As far as we know, this is the first study that analyzed the association between CTX usage and overall as well as cause-specific mortality in patients with SLE. In this large multi-centre retrospective study, we found an inverse association between CTX therapy and overall mortality in SLE patients. Patients having renal, neuropsychiatric, cardiopulmonary, gastrointestinal and hematological involvement may improve survivability if they were CTX users.
Up to now, there is only one study reported the association between CTX use and mortality of SLE patients. In South Korea, 413 patients who were diagnosed with SLE across three tertiary rheumatology centers between 1992 and 2016 were retrospectively evaluated; it was noted that the use of CTX was not significantly associated with mortality of SLE patients in univariable Cox analyses . However, this study has not performed multivariable analyses for CTX use, and further cause-specific mortality could not be examined due to the limited sample size. Moreover, previous studies reported that CTX improved renal but not overall survival . Petri et al noted that clinical symptoms and survival of SLE patients with major organ injuries were significantly improved with pulsed high-dose CTX therapy . In addition, there have been clinical studies that demonstrated the long-term efficacy of CTX in decreasing morbidity with no fatality cases in SLE patients .
In this present study, decreased overall mortality can be shown in patients taking low dosage of CTX (< 600mg/d), and a strong dose-response relationship was observed between decreased mortality of SLE and long-term CTX use. Previous studies have indicated that remission could be achieved with slow cumulative effect of CTX over time. Houssiau et al. showed in their study known as the “EURO-Lupus regimen” that low dose CTX provides a good alternative to high dose CTX as it yields good results clinically . In their 10 years follow up, they found that low dose of CTX is beneficial in the long term as 70% of patients that took this regimen did not require any pulse of CTX following their initial therapy. However, they reported that there was no significant difference in mortality between the two groups treated with low dose and high dose of CTX respectively . It should be noted that the patients’ ethnicity was white European and most of them presented with disease of moderate severity. A recent network meta-analysis of 11 RCTs found that low dose CTX was the most efficient as induction therapy in LN and had the most effect in lowering the risk of serious infections . Those evidences could support our findings that slow cumulative effect of CTX over time might improve survival of SLE patients.
Consistent with previous studies among Chinese population, infection, neuropsychiatric and renal insufficiency were among the most common cause of death in this study [8, 26]. Although decreased mortality from specific causes of death were found to be associated with CTX users, we still do not have a sufficient sample size to observed significant associations. However, our findings showed that CTX has better protective effects against overall mortality in organ involvements such as neuropsychiatric, renal, cardiopulmonary, gastrointestinal and hematological involvements. Our findings were consistent with the 2019 update of the EULAR recommendations for management of SLE that CTX is used for organ-threatening disease, especially renal, cardiopulmonary or neuropsychiatric involvement, as well as ‘rescue’ therapy in patients with life-threatening or refractory disease such as thrombocytopenia .
The mechanism of action of CTX is not well understood in spite of its heavy usage as an immuno-modulating agent in the treatment of SLE. CTX is a prodrug that requires bioactivation through multiple hepatic isoenzymes of cytochrome P450 (CYP2B and CYP3A), which metabolize it to 4-hydroxycyclophosphamide . The acylic tautomer of 4-hydroxycyclophosphamide is then cleaved non-enzymatically into phosphoramide mustard which is the therapeutic active compound and is supposed to cause alkylation and cross-linking of DNA, thereby inhibiting DNA replication which leads to cell death [29–31]. Some potential mechanisms from in vivo studies have been explained the protective effect of CTX on SLE. CTX impacts the immune system by depleting naïve, double negative (CD27 − IgD−) and pre-switched memory B cells. Also, it causes a decrease in circulating plasmacytoid dendritic cells and in some subsets of effector T cells (CD8 + CD44 + CD62L−), which might subside inflammation . Over time, CTX can inhibit plasmablast, which is a marker of disease activity . CTX increases alpha-2-macroglobulin, which has potent effect in decreasing leukocytes activity . Studies performed in animals demonstrated the effect of CTX in impairing the phagocytic activity of macrophages and decreasing the leucocyte counts [35, 36]. Those might explain the benefit of CTX in the treatment of chronic inflammatory diseases.
There are several limitations in our study. Firstly, as this was an observational study, we could not entirely get rid of unmeasured residual confounding, though adjustments were made in SLEDAI score, comorbidities and medications in the treatment. Secondly, due to the nature of our study being a retrospective design, information bias might be present. Since the use of CTX was estimated from hospital records, the duration and dosage of CTX might be overestimate because adherence was not taken into consideration. It would probably lead to an underestimation of the observed negative association toward null, making our observed association conservative. Thirdly, this study might not include patients with milder SLE. Nevertheless, this does not deter our goal of evaluating the protective effective of CTX use on mortality as the most severe end-stage of the disease spectrum generally has the greatest risk of complications as well as death. Fourthly, this study enrolled patients of Asian Chinese ethnicity and the results might not reflect in patients of African-American ethnicities as they are less responsive to CTX therapy . Despite those limitations, this study has some benefits. Given that it is a large multicenter cohort study, we were able to perform both multivariate and stratified analysis to investigate the association between CTX and overall and specific causes of mortality. Moreover, the dose-response relationships between duration and dosage of CTX and mortality in SLE were firstly estimated.