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      Risk of adverse events from different drugs for SLE: a systematic review and network meta-analysis

      systematic-review

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          Abstract

          Objective

          The comparative safety of immunosuppressive drugs, biologicals and glucocorticoids (GC) for patients with SLE remains controversial. We aimed to investigate the specific side effects of the available SLE drugs in this population of patients.

          Methods

          Electronic databases were systematically searched through September 2017 for randomised trials in patients with SLE. The primary outcomes were all-cause mortality and withdrawal related to adverse events (AEs). We performed a random-effects network meta-analysis to obtain estimates for primary and secondary outcomes and presented these estimates as ORs with 95% CIs.

          Results

          Forty-four studies comprising 9898 participants were included in the network meta-analysis. No drug regimen was considered to be safer for reducing all-cause mortality. However, compared with cyclophosphamide, azathioprine (OR 3.04, 95% CI (1.44 to 6.42)) and cyclosporine (OR 3.28, 95% CI (1.04 to 10.35)) were significantly less safety in AE-related withdrawals, and GC was ranked lowest and led to higher withdrawal rates. Tacrolimus (TAC) was ranked high and showed a benefit in many outcomes. Biologicals and chloroquine also showed good safety in all of the available outcomes, while the beneficial effects of other immunosuppressive drugs were not substantial in different types of serious adverse events.

          Conclusions

          TAC is the safest strategy for patients with SLE. Biologicals and chloroquine are also fairly safe for patients with SLE. The use of other immunosuppressive drugs and GC needs to be balanced against the potential harms of different types of AEs, and the practical safety of drug combinations still requires further trials to evaluate.

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          Most cited references51

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          The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis

          The objective of this systematic literature review was to determine the association between cardiovascular events (CVEs) and antirheumatic drugs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA)/psoriasis (Pso). Systematic searches were performed of MEDLINE, EMBASE and Cochrane databases (1960 to December 2012) and proceedings from major relevant congresses (2010–2012) for controlled studies and randomised trials reporting confirmed CVEs in patients with RA or PsA/Pso treated with antirheumatic drugs. Random-effects meta-analyses were performed on extracted data. Out of 2630 references screened, 34 studies were included: 28 in RA and 6 in PsA/Pso. In RA, a reduced risk of all CVEs was reported with tumour necrosis factor inhibitors (relative risk (RR), 0.70; 95% CI 0.54 to 0.90; p=0.005) and methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p=0.007). Non-steroidal anti-inflammatory drugs (NSAIDs) increased the risk of all CVEs (RR, 1.18; 95% CI 1.01 to 1.38; p=0.04), which may have been specifically related to the effects of rofecoxib. Corticosteroids increased the risk of all CVEs (RR, 1.47; 95% CI 1.34 to 1.60; p<0.001). In PsA/Pso, systemic therapy decreased the risk of all CVEs (RR, 0.75; 95% CI 0.63 to 0.91; p=0.003). In RA, tumour necrosis factor inhibitors and methotrexate are associated with a decreased risk of all CVEs while corticosteroids and NSAIDs are associated with an increased risk. Targeting inflammation with tumour necrosis factor inhibitors or methotrexate may have positive cardiovascular effects in RA. In PsA/Pso, limited evidence suggests that systemic therapies are associated with a decrease in all CVE risk.
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            Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.

            Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. Here, we report the comparison of MMF and IVC as induction treatment for active lupus nephritis in a multinational, two-phase (induction and maintenance) study. We randomly assigned 370 patients with classes III through V lupus nephritis to open-label MMF (target dosage 3 g/d) or IVC (0.5 to 1.0 g/m(2) in monthly pulses) in a 24-wk induction study. Both groups received prednisone, tapered from a maximum starting dosage of 60 mg/d. The primary end point was a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary end points included complete renal remission, systemic disease activity and damage, and safety. Overall, we did not detect a significantly different response rate between the two groups: 104 (56.2%) of 185 patients responded to MMF compared with 98 (53.0%) of 185 to IVC. Secondary end points were also similar between treatment groups. There were nine deaths in the MMF group and five in the IVC group. We did not detect significant differences between the MMF and IVC groups with regard to rates of adverse events, serious adverse events, or infections. Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis.
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              Evaluation of inconsistency in networks of interventions.

              The assumption of consistency, defined as agreement between direct and indirect sources of evidence, underlies the increasingly popular method of network meta-analysis. No evidence exists so far regarding the extent of inconsistency in full networks of interventions or the factors that control its statistical detection. In this paper we assess the prevalence of inconsistency from data of 40 published networks of interventions involving 303 loops of evidence. Inconsistency is evaluated in each loop by contrasting direct and indirect estimates and by employing an omnibus test of consistency for the entire network. We explore whether different effect measures for dichotomous outcomes are associated with differences in inconsistency, and evaluate whether different ways to estimate heterogeneity affect the magnitude and detection of inconsistency. Inconsistency was detected in from 2% to 9% of the tested loops, depending on the effect measure and heterogeneity estimation method. Loops that included comparisons informed by a single study were more likely to show inconsistency. About one-eighth of the networks were found to be inconsistent. The proportions of inconsistent loops do not materially change when different effect measures are used. Important heterogeneity or the overestimation of heterogeneity was associated with a small decrease in the prevalence of statistical inconsistency. The study suggests that changing the effect measure might improve statistical consistency, and that an analysis of sensitivity to the assumptions and an estimator of heterogeneity might be needed before reaching a conclusion about the absence of statistical inconsistency, particularly in networks with few studies.
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                Author and article information

                Journal
                Lupus Sci Med
                Lupus Sci Med
                lupusscimed
                lupus
                Lupus Science & Medicine
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2053-8790
                2018
                9 March 2018
                : 5
                : 1
                : e000253
                Affiliations
                [1 ]departmentDepartment of Dermatology , Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University , Changsha, China
                [2 ]departmentXiangya School of Medicine , Central South University , Changsha, China
                Author notes
                [Correspondence to ] Dr Qianjin Lu, Department of Dermatology, Hunan Key Laboratory ofMedical Epigenomics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; qianlu5860@ 123456gmail.com
                Article
                lupus-2017-000253
                10.1136/lupus-2017-000253
                5890859
                29644081
                a4a015ed-ad9b-40af-9b55-271ba41a492c
                © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 02 December 2017
                : 01 February 2018
                : 16 February 2018
                Funding
                Funded by: National Key Clinical Speciality Construction Project of National Health and Family Planning Commission of the People’s Republic of China;
                Funded by: National Key Research and Development Program of China;
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Categories
                Clinical Trials and Drug Discovery
                1506
                Original research article
                Custom metadata
                unlocked

                systemic lupus erythematosus,dmards (biologic),treatment,safety,adverse events

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