Background
Thrombotic microangiopathy (TMA) encompasses a range of severe disorders characterized by hemolytic anemia, thrombocytopenia, and organ damage [
1‐
3]. Thrombotic thrombocytopenic purpura (TTP), typical hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC-HUS), and atypical hemolytic uremic syndrome (aHUS) are clearly recognized as disorders caused by TMA. Other secondary TMAs triggered by various events such as malignant tumors, hematopoietic stem-cell transplantation, and drugs also exist. TTP is due to the deficiency of ADAMTS13, a plasma metalloprotease that cleaves endothelium-derived von Willebrand factor (VWF). STEC-HUS is caused by Shiga toxin-producing
Escherichia coli (STEC). aHUS, often also referred to as complement-mediated TMA, is caused by the genetic or acquired disposition in the complement alternative pathway resulting in uncontrolled terminal complement activation in association with trigger events; complement-related gene variants cannot be identified in approximately half of aHUS patients, and even patients without complement-related gene variants can have a clear complement dysregulation [
4‐
7]. Due to these different causes, despite clinically being very similar phenotypes, the various TMAs have specific treatment strategies. Owing to its severity, it is vital to differentially diagnose TMAs as quickly as possible to initiate the appropriate therapy in a timely manner [
8‐
11].
Diagnostic criteria for aHUS rely on the exclusion of STEC-HUS, TTP, and secondary TMA because there is no established method to assess the involvement of complement dysregulation in TMA pathophysiology [
8‐
10]. There are reliable clinical tests/markers to exclude STEC-HUS and TTP [
12,
13], whereas complete exclusion of the possibility of secondary TMA is often difficult due to lack of established methods, hindering timely and appropriate treatment of aHUS. Even though some biomarkers are expected to estimate complement activation level, there is no reliable and simple clinical marker to accurately diagnose aHUS [
14‐
16]. In addition, even though complement-related gene analysis can be used to confirm the genetic disposition in the complement alternative pathway, this is a lengthy procedure that is unavailable at the point-of-care. Accordingly, diagnosis of aHUS is highly dependent on the physician’s experience and skills.
To support the clinical diagnosis of aHUS, a scoring system was recently published [
17]. In the system, two scores are sequentially calculated for TMA screening and aHUS screening respectively. TMA score consists of 4 items ranging 0–10 points, and aHUS score consists of 10 items ranging from -15 to 11 points, in which higher scores indicate higher likelihood of aHUS [
17]. To date, no studies have examined the association between the scores and the response to specific treatment for aHUS.
Eculizumab, a recombinant humanized monoclonal anti-C5 antibody, suppresses C5 cleavage by C5 convertase resulting in inhibition of complement overactivation. Eculizumab has been approved for treatment of aHUS in Japan since 2013 [
18]. In this study, we used data from Japanese post-marketing surveillance (PMS), which registered pediatric and adult patients who were clinically diagnosed with aHUS and treated with ≥ 1 dose of eculizumab in real-world clinical practice; the design and results of the PMS have been published [
19‐
21].
In this study, the previously published scoring system was modified according to the parameters available in the PMS database, thereby enabling the calculation of TMA/aHUS scores for patients in the database. The association between the score and clinical response to eculizumab treatment was then assessed. Optimum cut-off values to support clinical diagnosis of aHUS were retrospectively estimated using the response criteria.
Discussion
Here we describe a modified version of an existing aHUS diagnostic scoring system, in which some parameters were replaced with clinically similar parameters collected by PMS’s case report form, and demonstrate the relationships between the TMA/aHUS score and response to eculizumab treatment in clinically diagnosed aHUS patients. Early initiation of treatment with a C5 inhibitor is recommended for patients with aHUS for better outcomes [
26], however, currently there are no available/readily usable clinical biomarkers to diagnose aHUS (complement-mediated TMA). The diagnosis of aHUS is highly dependent on the experience of the treating physicians, which can post challenges to initiate treatment with a C5 inhibitor in a timely manner. The TMA/aHUS scoring system presented here could be utilized as a supportive tool for aHUS diagnosis, and in patients with a score of ≥ 5, initiation of treatment of eculizumab could be considered.
Cut-off values of the modified scoring system were independently calculated and assessed using ROC curve analysis and negative predictive values in relation to treatment response to eculizumab, which could indicate complement-mediated TMA in patients. Cut-off value calculated from ROC curves showed high scores (10 or 11 points), likely because all patients in PMS were clinically diagnosed with aHUS. In contrast, the cut-off value derived from negative predictive values (5 points) could be clinically more appropriate to not miss patients who show any responses to C5 inhibitor, even if false positive might be concerned.
The coincidence in the cut-off value of 5 points independently calculated from original and modified scoring systems might suggest a similarity of those systems in differential diagnosis of aHUS. Unfortunately, this study utilized only the patients clinically diagnosed with aHUS and did not address differences of the scores in patients with aHUS, secondary TMA and other TMAs. In contrast, the original scoring system illustrated the importance of positive aHUS score and exclusion aHUS score for differential diagnosis of aHUS from other TMAs; the sum of positive and exclusion scores (range) was 5 (2–6) for aHUS, -3 (-5 to -2) for TTP, -3 (-5 to -2) for secondary TMA and -2.5 (-5 to 0) for TMA without aHUS. Thus, the original scoring system was carefully evaluated using patients diagnosed with aHUS, TTP, and secondary TMA, and volunteers without TMA, but the modified system has not been applied to patients without aHUS; therefore, a validation of the modified system will be required for further application. Importantly, 98% of patients clinically diagnosed with aHUS in PMS showed a TMA/aHUS score ≥ 5, which corresponded to the cut-off value in the original diagnostic score system [
17]; moreover, 96% showed treatment response to eculizumab, which might be evidence of complement-mediated TMA. These data suggest a relationship between a TMA/aHUS score ≥ 5 and a response to eculizumab, which in combination with physician expertise may help determine the proper treatment for each patient.
In addition, this study also did not address the differences of clinical responses in patients with aHUS (with trigger or underlying disease), secondary TMA and other TMAs. Therefore, further study will be needed to see the relationship between the score and clinical response to supportive care, PE/PI, or eculizumab in various TMAs.
In the current analysis, we applied early response criteria to patients enrolled in the PMS: patients were defined as responders if hematologic or renal parameters improved at any time within 90 days. When patients do not respond to C5 inhibitor, other treatment options for possible causes of TMA should be considered [
8‐
10,
22,
23]. Among the patients who met a TMA/aHUS score ≥ 5, seven patients did not demonstrate a response to eculizumab treatment. In contrast, there was one patient who showed renal function improvement after the initiation of eculizumab treatment despite the fact that his TMA/aHUS score was < 5 points. Therefore, in both patients who meet and do not meet the cut-off value, clinical signs of TMA and response to treatment should be carefully monitored after the initiation of eculizumab. The current analysis indicates that the TMA/aHUS score significantly decreases from baseline in patients who meet treatment response. This scoring system could thereby also be used as a supportive tool to evaluate eculizumab treatment response.
Both the original and modified scoring systems included the positive aHUS scored items “prodromal symptom” or “trigger”, defined as conditions which can induce complement overactivation causing aHUS; on the other hand, the exclusion aHUS score parameters included “underlying disease”. Interestingly, we demonstrated that 30/31 patients with underlying disease were scored ≥ 5, and that many of them showed partial response to eculizumab, indicating that these patients can be treated with eculizumab after appropriate clinical diagnosis with aHUS. However, the underlying diseases including malignant tumor, HSCT and chemotherapy may affect clinical characteristics in addition to TMA, making fully recovery difficult only with treatment of TMA. That might be why patients who did not show complete response had higher rate of underlying diseases.
In addition, patients who showed treatment response were younger and had higher rate of renal failure at the onset of TMA. The younger age of TMA onset might be correlated with renal dysfunction, since younger age of TMA onset predicted the risk of end-stage-renal-disease [adjusted hazard ratio 0.55 (95% confidence interval 0.41–0.73)] in a natural history study from the Global aHUS registry [
6].
Considering that significant difference was not observed in the median score between survivors and non-survivors, the score value and the outcome (i.e., survival/death) seem to be independent, indicating that eculizumab treatment should not be delayed if the score value is ≥ 5. It is important to note that the proportions of patients with extrarenal organ failure and underlying diseases were significantly higher among non-survivors. This result is consistent with that of a long-term safety analysis of 1321 eculizumab-treated patients with aHUS, in which 58 deaths were reported [
27]; in this analysis, the most common causes of death were infection, cancer, and cardiovascular events. These findings demonstrate the importance of managing any underlying diseases/infections and organ failure to improve the prognosis of patients with aHUS.
In the present study, patients who were clinically diagnosed with aHUS and received eculizumab were analyzed. Therefore, we were not able to examine the scores and response to eculizumab in patients without aHUS, or with aHUS who did not receive eculizumab. Additional studies targeting a wider range of patients other than the PMS are thereby needed to properly validate the aHUS diagnostic cutoff score of 5 using the TMA/aHUS score, and further assess its utility to predict treatment response with C5 inhibitors.
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