In the present study, we investigated the therapeutic potential of TAC as maintenance therapy for AAV treatment in a considerable number of patients for the first time. Furthermore, we demonstrated that patients who received TAC after AZA exhibited a higher rate of ESRD occurrence than those prescribed AZA alone as maintenance therapy, after CYC induction therapy. However, we found no significant differences in the rates of all-cause mortality, relapse, and ESRD occurrence between patients prescribed AZA alone and those prescribed TAC alone as maintenance therapy.
In this study, the most important conclusion is that the incidence of end-stage renal failure in patients who received TAC was higher than that in those who received AZA alone during the follow-up period. More precisely, patients administered TAC after AZA as maintenance therapy showed a high incidence of end-stage renal failure. What factors influenced these outcomes?
First, we questioned whether there was more severe glomerulonephritis or decreased renal function at the time of diagnosis in patients administered TAC after AZA when compared with those who received AZA alone [20, 21]. Although it was not statistically significant, baseline serum creatinine level was higher in patients administered TAC after AZA than in those administered AZA alone (2.8 vs. 1.1 mg/dL, P = 0.348). Interpretation of the statistics should be prudent owing to the small number of patients, and the differences in baseline creatinine levels should not be overlooked. Furthermore, we pondered whether there were any factors other than kidney-related variables that present a distinct difference at the time of diagnosis between patients who received TAC after AZA and those administered AZA alone. A greater proportion of patients who received TAC after AZA had underlying hypertension than those who received AZA alone (83.3% vs. 36.2%, P = 0.035) (Table 2). These factors may have affected the high incidence of ESRD in patients administered TAC after AZA.
We focused on the reasons for switching from AZA to TAC. Of the six patients administered TAC after AZA, five patients switched from AZA to TAC owing to a lack of efficacy and one patient owing to elevated levels of hepatic enzymes . Of the five patients who switched medications owing to a lack of efficacy, four suffered from decreased renal function, three of whom progressed to ESRD. In other words, prior to drug switching, a sudden decline in kidney function had commenced. However, in the case of patients who maintained AZA, there was little need for drug switching as no sudden decline in kidney function was observed. Therefore, it can be concluded that the decline of renal function while receiving AZA was the decisive reason for progression to ESRD, rather than that the renal function maintenance effect afforded by TAC was less than that of AZA. We believe that only two of six patients who received TAC only as maintenance therapy progressed to end-stage renal failure, which supports our hypothesis.
For maintenance therapy, drugs that have demonstrated efficacy through randomized controlled trials include AZA, MTX, and RTX . Among these, MTX is recommended as maintenance therapy in relatively non-severe AAV patients. In a study demonstrating the effectiveness of MMF and AZA as maintenance therapy after induction therapy, the relapse rate in patients who received MMF was higher than that in those who received AZA . Based on these findings, AZA has been the most widely used drug for maintenance therapy in the current general clinical settings .
Nevertheless, in this study, TAC was selected as maintenance therapy for the following reasons. In terms of TAC after AZA, all six patients who demonstrated a lack of AZA efficacy strongly opposed the re-administration of CYC, as well as RTX administration, owing to concerns regarding adverse drug reactions. MMF was excluded from consideration as the risk of recurrence with MMF was higher than that with AZA .
In contrast, with TAC as the first maintenance therapeutic regimen, all six patients demonstrated reasons for difficulties with AZA—two patients presented elevated liver enzyme levels and four patients presented leukocytopenia [22, 25]. The rate of kidney involvement was high (83.3%) in these six patients; however, RTX did not meet the criteria for health insurance coverage and the effectiveness of MTX as maintenance therapy for treating AAV patients with kidney involvement was not confirmed . TAC seemed to have significantly prevented ESRD, given that only two of five patients with kidney involvement who were prescribed TAC as the first maintenance therapy developed end-stage renal failure.
Currently, TAC has proven effective in lupus nephritis and is actively recommended for treating lupus nephritis as a combination therapy with prednisolone or prednisolone plus MMF based on randomized controlled trials [27–29]. Although lupus nephritis is characterized by the deposition of immune complexes, demonstrating considerably different pathological findings from AAV, the therapeutic effect of TAC could be significant as TH1, TH17, and effector T cells are actively involved in the pathogenesis of both diseases [16, 30]. Notably, this study provided evidence that the efficacy of TAC is comparable to that of AZA as an alternative therapeutic option in AAV patients. Therefore, a prospective clinical study to investigate the efficacy of TAC for treating AAV, particularly AAV with renal involvement, is warranted.
To the best of our knowledge, our report is the first pilot study investigating the therapeutic potential of TAC as maintenance therapy for AAV treatment in a considerable number of patients. However, our study has several limitations owing to its retrospective study design and the small number of patients who received TAC. The most significant limitation is that the disease status at the time of drug switching may differ between the groups. Future prospective studies with a larger patient population could overcome these limitations and validate our results. We believe that our study will make a significant contribution to the immediate clinical impact on patients with AAV and anticipate that our study will serve as an opportunity to initiate clinical studies demonstrating the therapeutic effect of TAC in the treatment of AAV.