Behcet's disease (BD) is a chronic multisystemic disease of unknown etiology. It can affect a variety of organs and can go into remission and relapse. Characteristic BD features include recurrent oral, genital, and mucosal ulceration, uveitis, and cutaneous lesions. The neurological, cardiovascular, gastrointestinal, and musculoskeletal systems may also be involved.1–3 Neutrophil hyperfunction, vasculitis, and autoimmune reactions appear to be responsible for the disease.4,5

Several laboratory tests have been studied for their ability to reflect disease activity, evaluate treatment efficacy, or predict future complications of BD, but no particular test has been found to detect disease activity.6–9 Nevertheless, the C-reactive protein (CRP) to albumin ratio (CAR) has been proposed as a better indicator of inflammatory response compared with CRP or albumin alone.10,11 CAR is a well-established predictor of a variety of diseases, including rheumatoid arthritis, BD uveitis, heart disease, and various cancers.12–14 Furthermore, higher levels of CAR are also associated with poor prognosis and worse treatment outcomes in systemic diseases.15,16

The neutrophil/albumin ratio (NAR) has been reported as a new inflammatory indicator in severe infection, cancer, and schizophrenia. In patients with cancer, a higher level of NAR was found to represent an increased inflammatory state, which poorly affects prognosis and treatment response.17 Neutrophils, the key components of the innate immune system, are activated and recruited to the target tissue by inflammatory mediators due to the chronic inflammatory status of BD, causing damage and organ dysfunction.18 Hypoalbuminemia in BD reflects the underlying active inflammatory state; the decrease in hepatic albumin production (a negative acute-phase reactant) may be caused by increased inflammatory mediators.19 However, NAR has not been studied in BD.

Thus, we aim to examine the value of the CAR and NAR in patients with BD in terms of their associations with clinical characteristics, as well as to determine their optimum cut-off levels. In this study, we hypothesized that CAR and NAR are associated with disease activity and can serve as novel inflammatory markers in BD.

The main clinical characteristics of the 75 patients with BD are summarized in Table 1. Oral ulceration (77.3%) and genital ulceration (69.3%) were the most common clinical features of patients with BD, whereas pulmonary and arterial involvement was the least common (1.33%). The mean duration of BD was 7.21±4.64 years. The median disease activity score assessed via BDCAF was 2 (range: 1–4). Accordingly, 39 patients were considered to have active BD.

Our study included 75 patients with BD with a mean age of 34.29±6.23 years (24 females, 51 males) and 75 healthy controls matched for age and sex (p>0.05). Patients with BD had significantly increased levels of ESR, CRP, albumin, WBCs, neutrophil, NLR, and PLR compared with those of controls (p≤0.05). Furthermore, patients with BD also had significantly increased NAR (1.08±0.34; p<0.0001) and CAR (2.49±1.73; p<0.0001) compared with those of controls. However, the two groups did not differ significantly in the other parameters, such as body mass index, hemoglobin level, and platelet and lymphocyte counts (p>0.05) (Table 2).

When we compared patients in the active (n=39) and inactive BD (n=36) state, significant differences were found in the ESR, CRP, WBC count, neutrophil count, serum albumin, and NLR (p=0.004, p<0.001, p=0.0039, p=0.001, p=0.002, and p=0.0008, respectively). Patients with active BD (n=39) had a significantly higher NAR compared with those with inactive BD (n=6, p<0.0001). Furthermore, patients with active BD had a significantly increased CAR compared with those with inactive BD (p<0.0001) (Table 3).

Gender and smoking habits were not significantly associated with either NAR or CAR among patients with BD (p>0.05). However, NAR levels tended to be higher in patients with BD with oral ulceration, articular involvement, and ocular involvement (i.e., active uveitis) (p=0.0416, p=0.0493, and p=0.0108, respectively) compared with those without involvement. Similarly, a significant difference regarding CAR was found in patients with BD with ocular involvement (active uveitis) (p=0.0349) compared with those without active uveitis. Thus, NAR was closely linked to the presence of oral ulcerations and articular manifestations, whereas CAR was not. Otherwise, neither NAR nor CAR levels were affected by the presence of vascular, pulmonary, cardiovascular, or neurological involvements in BD (p>0.05) (Table 4).

The ROC curve analyses for CAR and NAR as well as other inflammatory markers were performed to evaluate the disease activity in patients with BD included in the study. Specifically, CAR was compared with the CRP and albumin levels as presented in Table 5. The AUC of the NAR (0.849, 95% confidence interval [CI]: 0.747–0.921, p<0.0001) and CAR (0.777, 95% CI: 0.666–0.865, p<0.001) in patients with BD were higher than those of albumin, neutrophil count, CRP, and ESR. Fig. 1 depicts the discriminatory value of these indicators in relation to the BDCAF score.

Fig. 1.

(a) ROC curve of NAR in predicting active BD. (b) ROC curve of CAR in predicting active BD. (c) ROC curve of NAR and CAR versus other inflammatory markers in predicting active BD.

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In patients with BD, NAR had significant positive correlations with the presence of active uveitis (r=0.31, p<0.006), oral ulcerations (r=0.244, p=0.034), joint involvement (0.236, p=0.041), BDCAF score (r=0.59, p<0.001), ESR (r=0.153, p=0.028), CRP (r=0.230, p=0.04), neutrophil count (r=0.69, p<0.001), NLR (r=0.67, p<0.0001), and CAR (r=0.28, p=0.014). Moreover, CAR also had significant positive correlations with the presence of active uveitis (r=0.25, p=0.03), BDCAF score (r=0.541, p<0.001), CRP (r=0.49, p<0.0001), and NAR (r=0.28, p=0.014). Furthermore, both CAR (r=−0.369, p=0.011) and NAR (r=−0.451, p=0.0004) had significant negative correlations with serum albumin. Other parameters such as age, disease duration, mucocutaneus involvement, vascular involvement, and PLR were not correlated with either NAR or CAR (p>0.05) (Table 6, Fig. 2).

Fig. 2.

(a) The correlation between NAR and BDCAF in patients with BD. (b) Correlation between CAR and BDCAF in patients with BD. (c) Correlation of NAR and CRP in patients with BD (d) Correlation of NAR and CAR in patients with BD.

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The principal finding of the present study was that patients with BD had higher NAR and CAR values than healthy controls especially during the active stage of the disease, even in those of treated patients with BD. Moreover, comparisons showed that these two parameters were positively correlated with CRP, active uveitis, and BDCAF score. Previous studies have shown that CAR levels correlated with the activity of different autoimmune and rheumatic diseases.22 However, no studies have associated CAR and NAR with the different clinical manifestations and disease activity in patients with BD.

Although acute-phase protein, immunoglobulin, complement, autoantibody, lymphocyte, surface indicator, and cytokine levels are used as indicators of BD activity, there is no specific indicator for disease activation.6 Previously, the total BDCAF score was found to correlate well with both ESR and CRP levels, but there are still conflicting findings regarding the relationship between these parameters and clinical disease activity in BD.23 Recently, studies have suggested that CAR and NAR are reliable biomarkers of inflammation, and a combination of inflammatory markers including CAR and NAR can be used to indicate increased inflammatory status.24 Besides CAR and NAR, we also evaluated ESR, CRP, NLR, and PLR, all of which have been investigated in several studies.

Similarly, in a study comparing the inflammatory markers between patients with acutely exacerbated and remitted schizophrenia and healthy controls,24 CAR and NAR levels were found to be significantly higher in patients with schizophrenia than in control subjects. The authors proposed that a combination of inflammatory markers including CAR and NAR could be used to reflect the increased inflammatory status in schizophrenia. In accordance with this, a retrospective study of 32 patients with and 32 healthy controls found that CAR had the highest correlation with disease activity in patients with Takayasu arteritis.22

In our study, serum NAR was significantly increased in patients with active BD (n=39) compared with those with inactive BD (n=36, p<0.0001). Furthermore, patients with active BD had a significantly increased CAR compared with those with inactive BD (p<0.0001). Both CAR and NAR also had significant positive correlations with the BDCAF score.

Interestingly, NAR was significantly correlated with NLR (p≤0.05), whereas PLR was not correlated with either NAR or CAR (p>0.05). Significant differences in NLR values were also found in patients with active BD versus those with inactive BD; this is consistent with a previous Egyptian study, which concluded that NLR was higher in patients with active BD than in those with inactive BD (p<0.01). Although both NLR and PLR were correlated with BDCAF, the correlation of NLR with BDCAF was significantly stronger than that of PLR.25

Moreover, a recent study revealed that active BD was associated with higher NLR and PLR, but only a slight correlation between NLR and BD activity. Those authors recommended further separate investigations of PLR and NLR and their relationship with various manifestations of the disease, since NLR and PLR seem to have specific associations with BD activity.26

Similarly, two studies have found CAR to be a useful biomarker in describing the activity of inflammatory bowel diseases, including Crohn's disease and ulcerative colitis.26,27 This finding is consistent with other studies investigating the correlation of CAR and NAR with other inflammatory mediators in various diseases.24 On the other hand, in a cross-sectional study of 121 patients with rheumatoid arthritis assessing the relationship of CAR with disease activity, quality of life, and physical function, a significant but weak correlation between CAR and disease activity was found among the enrolled patients.11

Patients with BD with oral ulcerations had significantly higher articular involvement, ocular involvement (active uveitis), and NAR than in those without involvement. Similarly, patients with BD with active uveitis had a considerable difference in CAR value compared with those without active uveitis. Thus, NAR was closely associated with the presence of oral ulcerations and articular manifestations, whereas CAR was not. However, no studies have been conducted to compare CAR and NAR based on BD characteristics.

In our study, ROC interpretation revealed that the NAR and CAR values in patients with active BD had an AUC of 0.849 and 0.777, respectively, which are higher than those of albumin, neutrophil count, CRP, and ESR. The cut-off value of NAR in our study was >0.9744, and this had a sensitivity of 89.74% (the highest sensitivity percentage among patients with active BD) and a specificity of 80.56%. On the other hand, CAR had a cut-off value of >2.0444, with a sensitivity and specificity of 74.36% and 83.33%, respectively. To date, no studies have previously provided cut-off values or AUC for BD activity.

However, it was previously reported that the AUC of CAR was 0.801 when used to predict the existence of uveitis among patients with BD; this was remarkably high compared with the AUCs of other inflammatory biomarkers.28 In line with this, another study in patients with systemic sclerosis identified the AUC of CAR to be 0.788 (p=0.000), which was significant with a 95% CI of 0.651–0.925.29

Notably, CAR is accepted as an important parameter in the prognosis and follow-up of many diseases. It is used as a prognostic marker for disease activity and mortality, especially in inflammatory conditions, such as sepsis and septic shock.15 The novelty of this study lies in the comparison of CAR and NAR in patients with BD with different clinical and laboratory findings as well as disease activity.

BD is characterized by chronic relapsing episodes and may cause significant morbidity and mortality due to ocular, vascular, and neurological involvements. Early prediction of disease activity may enable clinicians to aggressively manage the disease to prevent the occurrence of complications.30 However, further research is still required to establish the optimal laboratory tests for predicting BD activity.

Our study had some limitations. First, this study was a single-center case–control study. Furthermore, the duration of the treatment in each patient could have changed CAR and NAR levels; this should be investigated in future studies to confirm their diagnostic potential. Nevertheless, large multicenter prospective studies are needed to verify our findings.

NAR and CAR are elevated in patients with BD and may contribute to the active disease state. Our results suggested that NAR and CAR are feasible and inexpensive tools for predicting BD activity.

All authors have contributed to designing the study, collecting and analyzing, interpretation of data, and preparing and revising the manuscript. Design of the study: DK, RZ, MH and WM. Recruitment of patients: DK, RZ, MH and WM. Data collection: DK, RZ, MH and WM. Manuscript preparation and revision: DK, RZ, MH and WM. All co-authors have approved the final version.

Each author made significant individual contributions to the following: the conception and design of the study, acquisition of data, analysis and interpretation of data, drafting of the article, critical revisions for important intellectual content, and approval of the final manuscript. Each author believes that the manuscript represents honest work. All authors contributed actively to the study.

Informed consents were obtained from all patients. An approval was obtained from the ethics committee of Faculty of Medicine, Zagazig University, and the approval number was ZU-IRB 6614/19-9-2019 and the study was conducted in conformity with Declaration of Helsinki.

The authors received no financial support for the research, authorship, and/or publication of this article.

There is no conflict of interest to the author's knowledge.