The study analyzed the results of laboratory tests at different stages of AAV disease and treatment. The course of the disease is very variable, the assessment of the patient is based on experience and extensive differential diagnosis. The clinical activity scales BVAS v3 and BVAS/WG have a documented value for the assessment of the severity of the disease, but the classification of symptoms depends on the experience of the doctor .
The study population was characterized by high disease activity, more than 78% of patients were diagnosed with the generalized and severe form. Renal involvement was confirmed in 75% of patients, with initially high creatinine levels, which in most patients did not return to normal despite the treatment. The studies by Houben et al. and Hanaoka et al. showed that the increased concentration of creatinine and the decrease in GFR below 60 ml/min/1.73m² at the time of diagnosis are late indicators of AAV activity in the kidneys, which is consistent with the presented work. Despite treatment, a significant proportion of patients remain in the advanced stage of chronic kidney disease, which significantly worsens the long-term prognosis [6,7].
The study showed a strong correlation between the presence of microhematuria and the activity of the disease in the kidneys. After achieving remission, erythrocyturia resolved in almost all patients. Monitoring of the urine sediment for the presence of red blood cells is of great importance for the assessment of inflammation within the glomeruli, and its resolution confirms remission, which has also been demonstrated in other studies [6-9]. The disappearance of proteinuria is likely to indicate remission of inflammation as well. Persistent proteinuria may be difficult to interpret, as it may result from irreversible changes in the kidneys or from the imposition of comorbidities such as hypertension or diabetes.
Patients with active vasculitis, particularly in the generalized and severe form, are characterized by a high intensity of inflammation. Secondary to inflammation, AAV patients had lower concentrations of hemoglobin and albumin in peripheral blood compared to the control group and to the evaluation performed in remission. These parameters strongly correlated with the severity of the disease (p=0.003, p=0.013). On the other hand, peripheral blood leukocytosis had a low value in AAV monitoring, which was also observed in the reports of other researchers . However, studies demonstrated a high correlation of the increased concentration of CRP and the ESR value with AAV activity, as well as with the severity of the disease. After effective treatment, CRP concentration returned to normal in all patients, and ESR decreased significantly. Similar observations were made in numerous clinical trials, although the non-specificity of these parameters and the inability to differentiate from infectious complications were emphasized [11, 12, 13]. The study by Kalsch et al. also showed that an increase in CRP and an acceleration of OB are observed only in the presence of clinical symptoms of AAV activity and are not useful in predicting an impending exacerbation . These parameters are also of low value in the assessment of localized and early systemic AAV, where the results may remain within the normal range despite the disease process.
The most important cause of death in the active phase of AAV are infectious complications, and the increase in inflammatory markers (leukocytosis, ESR, CRP) is equally typical for vasculitis and severe infection . Repeated measurements of procalcitonin concentrations proved to be very helpful in the differentiation of bacterial infection, and their effectiveness in diagnostics has been demonstrated in many clinical studies [16, 17].
In the presented study, procalcitonin concentration was significantly higher in active vasculitis than in remission. The highest values were found in patients with severe AAV, who developed respiratory failure, alveolar bleeding, the need for mechanical ventilation or NIV assisted respiration. In all these patients broad-spectrum antibiotic therapy was used. Two patients from this population eventually died from septic shock.
The correct procalcitonin concentration of <0.5 ng/ml is likely to exclude significant bacterial infection. In patients with AAV during the period of disease activity, results are often observed in the so-called gray zone (0.5-1.0 ng/ml), despite the absence of infectious symptoms, which may be due to a generalized inflammatory reaction. In the presented study, similarly to other clinical trials, procalcitonin concentration above 1.0 ng/ml was strongly associated with infectious complications, severe lower respiratory tract involvement and an increased risk of death [16, 17].
Numerous studies have shown an increased risk of venous thrombosis in the course of active AAV [18, 19]. The relationship of the markers stimulating the coagulation system and fibrinolysis with the activity of systemic vasculitis is less well documented . The platelet counts in the majority of patients with active GPA/MPA (82.14%) did not exceed the normal values, and the mean and median concentrations were low compared to the observations of other researchers . In the presented work and in numerous other studies, an increased concentration of fibrinogen was observed in severe active vasculitis [20,21]. The concentration of d-dimer proved to be a strong indicator of inflammation activity and a good marker of remission in other clinical studies as well [21, 22]. In the present work, a particularly high concentration of d-dimer was observed in the severe form of AAV (13.25 µg/ml), while in the generalized, early systemic and localized form it was significantly lower and did not differ significantly within these subgroups (2.08- 1.84 µg/ml). Despite the increased risk of /hemorrhage in this population, increased vigilance and appropriate prophylaxis of thromboembolism are necessary due to the above observations.
The complement system has long not been associated with small-vessel vasculitis connected with the presence of ANCA. A significant role of alternative activation in the pathogenesis of this disease has been demonstrated only in recent years, [23, 24, 25]. The studies by Augusto et al. and Crnogorac et al. showed a worse prognosis of patients with regard to survival and renal function in the group with decreased component values of the C3 complement system,. However, no such relationship was found for the C4 component . In the presented study, the concentrations of C3 and C4 complement components did not differ significantly depending on the activity of systemic vasculitis.
ANCA antibodies testing is crucial in the diagnosis of AAV. However, in monitoring disease activity, the interpretation of the results arouses controversy [4, 26, 27, 28, 29].
The presented study shows that in the population with newly diagnosed AAV and in exacerbation, the concentration of ANCA antibodies is significantly higher than in remission. This is confirmed by the strong relationship between the amount of ANCA and AAV activity. As in the reports of other researchers, it has been shown that a significant decrease of ANCA concentration in the serum correlates well with the achievement of clinical remission [30,31,32,33]. It was demonstrated, however, that in the majority of patients in remission, ANCA antibodies were not completely eliminated, and despite the decrease in concentration, they still remained at a significant level. The present study shows that ANCA antibodies were still detected in the serum in 52% of patients after 6 months of treatment despite the absence of disease activity (BVAS v3, BVAS/WG = 0 pts). We also observe patients whose ANCA concentration does not decrease or even increases despite effective treatment and the lack of clinical symptoms. In our study, ANCA antibodies also showed no correlation with AAV severity. This means that with high specificity for vasculitis, ANCA antibody measurements have limited sensitivity in disease monitoring, and any change in concentration should only be a guideline that requires interpretation in a clinical context .
In summary, the diagnosis of vasculitis is not easy, requires extensive clinical experience and access to immunological and histopathological tests. Appropriate treatment, both inductive and supportive, is even more challenging. The absence of markers unequivocally correlating with disease activity and differentiating from other clinical conditions makes management difficult. We expect that the results of the presented study will serve for a better interpretation of the available laboratory tests.