biological agent (P = 0.008), chlorambucil (P = 0.003), and anticoagulant (P = 0.02). VDI was also significantly correlated with age (P = 0.033), disease duration (P = 0.029), and duration of eye involvement (P = 0.003). Conclusion: VDI is significantly associated with most disease parameters of BD, except for parameters such as mucocutaneous manifestations and uncomplicated venous thrombosis; however, further studies may be needed to establish BD-specific damage index. Keywords: Vasculitis damage index, Behçet’s disease, Egyptian Patients Background than venous affection in BD; however, the prognosis is Behçet’s disease (BD) is a multisystem, inflammatory, poorer in such cases . Furthermore, recent data also autoimmune disease with unknown etiology and patho- verified the presence of accelerated classical subclinical genesis and unpredictable prognosis [1, 2]. BD is classified arterial damage, such as arteriosclerosis, even in patients among systemic vasculitides . Vascular involvement is a without overt vascular complications and may be comple- common finding in BD, which is significantly associated mentary to that of vasculitis . with higher morbidity and mortality rates, and may affect The prognosis for a patient with systemic vasculitis up to 40% of patients with BD, mostly in the form of deep has improved with treatment [8, 9]. However, the long- venous thrombosis (DVT) and superficial thrombophle- term outlook may be associated with accumulation of bitis [4–6]. Arterial vascular involvement is less frequent damage, from recurrent flares or treatment [9, 10]. Careful differentiation between activity and damage is * Correspondence: email@example.com mandatory to prevent unnecessary exposure to cytotoxic Rheumatology and Rehabilitation Department, Cairo University, Cairo, Egypt medications. Damage significantly influences both long- Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Elgengehy et al. Advances in Rheumatology (2021) 61:33 Page 2 of 7 term prognosis and quality of life, so systemic recording information provided by the patients and current med- of damage may be helpful in improving treatment deci- ical reports , while VDI was also calculated for each sion and predicting disease outcomes [1, 10]. patient at the time of recruitment . A comparative A well-established validated damage index, “vasculitis and correlative study of the VDI of our patients was damage index” (VDI) , is currently the most widely conducted with respect to different disease parameters. used assessment tool for damage in vasculitis. It is based It is to be noted that medical records of Behçet’s patients on a score derived from individual items from disease who died during the period of the study were reviewed onset and comprises 64 items (grouped into 11 organ- for the previously mentioned data. The study was per- based systems). The items were originally selected by formed in accordance with the Declaration of Helsinki consensus among experienced physicians. Damage was and approved by the local ethical committee. Informed defined by three key characteristics: irreversibility, pres- consent was obtained from all patients before their en- ence for > 3 months, and attribution of the lesion to vas- rollment in the study. culitis or its therapy. Each item was not weighted; therefore, all items contribute equally to the score. The Statistical analysis VDI has been used to demonstrate that irreversible dam- Data were processed and analyzed using the Statistical age occurs early in the disease course and has a signifi- Package for the Social Sciences (SPSS) software version cant effect on subsequent morbidity and mortality. 15 for Windows (SPSS Inc., Chicago, Illinois, USA). For Multi-organ involvement within 2 years is associated quantitative variables, median (minimum, maximum, with an increased risk of death . inter quartile range (IQR), or mean (±SD) were used. The Outcome Measures in Rheumatology (OMER- Frequency and percentage were presented for qualitative ACT) has defined the core set domain of outcome mea- variables. Mann–Whitney and Kruskal Wallis tests were sures for BD, and concluded that both measures of used to estimate differences in quantitative variables. disease activity and damage should be included, as sep- Spearman correlation test was used to test for correl- arate and complementary entities, into the core outcome ation between quantitative variables. A P-value < 0.05 set for BD . However, no BD damage index had been indicated statistical significance. developed until 2020, when Piga et al. published the first BD damage index (BODI) and validated it through sev- Results eral steps, one of which was the correlation with VDI, In the current study, the age of our patients ranged from and they concluded that pending further validation still 18 to 58 years, with a mean of 35.3 ± 8 years. Moreover, required . Thus, this study aimed to evaluate the re- 98 patients were male, and 11 were female (8.9:1). Oral lationship of the VDI to clinical manifestations and co- ulcers were reported in 94.5% of patients, genital ulcers morbidities in patients with BD. Our study may be a in 85.3%, uveitis in 69.7%, skin lesions in 39.4%, and vas- preliminary study to assess if VDI is suitable tool for cular involvement in 50.5%. Demographic and clinical damage assessment in patients with BD. data of our patients are shown in Table 1. Medications received by patients with BD are shown in Table 2. Patients and methods VDI in the current study ranged from 1 to 10, with a This cross-sectional study included 109 adult patients with mean of 3.5 ± 1.8, and was significantly associated with BD (98 men and 11 women [8.9:1]). Patients were re- major organ damage including; total thrombosis, total cruited consecutively (with exclusion of juvenile onset BD neurological manifestations (especially stroke and cranial patients), from 2016 to 2018, from the Rheumatology De- nerve affection), eye manifestations (uveitis, visual impair- partment (inpatient and outpatient clinic) of Cairo Uni- ment, cataract), and disease-related complications or associ- versity Hospitals, Egypt. All patients met the criteria of the ated comorbidities (avascular necrosis [AVN], osteoporosis, International Study Group for BD . Patients were sub- and diabetes). The use of immunosuppressive drugs in jected to full history taking, thorough clinical examination general was significantly associated with VDI, especially and all clinical manifestations were assessed if ever hap- cyclophosphamide, biological agent, chlorambucil, and anti- pened in the disease course, either acute or chronic or coagulant. VDI was also significantly correlated with age, both. Routine laboratory tests and relevant medications disease duration (P = 0.029), and duration of eye involve- used were recorded. The treatment protocol of our pa- ment. Details of association of VDI to different disease tients was generally in accordance with 2008 and 2018 variables are shown in Tables 3 and 4. Correlation of VDI EULAR recommendations [15, 16], with few modifications score with clinical variables is shown in Table 5. due to financial issues or special case situations. In the present study, disease activity was assessed for Discussion all patients by BD current activity form (BDCAF) by BD is a chronic autoimmune systemic vasculitis with an filling the items of the BDCAF according to the obscure pathogenesis . Vasculitis of BD can involve Elgengehy et al. Advances in Rheumatology (2021) 61:33 Page 3 of 7 Table 1 Demographic and clinical data of patients with BD Table 2 Medications received by patients with Behçet’s disease Parameter Patients with BD (n = 109) Medications Patients with BD (n = 109) Age, mean ± SD (range) 35.3 ± 8 (18–58) years Cyclophosphamide, n (%) 61 (56) Sex, male:female 98:11 (8.9:1) Azathioprine, n (%) 62 (56.9) Disease duration, median, minimum, 9,1, 38, 8.5 years Cyclosporine A, n (%) 39 (35.8) maximum, IQR Biologic therapy, n (%) 22 (20.2) Delay in diagnosis, median, minimum, 12, 0.2, 216, 48 months Colchicine, n (%) 2 (1.8) maximum, IQR MMF, n (%) 1 (0.9) BDCAF grades 0/1/2/3 50/45/11/3 Chlorambucil, n (%) 3 (2.8) Oral ulcers, n(%) 103 (94.5) Leflunomide, n (%) 1 (0.9) Genital ulcers, n(%) 93 (85.3) Anticoagulants, n (%) 40 (36.7) Skin lesions, n(%) 43 (39.4) BD Behçet’s disease, MMF Mycophenolate mofetil Eye (uveitis), n(%) 76(69.7) Duration of eye affection, 86.7 ± 60.1(2–264) months mean ± SD (range) that are unlikely to respond to immunosuppressive therapy . Therefore, a damage index is needed to Impaired vision, n(%) 62(56.9) quantify damage, aid in the separation of damage from Blindness, n(%) 12(11) disease activity, and rationalize selection of therapy. Cataract, n(%) 40(36.7) In the current study, the male/female ratio was quite Vascular involvement, n(%) 55 (50.5) high (8.9:1). This may be similar to some previous DVT, n(%) 29 (26.6) studies conducted on patients with BD in Egypt [21, 22]. DVT (no. of attacks), n(%) Once 9 (8.3) or twice 20 In addition, our university is a tertiary referral hospital, (18.3) receiving severe cases including vascular involvement, Thrombosis (arterial/venous), n(%) 52 (47.7) which has a higher frequency of male patients . Thrombosis (no. of attacks), n(%) Once 27 (24.8) or twice 25 Thrombosis is the most frequent vascular manifest- (22.9) ation in BD and an important factor of poor prognosis Aneurysms, n(%) 14 (12.8) . A study performed by Gerco et al. in 2018 revealed that the major causes of morbidity and mortality rates in Neurological involvement, n(%) 19 (17.4) BD result from ocular, major vascular, and neurological Cranial nerve affection, n(%) 12 (11) involvement . Ataxia, n(%) 3 (2.8) Amigo et al. reported that thrombotic events that are Coma, n(%) 1 (0.9) considered the hallmark of antiphospholipid syndrome Stroke, n(%) 9 (8.3) may cause irreversible damage from the onset of the dis- Arthritis, n(%) 12 (11) ease. In our opinion, this is also applicable for BD and may explain the association of thrombosis and VDI . AVN, n(%) 4 (3.7) In addition, most neurological manifestations and Osteoporosis, n(%) 7 (6.4) part of the total thromboses are caused by arterial Diabetes, n(%) 8 (7.3) affection, which was found to be associated with Mortality, n(%) 8 (7.3) greater mortality rate (13.5% in patients with BD with VDI 3.5 ± 1.8 (1–10) arterial lesions compared to 3.6% in those without BD Behçet’s disease, BDCAF BD current activity form, DVT Deep venous arterial involvement) . thrombosis, AVN Avascular necrosis, VDI Vasculitis damage index The association of VDI with uveitis and its complica- tion may also be predictable, if we consider that ocular any type and size of vessels, which explains why the inflammation develops in approximately 70% of patients disease has the ability of multi-systemic involvement and refractory ocular inflammation that may lead to , which could lead to serious morbidity and mor- blindness is common in those not responding well to tality . systemic corticosteroids combined with other immuno- In conditions associated with systemic vasculitis, a suppressive agents observed in patients with BD . comprehensive assessment of disease severity should in- Osteoporosis, AVN and diabetes; these specific dam- clude measurements of disease activity, damage, and age items are shared by different damage indices as SLIC functional status. Damage develops as a consequence of C for lupus  and even VDI itself because they com- recurrent or persistent active disease or its treatment monly result from high cumulative doses of glucocorti- and is defined as the accumulation of non-healing scars coids used for the treatment of different manifestations Elgengehy et al. Advances in Rheumatology (2021) 61:33 Page 4 of 7 Table 3 Comparison of Vasculitis Damage Index (VDI) with Table 3 Comparison of Vasculitis Damage Index (VDI) with respect to demographic and clinical manifestations respect to demographic and clinical manifestations (Continued) VDI score VDI score Minimun-Maximum Median (IQR) P-value Minimun-Maximum Median (IQR) P-value Sex No 1–8 3 (2) Male 1–10 3 (2) 0.1* Osteoporosis Female 1–7 5 (2) Yes 3–10 7 (7) 0.01* Oral ulcers No 1–8 4 (1) Yes 1–10 3 (3) 0.21* Uveitis No 1–3 3 (1) Yes 1–10 4 (3) 0.005* Genital ulcers No 1–8 3 (2) Yes 1–10 3 (3) 0.487* Vision No 1–8 3 (2) Normal 1–8 2 (1) < 0.0001** Other skin lesions Impaired 1–7 3 (2) Yes 1–8 3 (3) 0.197* Blindness 2–10 5 (5) No 1–10 3 (2) Cataract Vascular involvement No involvement 1–8 2 (2) < 0.0001** Yes 1–10 4 (3) 0.073* Single eye 3–10 5 (4) involvement No 1–7 3 (2) Both eye 2–7 4 (2) DVT attacks involvement Yes 1–8 4 (3) 0.566* Diabetes No 1–10 3 (2) Yes 3–10 4 (4) 0.012* Arterial or venous No 1–8 3 (2) thrombosis *Mann–Whitney test, **Kruskal–Wallis test, *** no IQR is calculated; as only 3 Yes 1–10 4 (3) 0.022* patients had ataxia. VDI Vasculitis damage index, BD Behçet’s disease, DVT Deep venous thrombosis, AVN Avascular necrosis No 1–8 3 (2) Aneurysm of rheumatic diseases thus it is not surprising to find an Yes 1–8 3 (2) 0.539* association between these damage items and VDI. No 1–10 3 (2) Systemic immunosuppressive and biological agents are Neurological affection the standard therapy for severe organ involvement in BD [30–32], and the goal of management is early treatment Yes 3–10 5 (2) < 0.0001* to avoid recurrences and irreversible damage to the vital No 1–8 3 (2) organs . As other autoimmune diseases, medications Cranial nerve used may be associated with serious side effects and affection damage [31, 34, 35]. In our study, the use of immuno- Yes 5–10 6 (3) < 0.0001* suppressive drugs in general was significantly associated No 1–8 3 (2) with VDI, especially cyclophosphamide, infliximab, and Ataxia chlorambucil, in addition to anticoagulant, while the use Yes 4–74*** 0.102* of other medications that may be used in BD for milder No 1–10 5 (2) presentation, such as colchicine and azathioprine, was not significantly associated with VDI. In our opinion, Stroke although such medications may improve survival and Yes 3–6 4 (1) 0.014* disease outcomes, they should be reserved for severe No 1–10 3 (2) aggressive disease manifestations, as these medications Arthritis may show some serious side effects, increasing the Yes 1–8 4 (1) 0.741* damage; thus, the association of immunosuppressive No 1–10 3 (2) drug use and VDI could be expected, also from another point of view such medications may be used to treat AVN active, aggressive disease, which itself may be associated Yes 3–10 7 (7) 0.015* with increased damage. Elgengehy et al. Advances in Rheumatology (2021) 61:33 Page 5 of 7 Table 4 Comparison of Vasculitis Damage Index (VDI) with It seems expected that longer disease duration and respect to the medication received duration of eye involvement may be associated with in- VDI score creased damage, which is the case in our study, as VDI was significantly correlated with disease duration and Minimun-Maximum Median (IQR) P-value eye involvement. However, the correlation between VDI Immunosuppressive drugs and age (P = 0.033), may contradict the decreased mor- Yes 1–10 3 (2) 0.039* tality rate in patients with BD aged > 35 years reported No 1–4 3.5 (2) by Saadoun et al. , In our opinion this decline in CYC mortality after age of 35, may raise an important point, Yes 1–10 4 (3) < 0.0001* that elderly onset BD patients may show milder disease No 1–7 2.5 (1) manifestations as some elderly onset lupus, which is ap- point that may require further studies. AZA In this study, we found that VDI is correlated with Yes 1–10 3 (3) 0.294* most aggressive disease manifestations of BD. However, No 1–8 3 (2) some damage found in patients with BD may not be CSA covered by VDI, especially damage related to genital ul- Yes 1–10 3 (2) 0.874* cers or venous occlusion, e.g., Budd Chiari syndrome, No 1–8 3 (3) vena caval thrombosis, and cerebral venous sinus throm- bosis. Moreover, the development of venous thrombosis Biological (unless complicated) or recurrent venous thrombosis is Yes 1–10 4(2) 0.008* excluded in the VDI. In contrast, some items mentioned No 1–8 3 (2) in VDI may not be of value in patients with BD, such as Colchicine alopecia and proteinuria. Thus, according to the afore- Yes 2–2 2** 0.16* mentioned reasons, in our opinion, BD modified specific No 1–10 3 (2) VDI version as that studied by Piga et al. 2020 and in- cluding many modified items of VDI , may be Chlorambucil needed for better assessment of damage in patients with Yes 7–10 8** 0.003* BD, which must be assessed in further prospective, large No 1–8 3 (2) scale, longitudinal studies. Anticoagulant Among strengths of our study is that, it is one of the Yes 1–10 4(4) 0.02* pioneer studies in attempt to evaluate Damage index for No 1–7 3 (2) BD. On the other hand, study limitations include: we did not assess the inter-rater agreement by evaluating *Mann–Whitney test, **no IQR is calculated; as the number of patients who recieved the drug was less than 4. CYC Cyclophosphamide, AZA Azathioprine, Cohen’s kappa and the interclass correlation coefficient CSA Cyclosporine A (ICC), we also did not correlate VDI with the number of flares, cumulative corticosteroid doses, or delay in im- munosuppressive therapy. Vasculitis is a main pathologic finding in BD, and damage index is required in most rheumatic diseases to quantify damage, aid in the separation of damage from disease activity, and rationalize selection of therapy. Fortunately; a recent damage index for Behçet’s disease Table 5 Correlation of the Vasculitis Damage Index (VDI) score has been validated “Behçet’s syndrome overall damage with some patients´ demographic and clinical variables index (BODI)” most items of which, has been derived Variable VDI in patients with BD (n = 109) a from VDI, however further validation is needed for such r*P damage index to be established as concluded by their Delay in diagnosis 0.02 0.84 authors. BDCAF 0.15 0.13 Age 0.2 0.03 Conclusions Disease duration 0.21 0.03 VDI is significantly associated with most disease parame- Stroke score 0.09 0.8 ters of BD, except for parameters such as mucocutaneous manifestations and uncomplicated venous thrombosis; Duration of eye affection 0.34 0.003 a however, further studies may be needed to establish and Spearman correlation coefficient. *P is significant at < 0.05. VDI Vasculitis damage index, BD Behçet’s disease, BDCAF BD current activity form validate VDI derived BD-specific damage index. Elgengehy et al. Advances in Rheumatology (2021) 61:33 Page 6 of 7 Acknowledgements standardized clinical assessment of damage in the systemic vasculitides. Non applicable. Arthritis Rheum. 1997;40(2):371–80. https://doi.org/10.1002/art.1780400222. 12. Watts RA, Scott DG. Recent developments in the classification and assessment of vasculitis. Best Pract Res Clin Rheumatol. 2009;23(3):429–43. 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Published: Jun 9, 2021