This systematic literature review synthesized the burden of AEs associated with immunosuppressant therapies in patients with SLE. Overall, MMF, AZA, MTX, CYC, and CsA are associated with a high incidence of AEs including infections, hematological toxicities, GI events, and ovarian toxicities. Despite the availability of primary research on the incidence of AEs associated with immunosuppressants, the data are difficult to compare across studies in view of differences in study design. Discontinuation rates for these treatments have been observed between 0% and 44.4% [18
Our systematic review has revealed several limitations in the current body of knowledge. For example, few studies evaluate the side effects of either MTX or CsA in patients with SLE and studies generally do not clearly distinguish between treatment-related AEs and those associated with SLE. Further, costs of managing side effects associated with immunosuppressants in patients with SLE are essentially nonexistent in the literature. Such studies are needed to better characterize the clinical and economic burdens of SLE immunosuppressant therapy to better understand the overall value of such therapy.
Several systematic literature reviews and meta-analyses comparing the incidence of AEs associated with immunosuppressants in SLE, mainly MMF and CYC, have been published, but with varying conclusions [9
] about treatment safety profiles. Specifically, systematic literature reviews have drawn different conclusions regarding the relative frequency of leucopenia, alopecia, and amenorrhea in patients taking MMF or CYC [10
]. Findings from this systematic literature review indicate that MMF was associated with lower rates of gynecological toxicities and infection than CYC, but the statistical significance of this difference has been questioned in some studies [17
]. Lee et al. observed similar safety profiles related to MMF and AZA for maintenance therapy [11
], which was consistent with the findings of this literature review as well as with those from a recently published RCT [17
]. However, one study in this review found AZA to be associated with more hematological cytopenias than MMF, and a newly published RCT found that significantly more patients discontinued treatment due to AEs when taking AZA than when receiving MMF [23
Few systematic reviews assessed incidence of hospitalization. Both Lee et al. and Moore and Derry found that the incidence of hospitalization associated with AEs was lower in patients with lupus nephritis taking MMF than in those taking CYC [9
]. The present systematic review also came to this conclusion. Because resource use was generally reported as hospitalizations due to AEs, and frequency measures used to report hospitalization varied among the studies, there was an inability to make comparisons between studies. Therefore, conclusions were drawn based on studies directly comparing the drugs of interest. For example, one study reports a single hospital day per patient-year for patients receiving MMF compared with ten for patients taking CYC [19
]. Further, Moore et al. observed that discontinuation due to AEs was not significantly different between patients receiving MMF and CYC [9
]. While this outcome was not statistically compared in the studies in our review, this finding is consistent with the comparisons of the results among the included studies.
This systematic literature review is unique from previously published systematic literature reviews. For example, one of the objectives of this review was to identify studies evaluating resource use and costs associated with side effects of CYC, AZA, MMF, MTX and CsA in patients with SLE. Further, this review included studies of SLE patients of all subtypes, whereas the majority of previously published reviews focused on lupus nephritis patients only. This study also compares the literature associated with five immunosuppressants instead of only MMF and CYC. Additionally, the review included immunosuppressants acting as both induction and maintenance therapies instead of focusing only induction therapy.
This study has some limitations. First, a systematic literature review is limited by the effectiveness of its predefined search strategy (e.g., search terms, databases used, inclusion/exclusion criteria, etc) to identify all relevant articles on the topic of interest. Second, the data are difficult to compare across studies due to the diversity in study methodology, including dosing regimens, study and follow-up duration, and the varying concomitant therapeutic regimens. Further study is warranted to assess the potential for using meta-analysis to quantitatively synthesize the burden of AEs associated with each immunosuppressant of interest and provide more precise incidence estimates. Another limitation in this study comes from the short duration of many of the studies included in this review. Because long-term use of immunosuppressants may be associated with increased oncogenicity [60
], the risk of malignancy may be underreported herein. Finally, this study does not take into account the role of corticosteroids in the predisposition to infection in SLE [61
]. Thus, the attribution of infection to one or another immunosuppressive agent could as well be related to the concomitant use of oral or parenteral corticosteroids.
In summary, this paper provides a comprehensive overview of the side effects associated with immunosuppressant medications that are used in the management of SLE. Since immunosuppressants are used to treat SLE patients who are not optimally controlled on other forms of therapy and because SLE is a chronic disease with persistent inflammatory disease activity, this paper further highlights the need for treatment options with better long-term safety profiles. Biologics, which have more targeted mechanisms of action, are now being used to treat immune-mediated disorders, such as SLE, and, in theory, use of these targeted agents may result in fewer drug-related adverse events than conventional immunosuppressants; however, the cost implications of using these treatments for SLE remain unknown [63
]. Belimumab is the first biologic therapy introduced for SLE, but has not been used for a sufficient period of time to calculate a cost-benefit analysis as has been done with biologics for some other conditions [65