In the current study we demonstrate that concentration of survivin is notably increased in sera of children with JIA compared to healthy controls, what is in line with the previous observations in adults with RA and children with JIA [8, 16 - 20]. Additionally, we show that gender, age and different JIA onset types did not influence significantly survivin concentration in serum, as well as, in joint fluid.
To our knowledge there is only one other study assessing the survivin in sera of children with JIA . We associated the survivin level not only with laboratory data, but also with radiological status of the affected joints and with synovitis grade evaluated by ultrasonography (PDUS) of the inflamed joints. Moreover, this is the first paper that compares survivin concentration in serum and available matched synovial fluid of children with JIA.
Previously, it was speculated that survivin is produced and secreted locally in the inflamed joints [7, 18, 21]. Here, we confirm the results obtained in adults with RA, indicating, that there is a strong positive correlation between survivin level in serum and matched synovial fluid [7, 18, 21]. Additionally, our present study demonstrates that higher survivin concentration is detected in joint fluid than in matched serum. However, the number of available synovial fluid samples in our study was small. Nevertheless, the grade of synovitis evaluated by ultrasonography (PDUS) of the inflamed joint does not influence the survivin concentration in synovial fluid of our study group.
In the patients, early after RA diagnosis, positivity of survivin predicts joint destruction and resistance to anti-rheumatic treatment [7 – 9]. Interestingly, in our research we do not register higher survivin concentration in children with JIA and worse radiological joint destruction. This could be explained with high number of children with newly diagnosed JIA and the fact that radiological damage in children contrary to adults is rarely observed at the early stage of the JIA, as children have potential for bone regeneration [2,4,6]. Thus, we failed to confirm survivin prognostic potential for the active and destructive course of the rheumatoid process [7, 11, 21-23].
Surprisingly, we do not find significant prior association between high survivin level and high disease activity found in adults with RA and in children with JIA [8, 11, 16, 17, 19]. Almost 63% of our study group consisted of children with oligoarticular JIA, mostly with low disease activity and short duration time of JIA symptoms. On the other side, it is confirmed that survivin level is irrespective of disease duration time. It has been postulated, that rheumatoid process starts years before clinical symptoms and may be identified by autoantibody measurement. Previous studies advocated survivin to provide insight in the pre-antibody process. Some authors suggest that survivin occurs at the earlier phase of disease development followed by autoantibody production [8, 17]. Our results indicate that survivin concentration is independent of the disease duration time – could be increased in sera of newly diagnosed children at the beginning of the disease and after years, even in patients who had been biologically treated. However, some authors noticed significant decrease in survivin levels from baseline over 2 years of follow-up .
The combination of various markers increases further risk of rheumatoid process and may assist its preclinical diagnosis. The other important finding of this study is the fact that anti-CCP (ACPA) positive children with JIA have increased level of survivin in serum comparing to ACPA negative patients, what supports previous studies in adults with RA . However, other authors did not notice dependency of survivin presence on ACPA or RF positivity in RA patients . They also underlined that neither the presence of RF or ACPA, nor the combined multi-biomarker disease activity score supported discrimination in the disease outcome achieved by survivin measurements. We did not find significant association between anti-CCP antibodies positivity and higher survivin level in synovial fluid of JIA patients. At the cut off (17.37 pg/ml) established according to ROC analysis survivin positivity was found in majority of children with JIA, including all but one child biologically treated. Thus, we confirm the ability of survivin to distinguish children with JIA with sensitivity of 0.843 and of specificity 0.931. The numbers are similar to that obtained by other researchers [8, 16]. However, two (6.9%) children from our control group were survivin positive, but their serum survivin concentration was just at the cut-off value (both exactly: 17.37 pg/ml). Similar percentage of the survivin positivity in the control groups received other authors - 5.2% - 6.6% [11, 19, 21]. It could be speculated that it is possible that these children in the future could present JIA symptoms as survivin occurs before clinical manifestation, even in the pre-antibody period. As in our study group the percentage of children with JIA does not correspond to the prevalence of JIA in the general population we did not calculate PPV and NPV.
Our results support earlier conclusions in adults and children, that: age, gender, JIA onset subtype, disease duration time and presence of RF are similar in survivin positive children with JIA, as compared with those survivin negative [11, 19, 21]. The combined presence of survivin and autoantibodies was found in small group of our children with JIA. One third (19/59 – 32.2%) of our survivin positive study group was recognized positive for RF or ACPA and only two children were simultaneously positive for both RF, as well as, ACPA. These results are similar to ones obtained by others. Data showed increased risk of JIA development is irrespective to ACPA status. This provides further support to the hypothesis that survivin is a unique biomarker that recognize additional group of JIA patients with negative autoantibodies.
We assessed the survivin levels also in group of children with JIA biologically treated. Nevertheless, that group of patients was small, it was noticed that high survivin concentration and its positivity is independent of TNF-α treatment, what is in line with previous observations in adults with RA [7,11,18,21]. On the other hand, some researchers proved that survivin concentration is decreased in TNF-α treatment adult RA responders [24,25]. In our study biologically treated patients with JIA were previously unsuccessfully administered with conventional synthetic DMARDs for a quite long period of time (above one year). Some researchers concluded that survivin could be the marker of DMARDs non-responders [11,23,24]. However, to verify that statement in children, the group of patients with JIA treated with conventional synthetic DMARDs should be also included into the study, what is the area for future studies. Nevertheless, the observations focusing on the influence of treatment on survivin release are conflicting. The process triggering and abrogating survivin release in patients with rheumatoid process could therefore pave a way to efficient therapeutic control of the disease .
We are aware of the limitations of our research. First of all, there was a small control group of healthy children. To confirm the ability of survivin to differentiate JIA from other causes of joint inflammation (example: reactive arthritis), the sufficiently large group of such patients should be also included into the future study. Additionally, our study group had long disease duration time, with conventional synthetic DMARDs treatment failure before implementation of TNF-α inhibitors and there is no group of children with JIA treated with DMARDs to compare. Furthermore, only two subtypes of JIA onset are properly represented, and there is small number of joint fluid samples available. What is more, there was small group of children with JIA biologically treated and only with TNF-α inhibitors – no group treated with other biologicals to compare. Further studies are required to establish relationship between survivin level and apoptotic cytokine dynamics in JIA patients.