This study assessed the association of ESR and CRP, two simple and inexpensive blood tests, with BD activity and a range of its manifestations in drug-naive patients. ESR was significantly higher in patients with active BD rather than inactive disease. ESR and CRP values were higher in patients with active oral, genital, and vascular manifestations compared to subjects with no expressions of these symptoms. In logistic regression models, predictive values of ESR showed promising results in measuring BD activity, for each ten units increase in ESR the likelihood of active BD is increased by 90% (OR: 1.09, AUC: 0.79). The sensitivity and specificity of ESR levels were 71% and 75% for prediction of active BD, and 81% and 83% for its active vascular manifestations. Both ESR and CRP indices were also reliable predictive values for active vascular manifestations of BD (OR:1.03 AUC:0.85 for ESR, and OR:1.98 AUC:0.86 for CRP). However, these paraclinical parameters were unable to predict disease activity based on IBDDAM scores.
ESR and CRP levels are elevated in various conditions, including inflammations, infections, and malignancies . Despite their good sensitivity in determination of an inflammatory state, ESR and CRP's lack of specificity in differentiating the underlying cause limited their clinical application in diagnosis or assessment of a certain condition . ESR remained as a tool for diagnosis or response measurement to therapy for only few diseases: polymyalgia rheumatica, temporal arteritis, and rheumatoid arthritis . T-cell hypersensitivity in BD could result in activation of immunity cascade and subsequently overstimulation of innate immune system . Hyperexpression of acute phase reactants like CRP which binds to desired antigens in inflammation site, as well as increased fibrinogen release from damaged tissue which delays our RBCs' sedimentation, could justify the elevation of ESR and CRP levels in BD patients . Also following previous studies on CRP increase in cardiovascular event, our significant elevated ESR and CRP result in active vascular manifestations of the disease could be justified .
Numerous studies assessed ESR and CRP values in BD patients. Isik et al. study on 21 BD patients compared to 25 healthy controls showed significantly increased ESR and CRP values in BD patients . Alli et al. also found this statistically significant but weak correlations between disease activity scores and ESR and CRP indices in a study on 213 BD patients . Although none of these studies compared their results in different manifestations of BD. On the other hand, other studies that investigated these values in specific manifestations of the disease showed controversial results. In a study on 60 patients with BD, Lehner et al. found a statistically significant difference in ESR values for all disease manifestations except for neurologic symptoms . However, these significant differences were only observed in patients with erythema nodusom, vascular and arthritic involvement in a study by Müftüoǧlu et al. on 150 BD patients .
These controversial results and lack of evidence on ESR and CRP values in BD manifestations required further investigations on this matter. Our study results not only showed significant difference in patients with active disease compared to inactive disease, but also were able to differentiate some of BD manifestations, especially vascular, based on ESR and CRP indices. Also, these simple paraclinical tools represented reliable predictive values for BD activity and its vascular symptoms.
In a study in 1986, Müftüoǧlu et al. showed significantly higher ESR and CRP results in patients with active BD rather than inactive or control group . This result was also supported by Tanacan et al. study in 2020 which ESR and CRP levels in 103 active BD patients showed a statistically significant difference compared to 63 patients in the inactive disease group . Our study results also confirm this hypothesis since ESR and CRP values in 450 individuals with active BD showed considerable difference compared to 64 inactive BD patients. Following our previous study results confirming serum CRP levels to be significantly higher in BD patients than in the normal population , the current study implies that CRP values could be further utilized to differentiate active and inactive BD behavior.
To establish a thorough connection between laboratory results and different manifestations of BD concerned researchers in recent years [31,32,33]. Complete blood count (CBC) test components including RDW and MPV , NLR and PLR , and various cytokines like TNF-α, IL-6 and IL-8 [35, 36] have been discussed on this matter in previous studies. Lehner et al. in a study with 60 patients with Behcet's syndrome and 34 matched controls, except for the neurological group, ESR and CRP were significantly elevated in different manifestations of BD with the highest amount in arthritic type . On the other hand, Müftüoǧlu et al. found this considerable difference in erythema nodosum and acute thrombophlebitis for both ESR and CRP levels, and in arthritic type only for ESR (p < 0.01). Their study results showed no significant difference for ESR and CRP values in central nervous system (CNS) manifestations and, interestingly, ocular and mucocutaneous involvement. In the current study, significant differences in serum ESR and CRP levels were evident in oral, genital, vascular, arthritic, and dermal manifestations, with the highest levels for active vascular signs (p < 0.001). As mentioned in previous studies, our results also failed to establish a significant difference in ESR and CRP values in active CNS involvement, gastrointestinal manifestations, and patients with epididymitis. The extreme rarity of these manifestations , in our study 7 (1.4%) for active CNS signs, 6 (1.2%) for epididymitis, and only 2 (0.6%) for active GI involvement, could vindicate this incapability, as both Müftüoǧlu et al. and Lehner et al. believed the same [21, 23].
As a supplementary histopathologic tool for the diagnosis of BD, the Pathergy test was one of the variables our study favored to investigate . In comparison between 408 (79.4%) BD patients with negative and 106 (20.6%) with positive pathergy test, ESR and CRP values were significantly higher in the latter group (p = 0.017 and p = 0.011, respectively). We investigated the overall activity of BD in our participants with the IBDDAM scale, a dynamic quantitive checklist based on manifested symptoms duration and severity . Our results lack the strength to establish a solid predictive value for IBDDAM score in none of four variables investigated with multiple linear regression, including age (p = 0.12), gender (p = 0.47), serum ESR (p = 0.14), and CRP (p = 0.36) levels. The predictive value of ESR and CRP for different BD manifestations was also assessed with binomial logistic regression. This analysis revealed ESR as a reliable predictor of active BD (patients with at least one active presentation, p < 0.001, AUC = 0.79) and active vascular manifestations (p < 0.001, AUC = 0.85). CRP predictive value was also significant for vascular involvement of BD (p < 0.001, AUC = 0.86). The sensitivity and specificity of serum ESR levels were 71% and 75% for active BD, 81%, and 83% for active vascular manifestations.
We had several limitations in the course of this study. Although ESR and CRP results showed promising correlations with BD activity and its different presentations, our cross-sectional study investigated samples from a single tertiary center retrospectively. The value of these findings could be evaluated with future prospective cohort studies on a database from multiple centers. Our analysis was unable to measure the difference of ESR and CRP values in some manifestations of BD, like active CNS or GI involvement, due to insufficient samples. We recommend future studies investigating these parameters in BD patients with active CNS symptoms, epididymitis, or active GI presentations. Since ESR and CRP values are affected by several conditions, we suggest future studies to investigate these parameters for longer periods in patients using medical treatment or facing other comorbidities which could give us a better understanding of confounding factors affecting ESR and CRP levels. Since the current study excluded patients with active infection or other conditions like inflammatory diseases, the predictive value of ESR and CRP for BD activity is limited and needed to be further evaluated in these conditions (such as complicated infections). We also like to suggest the investigation of different and symptoms' intensity and possible changes in these values.
In conclusion, serum ESR and CRP levels are significantly higher in patients with active BD and its different active manifestations. These two routinely used inexpensive tests also showed a reliable predictive value for active BD disease and active vascular involvement. However, future studies are necessary to validate this matter.