1087 studies were identified. Seventy-nine studies were further assessed. Forty-four studies were included with 16889 patients, 15 distinct drug groups and 25 biological agents. Characteristics of the studies including patient characteristics and study protocols are summarised in the supplementary information. PRISMA flow diagram is shown below (Fig. 1), and the PRISMA checklist is included in the supplementary information.
CD80/86 inhibition
CD80/86 is expressed by antigen presenting cells such as plasmacytoid dendritic cells and B cells. CD80/86 ligate CD28, a co-stimulatory receptor expressed on T cells. CD28 stimulation in conjunction with T cell receptor engagement prolongs and increases T cell differentiation and production of IL2, with subsequent B cell proliferation and differentiation into antibody producing plasma cells.
Abatacept
Abatacept is a fusion protein composed of a CTLA-4 molecule linked to the Fc portion of IgG1. This selectively and competitively antagonises CD80 and CD86 receptors on an antigen presenting cell, limiting CD28 mediated T cell activation.
Four studies 2–5included 1017 patients. Three recruited patients with lupus nephritis whereas Merrill 2010 2 excluded patients with renal involvement.
No outcomes achieved significance. Serious adverse events were significantly raised only in Merrill 2010 (RR 2.93, CI 1.06 to 8.05, P = 0.04) but not in the pooled data of all the Abatacept studies (RR 1.17, CI 0.87 to 1.58, P = 0.30) (Fig. 2).
Anti-interferon monoclonal antibody
T1 IFN is considered the canonical SLE cytokine impairing immune tolerance through multiple mechanisms. Three anti-interferon monoclonal antibodies have been assessed in this review. Anifrolumab which binds to both IFN-α/β receptors, Rontalizumab and Sifalimumab which selectively bind to IFN-α receptors.
Anifrolumab
Anifrolumab is a fully human, IgG1k monoclonal antibody that binds to IFN-α/β receptor and prevents signalling by all types of I IFNs.
Three studies addressed the use of Anifrolumab in SLE: Furie 2017 6, Furie 2019 7 and Morand 2020 8 and included 1124 patients. The main outcomes studied were SRI and BICLA response.
SRI 4 at 24 weeks did not achieve statistical significance (RR 1.34, CI 0.84 to 2.15, P = 0.22, 2 studies 6,7 ), though results from Furie 2017 alone were significant (RR 1.79, CI 1.12 to 2.85, P = 0.01) (Fig. 3a)
SRI 4 at 52 weeks did not achieve statistical significance (RR 1.40, CI 0.94 to 2.08, P = 0.10, 2 studies 6,7 ), though results from Furie 2017 alone were significant (RR 1.76, CI 1.22 to 2.53, P = 0.002) (Fig. 3b)
In a single study 7 at 52 weeks, Anifrolumab significantly increased SRI 5 (RR 1.37, CI 1.05 to 1.78, P = 0.02) (Fig. 4), SRI 7 (RR 1.86, CI 1.27 to 2.72, P = 0.001) (Fig. 5), and SRI 8 (RR 1.97, CI 1.32 to 2.95, P = 0.0009) (Fig. 6), but not SRI 6 (RR 1.29, CI 0.99 to 1.69, P = 0.06), though the results trended towards significance (Fig. 7)
Anifrolumab significantly increased BICLA response at 52 weeks in all 3 studies (RR 1.56, CI 1.33 to 1.84, P < 0000.1) (Fig. 8).
Prednisone dose reduction to < 10mg/day was increased with Anifrolumab treatment (RR 1.46, CI 1.16 to 1.84, P = 0.001, 3 studies) (Fig. 9).
Adverse events were increased with Anifrolumab treatment, (RR 1.09, CI 1.04 to 1.15, P = 0.001, 3 studies) (Fig. 10), with a higher incidence of herpes zoster infections, but there were significantly fewer serious adverse events, (RR 0.68, CI 0.49 to 0.95, P = 0.02, 3 studies) compared to controls (Fig. 2). The other safety outcomes did not reach statistical significance.
Rontalizumab
Rontalizumab is a human anti-IFN-α monoclonal antibody that binds to all 12 IFN-α subtypes preventing signalling through the type I IFN receptor.
One study 9 including 238 patients addressed the use of Rontalizumab in SLE: Kalunian 2016. Patients with lupus nephritis were excluded. At 24 weeks, Rontalizumab did not improve SRI 4 (RR 1.11, CI 0.83 to 1.48, P = 0.47) (Fig. 3a), though there were steroid sparing benefits with an increased number of patients tapering their steroids to a prednisone equivalent of ≤ 10mg/day (RR 1.21, CI 1.0 to 1.46, P = 0.05) (Fig. 9). There were no significant differences in safety outcomes.
Sifalimumab
Sifalimumab is a fully human, immunoglobulin G1 κ monoclonal antibody that binds to and neutralises the majority of IFN-α subtypes.
In a single study10, at 52 weeks, Sifalimumab improved SRI 4, (RR 1.28, CI 1.02 to 1.61, P = 0.03) (Fig. 3b) and SRI 6 (RR 1.32, CI 1.01 to 1.73, P = 0.04) (Fig. 7). SRI 5 at 52 weeks (RR1.27, CI 0.98 to 1.65, P = 0.07) (Fig. 4) and BICLA at 52 weeks (RR 1.29, CI 0.98 to 1.71, P = 0.07) (Fig. 8) trended towards but did not achieve significance. There were no steroid sparing benefits, with no difference in the reduction in prednisone < 7.5mg/day with 25% reduction from baseline dosage (RR 1.21, CI 0.41 to 3.54, P = 0.73) (Fig. 11). Adverse events were not increased with the use of Sifalimumab, though there were higher rates of herpes zoster compared to placebo (5.9% vs 0.9%)
Anti BAFF/BLyS and APRIL monoclonal antibody
BAFF and APRIL are cytokines from the TNF family, secreted by most myeloid and lymphoid cells, and bind to TACI, BCMA and BAFF receptors. Ligation of BAFF receptors promote B cell survival, immunoglobulin class switching and secretion. BAFF binds to all 3 receptors, whereas APRIL only binds to TACI and BCMA. Blisibimod and Tabalumab inhibit soluble and membrane bound BAFF and Belimumab binds to soluble human BAFF. Atacicept and Telitacicept block both BlyS and APRIL.
Belimumab
Belimumab is a human IgG1 monoclonal antibody that binds soluble human BlyS. It is currently only indicated for use in SLE not responding to standard of care therapy.
Seven studies 11–17including 4022 patients. Furie 2020 16 and Atisha Fregoso 2021 17 included patients with lupus nephritis.
At 52 weeks, Belimumab use significantly increased SRI 4 (RR 1.27, CI 1.18 to 1.38, P < 0.0001, 4 studies) (Fig. 3b). In a single study at 52 weeks, improvements were demonstrated in SRI 5 (RR 1.56, CI 1.20 to 2.03, P = 0.0009) (Fig. 4), SRI 6 (RR 1.57, CI 1.19 to 2.08, P = 0.001) (Fig. 7) and SRI 8 (RR 1.50, CI 1.01 to 2.22, P = 0.05) (Fig. 6). In two studies, SRI 7 at 52 weeks significantly increased (RR 1.43, CI 1.13 to 1.81, P = 0.003) (Fig. 5).
Belimumab did not alter CRR/PRR at 1 year (RR 1.28, CI 0.67 to 2.45, P = 0.45, 1 study) but showed a significant effect at 2 years (RR 1.29, CI 1.04 to 1.61, P = 0.03, 2 studies) (Fig. 12b).
Belimumab significantly increased the number of patients able reduce prednisone dosages to ≤ 7.5mg/day (RR 1.45, CI 1.16 to 1.80, P = 0.0009, 5 studies (Fig. 11).
There were no significant difference in serious adverse events (RR 0.88, 0.72 to 1.08, P = 0.24, 6 studies) (Fig. 2) or in other reported safety outcomes.
Blisibimod
Blisibimod is a selective inhibitor of soluble BAFF and membrane-bound BAFF, composed of a tetrameric BAFF binding domain fused to a human IgG1. Two studies 18,19 included 988 patients. Patients with severe lupus nephritis were excluded.
Blisibimod increased SRI 4 at 24 weeks only in Merrill 2018 19, (RR 1.19, CI 1.00 to 1.41, P = 0.05, 2 studies) (Fig. 3a), but not SRI 4 and 6 at 52 weeks or SRI 5 to 8 at 24 weeks. Blisibimod reduced prednisone dosage below 10mg/day (RR 1.64, CI 1.07 to 2.52, P = 0.02, 1 study 19 (Fig. 9).
Infusion related adverse events were increased (RR 1.85, CI 1.21 to 2.81, P = 0.004, 1 study 19 (Fig. 13). There were no significant increase in other adverse events.
Tabalumab
Tabalumab is a fully human IgG4 monoclonal antibody, that binds and neutralises both membrane and soluble BAFF. Two studies 20,21 included 2262 patients. Patients with severe lupus nephritis were excluded.
Tabalumab significantly increased SRI 5 at 52 weeks (RR 1.23, CI 1.06 to 1.42, P = 0.005, 2 studies) (Fig. 4). Tabalumab did not significantly decrease prednisone doses (RR 1.21, CI 0.78 to 1.89, P = 0.39, 2 studies).
Infusion related adverse events were significantly higher with Tabalumab, (RR 1.63, CI 1.05 to 2.53, P = 0.03, 2 studies) (Fig. 13). Tabalumab did not increase withdrawals from the study, serious infections or death.
Atacicept
Atacicept is a recombinant fusion protein comprising the extracellular domain of the TACI receptor joined to a human IgG1 Fc domain that blocks B-cell activating factor BlyS and APRIL.
Two studies 22,23 included 767 patients. Patients with lupus nephritis were excluded.
In one study 23, Atacicept did not increase SRI 4 (RR 1.27, CI 0.99 to 1.63, P = 0.06) (Fig. 3a), SRI 6 (RR 1.13, CI 0.79 to 1.62, P = 0.49) and BICLA (RR 1.13, CI 0.87 to 1.47, P = 0.36) at 24 weeks.
There were no steroid sparing benefits or significant differences in the safety outcomes.
Telitacicept
Telitacicept is a fusion protein comprising a recombinant TACI receptor fused to the Fc domain of human IgG, which binds to and neutralises the BLyS and APRIL, suppressing development and maturation of plasma cells and mature B cells.
One study 24 included 202 patients. Patients with severe lupus nephritis were excluded.
SRI 4 at 52 weeks was significantly increased with Telitacicept (RR 2.12, CI 1.48 to 3.03, P < 0.00001) (Fig. 3b).
There were no significant differences in reported safety outcomes of adverse events, serious adverse events and death.
Anti-CD20 monoclonal antibody
Three anti CD20 monoclonal antibodies are examined in this review, Rituximab (murine-human chimeric), Ocrelizumab and Obinutuzumab (humanised).
Obinutuzumab
Obinutuzumab is a recombinant type II anti-CD20 and IgG1 Fc-optimised humanised monoclonal antibody, which has improved mAb-FcγRIIIA interaction and direct and immune effector cell-mediated cytotoxicity compared to Rituximab.
One study 25 included 125 patients. Patients with lupus nephritis ISPN/RPS 2003 class III/IV were included in the study.
Combined CRR/PRR at 1 year was increased (RR 1.60, CI 1.27 to 2.02, P < 0.0001) (Fig. 12a) and 2 years (RR 1.83, CI 1.06 to 3.16, P = 0.03) (Fig. 12b).
There were fewer grade 3 or higher related infectious events with Obinutuzumab (RR 0.29, CI 0.10 to 0.85, P = 0.02) (Fig. 14), but no significant differences in the other safety outcomes.
Ocrelizumab
Ocrelizumab is a humanised monoclonal antibody against CD20 and may have greater antibody dependent cellular toxicity and less complement dependent cytotoxicty compared to Rituximab which is a chimeric monoclonal antibody. One study 26 included 378 patients with lupus nephritis.
Combined CRR/PRR at 1 year was not increased (RR 1.22, CI 0.97 to 1.55, P = 0.09).
There were no significant differences in the pooled safety outcomes, but a higher rate of serious infections were seen in patients receiving MMF compared to ELNT induction
Rituximab
Rituximab is a type 1 chimeric anti-CD20 monoclonal antibody directed to the CD20 antigen on the surface of B lymphocytes, causing apoptosis, complement activation and cell mediated cytotoxicity.
Two studies 27,28 included 401 patients. Rovin 2012 28 only included patients with lupus nephritis class III/IV +/- V. Rituximab did not increase CRR/PRR at 1 year, (RR 1.24, CI 0.90 to 1.71, P = 0.19, 1 study 28). There was no reduction in the number of patients achieving prednisone < 10mg/day (RR 0.81, CI 0.37 to 1.80, P = 0.60), 1 study27
Ustekinumab
Ustekinumab is a fully humanised monoclonal antibody against the p40 subunit found on both IL-12 and IL-23. IL-12 has a key role in inducing Th cell differentiation to Th1 cells, and IL-23 in Th17 cell activation and subsequent IL-17 secretion.
One study 29 included 102 patients. Patients with lupus nephritis class III/IV were excluded.
Ustekinumab increased SRI 4 at 24 weeks (RR 1.85, CI 1.15 to 2.97, P = 0.01) (Fig. 3a), SRI 5 at 24 weeks (RR 2.02, CI 1.06 to 3.86, P = 0.03) (Fig. 15) and SRI 6 at 24 weeks (RR 2.27, CI 1.14 to 4.52, P = 0.02) (Fig. 16), but not BICLA at 24 weeks (P = 0.86). Ustekinumab use did not increase any adverse events.
Group Of Drugs Without Significant Results
There were no significant outcomes in the disease activity indices, composite responder rates or adverse events in the following group of drugs; anti-dsDNA complexing Abetimus 30selective JAK 1 and 2 inhibitors Baricitinib 31, BTK inhibitors Evobrutinib 32, Fenebrutinib 33, high affinity cereblon ligand CC-220/Iberdomide 34,35, tolerogenic peptides Edratide 36, anti CD22 monoclonal antibody Epratuzumab 37–39, anti IL-6 antibody PF-04326921 4040 Vobarilizumab 41 anti IL-10 monoclonal antibody BT063 42, P140 peptide Lupuzor 43 and recombinant soluble human FcyRIIb SM101 44
Summary Of Findings
The main results of this review are presented in the summary of findings tables. Outcomes with significant results presented include composite outcomes, renal outcomes, glucocorticoid dose reduction, and adverse events. The complete GRADE tables are shown below ( Refer Table 1: Composite outcomes, Table 2:Renal outcomes, Table 3: Glucocorticoid dose reduction, Table 4: Adverse events)
Table 1
Biologics compared to placebo for the treatment of Systemic Lupus Erythematosus measured by composite responder rates |
Patient or population: Systemic Lupus Erythematosus Setting: Inpatients then outpatients Intervention: Biologics Comparison: Standard of care, placebo |
Outcomes | № of participants (studies) Follow-up | Certainty of the evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects |
Risk with Standard of care | Risk difference with Biologics |
(SRI) 4 at 52 weeks - Anifrolumab | 762 (2 RCTs) | ⨁⨁⨁◯ Moderate1,2,a,b,c,e | RR 1.40 (0.94 to 2.08) | 350 per 1,000 | 140 more per 1,000 (21 fewer to 378 more) |
(SRI) 4 at 52 weeks - Sifalimumab | 431 (1 RCT) | ⨁⨁⨁◯ Moderatef | RR 1.28 (1.02 to 1.61) | 454 per 1,000 | 127 more per 1,000 (9 more to 277 more) |
(SRI) 4 at 52 weeks - Belimumab | 3180 (4 RCTs) | ⨁⨁⨁⨁ Highh | RR 1.27 (1.18 to 1.38) | 415 per 1,000 | 112 more per 1,000 (75 more to 158 more) |
(SRI) 4 at 52 weeks - Telitacicept | 249 (1 RCT) | ⨁⨁◯◯ Lowd,e,f,g | RR 2.12 (1.48 to 3.03) | 339 per 1,000 | 379 more per 1,000 (163 more to 688 more) |
BICLA response at 52 weeks - Anifrolumab | 1121 (3 RCTs) | ⨁⨁⨁◯ Moderatea,b,c,i | RR 1.56 (1.33 to 1.84) | 293 per 1,000 | 164 more per 1,000 (97 more to 246 more) |
BICLA response at 52 weeks - Sifalimumab | 431 (1 RCT) | ⨁⨁⨁◯ Moderatee,f | RR 1.29 (0.98 to 1.71) | 361 per 1,000 | 105 more per 1,000 (7 fewer to 256 more) |
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio |
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. |
Explanations |
a. allocation concealment method not stated |
b. randomisation method not stated |
c. selective reporting, multiple analyses of data |
d. Wide CI |
e. single study |
f. Did not meet OIS criterion |
g. study protocols unavailable |
h. I2 = 0, significant P and consistently overlapping CI |
i. selective reporting, change in primary outcome resulting in significant outcome (Morand 2020) |
Table 2
Biologics compared to placebo for the treatment of Systemic Lupus Erythematosus measured by renal outcomes |
Patient or population: Systemic Lupus Erythematosus Setting: Inpatients then outpatients Intervention: Biologics Comparison: Standard of care, placebo |
Outcomes | № of participants (studies) Follow-up | Certainty of the evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects |
Risk with placebo | Risk difference with Renal outcomes |
Partial and/or complete renal response by 1 year - Abatacept | 377 (2 RCTs) | ⨁⨁◯◯ Lowa,b,c,d | RR 0.98 (0.78 to 1.23) | 436 per 1,000 | 9 fewer per 1,000 (96 fewer to 100 more) |
Partial and/or complete renal response by 1 year - Belimumab | 43 (1 RCT) | ⨁◯◯◯ Very lowc,d,e | RR 1.28 (0.67 to 2.45) | 409 per 1,000 | 115 more per 1,000 (135 fewer to 593 more) |
Partial and/or complete renal response by 1 year - Obinutuzumab | 125 (1 RCT) | ⨁⨁⨁◯ Moderated | RR 1.60 (1.27 to 2.02) | 565 per 1,000 | 339 more per 1,000 (152 more to 576 more) |
Partial and/or complete renal response by 1 year - Ocrelizumab | 223 (1 RCT) | ⨁⨁◯◯ Lowa,b,d,f | RR 1.22 (0.97 to 1.55) | 547 per 1,000 | 120 more per 1,000 (16 fewer to 301 more) |
Partial and/or complete renal response by 1 year - Rituximab | 144 (1 RCT) | ⨁⨁⨁◯ Moderatea,b,d | RR 1.24 (0.90 to 1.71) | 458 per 1,000 | 110 more per 1,000 (46 fewer to 325 more) |
Partial and/or complete renal response by 2 years - Belimumab | 488 (2 RCTs) | ⨁◯◯◯ Very lowd,g,h | RR 1.28 (1.03 to 1.58) | 361 per 1,000 | 101 more per 1,000 (11 more to 209 more) |
Partial and/or complete renal response by 2 years - Obinituzumab | 125 (1 RCT) | ⨁⨁⨁◯ Moderatec,d | RR 1.83 (1.06 to 3.16) | 226 per 1,000 | 187 more per 1,000 (14 more to 488 more) |
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio |
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. |
Explanations |
a. randomisation method not specified |
b. allocation concealment method not specified |
c. Wide CI |
d. Not meeting OIS criteria |
e. not blinded, open label |
f. attrition bias, premature termination of study with incomplete reporting of primary endpoints |
g. not blinded, open label ( Atisha Fregoso 2021) |
h. significant P value and 0% heterogeneity but CI from Atisha Fregoso wide and overlaps significant/non significance |
Table 3
Glucocorticoid dose reduction
Biologics compared to placebo for the treatment of Systemic Lupus Erythematosus measured by glucocorticoid dose reduction |
Patient or population: Systemic Lupus Erythematosus 1. Setting: Inpatients then outpatients Intervention: Biologics Comparison: Standard of care, placebo |
Outcomes | № of participants (studies) Follow-up | Certainty of the evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects |
Risk with placebo | Risk difference with Glucocorticoid dose |
number of patients with prednisone equivalent ≤ 7.5mg/day, with reduction ≥ 25% from baseline - Belimumab | 2317 (5 RCTs) | ⨁⨁⨁◯ Moderatec,d | RR 1.45 (1.16 to 1.80) | 121 per 1,000 | 54 more per 1,000 (19 more to 97 more) |
number of patients with prednisone equivalent ≤ 7.5mg/day, with reduction ≥ 25% from baseline - Tabalumab | 999 (2 RCTs) | ⨁◯◯◯ Very lowa,b,d,e | RR 1.21 (0.78 to 1.89) | 144 per 1,000 | 30 more per 1,000 (32 fewer to 128 more) |
number of patients with prednisone equivalent ≤ 10mg/day - Anifrolumab | 605 (3 RCTs) | ⨁⨁◯◯ Lowa,d,e,f | RR 1.46 (1.16 to 1.84) | 301 per 1,000 | 139 more per 1,000 (48 more to 253 more) |
number of patients with prednisone equivalent ≤ 10mg/day - Rontalizumab | 235 (1 RCT) | ⨁⨁⨁◯ Moderatea,c,d | RR 1.21 (1.00 to 1.46) | 633 per 1,000 | 133 more per 1,000 (0 fewer to 291 more) |
number of patients with prednisone equivalent ≤ 10mg/day - Blisibimod | 442 (1 RCT) | ⨁⨁⨁◯ Moderatec,d | RR 1.64 (1.07 to 2.52) | 132 per 1,000 | 84 more per 1,000 (9 more to 201 more) |
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio |
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. |
Explanations |
a. allocation concealment method not stated |
b. Wide CI |
c. Single study |
d. Not meeting OIS criteria |
e. randomisation method not stated |
f. selective reporting bias, multiple analyses of data |
Table 4
Biologics compared to placebo for the treatment of Systemic Lupus Erythematosus measured by adverse events |
Patient or population: Systemic Lupus Erythematosus Setting: Inpatients then outpatients Intervention: Biologics Comparison: Standard of care, placebo |
Outcomes | № of participants (studies) Follow-up | Certainty of the evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects |
Risk with placebo | Risk difference with Adverse events |
AEs - Anifrolumab | 1124 (3 RCTs) | ⨁⨁⨁◯ Moderatea | RR 1.09 (1.04 to 1.15) | 805 per 1,000 | 72 more per 1,000 (32 more to 121 more) |
AEs - CC-220 | 330 (2 RCTs) | ⨁⨁◯◯ Lowa,b | RR 1.23 (0.84 to 1.80) | 363 per 1,000 | 83 more per 1,000 (58 fewer to 290 more) |
Serious AEs - Abatacept | 1017 (4 RCTs) | ⨁⨁⨁◯ Moderatea | RR 1.17 (0.87 to 1.58) | 219 per 1,000 | 37 more per 1,000 (28 fewer to 127 more) |
Serious AEs - Anifrolumab | 1124 (3 RCTs) | ⨁⨁⨁◯ Moderatea | RR 0.68 (0.49 to 0.95) | 188 per 1,000 | 60 fewer per 1,000 (96 fewer to 9 fewer) |
Serious AEs - Belimumab | 4122 (6 RCTs) | ⨁⨁⨁◯ Moderatee | RR 0.88 (0.72 to 1.08) | 196 per 1,000 | 24 fewer per 1,000 (55 fewer to 16 more) |
Serious AEs - Blisibimod | 987 (2 RCTs) | ⨁⨁⨁◯ Moderatea | RR 0.73 (0.53 to 0.99) | 165 per 1,000 | 44 fewer per 1,000 (77 fewer to 2 fewer) |
Treatment related AEs - Belimumab | 1989 (3 RCTs) | ⨁⨁⨁◯ Moderatea | RR 1.12 (0.99 to 1.26) | 334 per 1,000 | 40 more per 1,000 (3 fewer to 87 more) |
Treatment related AEs - Blisibimod | 987 (2 RCTs) | ⨁⨁⨁⨁ High | RR 1.26 (0.89 to 1.78) | 314 per 1,000 | 82 more per 1,000 (35 fewer to 245 more) |
Treatment related AEs - CC-220 | 330 (2 RCTs) | ⨁⨁⨁◯ Moderatea | RR 1.39 (1.02 to 1.90) | 319 per 1,000 | 124 more per 1,000 (6 more to 287 more) |
Infusion related AE - Belimumab | 1716 (3 RCTs) | ⨁⨁◯◯ Lowa,c,d | RR 1.15 (0.81 to 1.64) | 101 per 1,000 | 15 more per 1,000 (19 fewer to 65 more) |
Infusion related AE - Blisibimod | 441 (1 RCT) | ⨁⨁⨁◯ Moderatea | RR 1.85 (1.21 to 2.81) | 133 per 1,000 | 113 more per 1,000 (28 more to 240 more) |
Infusion related AE - Tabalumab | 2283 (2 RCTs) | ⨁⨁⨁◯ Moderatea | RR 1.63 (1.05 to 2.53) | 33 per 1,000 | 21 more per 1,000 (2 more to 50 more) |
Infection related grade 3 or higher AE - Obinutuzumab | 125 (1 RCT) | ⨁⨁⨁◯ Moderatea | RR 0.29 (0.10 to 0.85) | 213 per 1,000 | 151 fewer per 1,000 (192 fewer to 32 fewer) |
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio |
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. |
Explanations |
a. didn't meet OIS criteria |
b. high heterogeneity |
c. allocation concealment method not stated |
d. wide CI |
e. high heterogeneity and 2 studies suggesting reduction in events, 4 don't |
Risk Of Bias
Risk of bias graph (Fig. 17) and risk of bias summary ( Fig. 18 ) is shown below.