Skip to main content
Download PDF

Safety and efficacy of biological agents in the treatment of Systemic Lupus Erythematosus (SLE)

BMC Rheumatology volume 7, Article number: 37 (2023) Cite this article

Abstract

Background

To determine the safety and efficacy of biological agents used in the treatment of systemic lupus erythematosus (SLE) in adults.

Methods

Systematic review and meta-analysis following PRISMA guidelines.

Data sources

MEDLINE (through Pubmed), EMBASE, Cochrane library, Clinicaltrials.gov, Australianclinicaltrials.gov.au, ANZCTR.org.au and WHO International Clinical Trials Registry Platform for studies published from 20 May 2021 and 15 years prior. A grey literature search was performed and completed on 31 May 2021.

Study criteria

Phase II, III or quasi randomised controlled trials, studies with only cerebral or cutaneous lupus were excluded. Data extraction: Two authors independently screened studies for eligibility, extracted, reviewed data for accuracy, and used the Cochrane tool to assess risk of bias.

Results

Forty-four studies were identified, consisting of 15 groups of drugs and 25 different biological agents, totalling 16,889 patients. The main outcomes assessed included Systemic Lupus Erythematosus Responder Index (SRI), BILAG-Based Composite Lupus Assessment (BICLA) and combined combined/partial renal remission (CRR/PRR).

Four groups of biologics were found to improve outcomes. Anti-interferons: Anifrolumab increased BICLA response and SRI 5 to 8, decreased prednisone dosages, with increased herpes zoster infections, but fewer serious adverse events. Sifalimumab improved SRI but also increased herpes zoster infections. Anti BAFF/BLyS and/or APRIL: Belimumab consistently improved SRI 4, decreased prednisone dosages, increased combined CRR/PRR, and had no adverse safety outcomes. Tabalumab increased SRI 5 at 52 weeks with no steroid sparing effect but was associated with increased infusion related adverse events. Telitacicept improved SRI 4 at 52 weeks, with no increased adverse events, though data was rather sparse. Anti CD-20 monoclonal antibody, Obinutuzumab increased combined CRR/PRR at 1 and 2 years. Anti IL12/23 monoclonal antibody, Ustekinumab, increased SRI 4 to 6, but not BICLA at 24 weeks, with no concerning safety outcomes.

Conclusion

Multiple biologic agents are shown in high quality studies to have a significant therapeutic impact on outcomes in SLE.

Peer Review reports

Background

Systemic Lupus Erythematosus (SLE) is an autoimmune disease of unknown aetiology with multiple manifestations including musculoskeletal, renal, haematological, serosal, and neuropsychiatric involvement. Treatment for SLE to date is centred on immunosuppression and anti-inflammatory therapy, depending on the degree of end organ involvement. Pregnant and non-pregnant lupus patients benefit from the use of hydroxychloroquine (HCQ), with reductions in lupus flares, end organ damage, loss of bone mass, thrombosis, cumulative steroid usage and increased long term survival [1]. Non-steroidal anti-inflammatory drugs (NSAIDs) may be used to manage milder manifestations such as musculoskeletal or mucocutaneous manifestations. Chronic glucocorticoid (GC) therapy is associated with cumulative dose toxicity. However, given its efficacy it is often used in lower doses as a component of maintenance therapy, or in higher doses for the treatment of disease flares depending on the severity of end organ involvement. Other immunosuppressants used include mycophenolate mofetil (MMF), cyclophosphamide (CYC) and calcineurin inhibitors such as tacrolimus (TAC) and azathioprine (AZA). “Standard of care” therapy is typically defined in clinical trials to include these agents.

Multiple biological agents have recently emerged as potential novel treatments for SLE. In this review we aim to summarise the available data from randomised controlled trials for the efficacy of biologics in SLE, and to highlight potential therapies which require further data.

Methods

All phase II, and III clinical trials or randomised control trials or quasi randomised controlled trial enrolling adult patients with SLE according to standard criteria, examining biologic agent/s compared to placebo, other immunosuppressive drug/s or standard of care were examined.

Outcome measures included change in validated disease activity indices such as SLEDAI, SELENA-SLEDAI, SLEDAI-2 K, BILAG, BILAG-2004, SLICC/ACR score. Adverse events and death were also recorded.

Search methods are documented in the online supplement. Two authors independently examined all studies and extracted data. Dichotomous outcome results were expressed as risk ratios (RR) with 95% confidence intervals (CI), with data pooled using random effects models. Data with continuous outcomes were not measured in this review. The Cochrane risk of bias tool was used by both authors to independently assess the quality of included studies.

Results

One thousand eighty-seven studies were identified. Seventy-nine studies were further assessed. Forty-four studies were included with 16,889 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.

Fig. 1
figure 1

PRISMA flow

Full size image

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 [2,3,4,5] included 1017 patients. Three of the studies 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).

Fig. 2
figure 2

Serious adverse events

Full size image

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).

Fig. 3
figure 3

A SRI 4 at 24 weeks, B SRI 4 at 52 weeks

Full size image

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).

Fig. 4
figure 4

SRI 5 at 52 weeks

Full size image
Fig. 5
figure 5

SRI 7 at 52 weeks

Full size image
Fig. 6
figure 6

SRI 8 at 52 weeks

Full size image
Fig. 7
figure 7

SRI 6 at 52 weeks

Full size image

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).

Fig. 8
figure 8

BICLA at 52 weeks

Full size image

Prednisone dose reduction to < 10 mg/day was increased with Anifrolumab treatment (RR 1.46, CI 1.16 to 1.84, P = 0.001, 3 studies) (Fig. 9).

Fig. 9
figure 9

Change in prednisone dosages to ≤ 10 mg/day

Full size image

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.

Fig. 10
figure 10

Adverse events

Full size image

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 ≤ 10 mg/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 study [10], 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 < 7.5 mg/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%).

Fig. 11
figure 11

Change in prednisone dosages to ≤ 7.5 mg and > 25% reduction from baseline dosage

Full size image

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 [11,12,13,14,15,16,17] including 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).

Fig. 12
figure 12

A Combined complete and partial renal remission at 1 year, B combined complete and partial renal remission at 2 years

Full size image

Belimumab significantly increased the number of patients able reduce prednisone dosages to ≤ 7.5 mg/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 10 mg/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.

Fig. 13
figure 13

Infusion related adverse events

Full size image

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.

Fig. 14
figure 14

Grade 3 or higher related infectious events

Full size image

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 < 10 mg/day (RR 0.81, CI 0.37 to 1.80, P = 0.60), 1 study [27].

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.

Fig. 15
figure 15

SRI 5 at 24 weeks

Full size image
Fig. 16
figure 16

SRI 6 at 24 weeks

Full size image

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 [30] selective 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 [37,38,39], anti IL-6 antibody PF-04326921 [40] 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 Composite outcomes
Full size table
Table 2 Renal outcomes
Full size table
Table 3 Glucocorticoid dose reduction
Full size table
Table 4 Adverse events
Full size table

Risk of bias

Risk of bias graph (Fig. 17) and risk of bias summary (Fig. 18) is shown below.

Fig. 17
figure 17

Risk of bias graph

Full size image
Fig. 18
figure 18

Risk of bias summary

Full size image

Discussion

Summary of main positive and negative outcomes of our study.

We have summarised the RCT data available on 25 biological agents from 15 different drug groups in the treatment of SLE. The majority of these drugs have limited data available and will require further trials to determine their efficacy in various patient groups.

Currently Belimumab is shown to have the most significant data suggesting that it is effective in SLE without a major adverse effect profile. There is high quality evidence showing Belimumab improves composite outcomes measured by SRI. The level of evidence for other biologics with significant outcomes range from low to moderate (Summary of findings: Composite outcomes). Other newer treatments have shown significant efficacy but in more specific outcomes and will need further trials to clearly delineate their strengths and weaknesses.

The main outcomes assessed in these studies were SRI, BICLA, and combined CRR/PRR. Of the 25 biologic agents, only anti-interferon, anti BAFF/BLyS and/or APRIL, anti IL12/23 and anti CD20 monoclonal antibodies were found to improve outcomes.

Anifrolumab increased BICLA response at 52 weeks, SRI 5 to 8 in a single study (Furie 2019), decreased prednisone dosages, with increased adverse events with herpes zoster infections, but with lesser serious adverse events. Sifalimumab also improved SRI but also increased herpes zoster infections. Among the anti BAFF/Blys and/or APRIL monoclonal antibodies, Belimumab consistently improved SRI 4, decreased prednisone dosages, increased combined CRR/PRR in a single study, and had no adverse safety outcomes. Tabalumab increased SRI 5 at 52 weeks with no steroid sparing effect but was associated with increased infusion related adverse events. Telitacicept also improved SRI 4 at 52 weeks, without data on its effect on steroid dosages. Of the three anti CD-20 monoclonal antibodies, only Obinutuzumab increased combined CRR/PRR at 1 and 2 years, with lower grade 3 or higher infectious events. The single anti IL12/23 monoclonal antibody, Ustekinumab, increased SRI 4 to 6, but not BICLA at 24 weeks, with no concerning safety outcomes.

Despite positive results in some of these biologics, several of their developments have since been terminated. There are no further trials planned for Tabalumab ( two phase III trials) by the parent pharmaceutical company as it was not felt to have reached significant efficacy compared to existing treatments, and Sifalimumab's development (one phase IIb trial) has been ceased in favour of Anifrolumab. Following the completion of this review, a phase III trial of Ustekinumab involving 516 patients showed no superiority compared to placebo when measuring SRI 4 as a primary endpoint [45].

Our review did not include non-biologics such as the calcineurin inhibitor Voclosporin which has shown benefit in proteinuria reduction in patients with lupus nephritis [46].

The other remaining drug classes and biological agents did not improve any of the outcomes assessed in the study and had no other notable safety outcomes.

Difficulties with outcome measures

Prior to the introduction of SRI and BICLA, trials reported outcomes using individual BILAG, SLICC, SLEDAI based scores such as SLEDAI-2 K and SELENA-SLEDAI as their outcome measures. There were inconsistencies with how these scores were reported to denote significant results. Examples included BILAG as a numerical score determined by the study authors (and outcomes reporting changes in percentages, mean BILAG score differences compared to baseline) and differing organ domain severity scores (eg 1A and 2B, 1A and 1B, B only, C in all domains) and SLEDAI based metrics using varying decrease in points, expressed in means, medians or percentage of changes in baseline values.

SRI4 response is defined as SLEDAI improvement of 4 points or more, PGA not worsening by 0.3 points or more (10% or more), and BILAG having no new As and not having two or more new Bs. SRI 5, 6 and 7 correspond to an increase in improvement in SLEDAI points, without changes to the other criteria. BICLA response is defined as a reduction of all baseline BILAG-2004 A and B domain scores to B/C/D and C/D, no worsening in any organ system; no worsening of SLEDAI-2 K score from baseline, and no worsening ≥ 0.3 points (< 10% worsening) in Physician's Global Assessment, and no non-protocol treatment (new or increased immunosuppressives, antimalarials, corticosteroids or premature discontinuation of study treatment).

Comparing SRI and BICLA, SRI places more emphasis on SLEDAI improvement which does not evaluate the degree of individual component improvement, compared to the more comprehensive BILAG based BICLA, which does not evaluate for serological improvements. Ohmura 2021 [47] summarises the differences between the existing SLE activity indexes in clinical trials. Quality of life outcome measures also suffered from the aforementioned issues.

As SRI and BICLA incorporates a standardised change in BILAG, SELENA-SLEDAI/SLEDAI-2 K and PGA in their scoring, the authors of this study decided to omit data reporting other disease and quality of life outcomes outside of SRI and BICLA. This is mainly to maximise data that can be appropriately compared across studies, the main utility of a systematic review such as this.

Studies of lupus nephritis also did not use standardised definitions of complete or partial renal remissions (Table 5: Renal outcomes). Neither did they provide adequate reporting on other renal outcomes time to ESRD, or changes in serum creatinine/eGFR.

Table 5 Renal outcomes
Full size table

Comparison with other systematic reviews

Four other reviews examined the use of biologic agents in the treatment of SLE. A meta-analysis by Oon 2018 [48] that Belimumab, Tabalumab and Epratuzumab had steroid sparing effects, which differed from our finding of only Belimumab had a significant steroid sparing effect. We did not include the data of steroid doses in the Epratuzumab studies of Wallace (EMBLEM) 2013 and Clowse 2017 as they were reported as mean ± SD and Wallace 2013 (ALLEVIATE) which reported them as medians without sufficient IQR data. Borba 2014 [49] which assessed 7 biologic agents similarly concluded that Belimumab improved disease response in the outcomes assessed compared to placebo. Singh 2021 [50] assessed 6 RCTs of Belimumab and concluded that Belimumab was effective in increasing SELENA-SLEDAI (≥ 4 point improvement) and reduction in glucocorticoid dosages. Sciascia 2017 [51] assessed the efficacy of Belimumab in renal outcomes and reported a decrease in proteinuria in patients treated with Belimumab but were unable to arrive to any conclusions for other parameters of renal response due to differing criteria across the studies. We did not include data describing renal outcomes such as number of and time to renal flares, and proteinuria due to the heterogeneous methods of reporting them across the studies, limiting their applicability in a systematic review.

Conclusions

Recommendations for patient treatments

Based on current data, Anifrolumab, Sifalimumab, Belimumab, Tabalumab, Telitacicept, are effective treatments in the treatment of SLE without lupus nephritis. Anifrolumab and Belimumab are useful in decreasing the steroid burden in these patients when compared to other biologics. In patients with lupus nephritis, Belimumab and Obinutuzumab are effective treatments. There is insufficient data to recommend for or against the use of biologics in CNS lupus due to their exclusion from trials. Patients treated with Anifrolumab or Sifalimumab should consider herpes zoster vaccination prior to commencing treatment.

Recommendations for further research

Our review has revealed and summarised a wealth of studies in the treatment of SLE with biological agents and demonstrated the limited availability of data in many of these agents and the need for further studies to elucidate the efficacy of each agent in SLE treatment.

Comparison between agents will need to emerge as a research question in the near future. Other potential areas to consider will be the combination of treatments from different drug groups to improve the overall efficacy of disease control over time.

Studies involving biologics in SLE have heterogeneous endpoints and duration. The majority of the studies selectively excluded renal lupus involvement, though the criteria for exclusion varied widely, from active urinary sediment and mildly decreased eGFR to rapidly progressing glomerulonephritis. As lupus nephritis remains a leading cause of morbidity and mortality in SLE, a larger number of trials with a standardised definition of renal composite end points is required.

Trials in the treatment of SLE need to standardise outcomes and reporting in order that results can contribute to a coherent picture of treatment efficacy and safety.

Availability of data and materials

The published article contains summarised versions of significant results generated and analysed during this study. A full set of the unedited data presented via forest plots is provided in the supplementary files.

Abbreviations

AM:

Antimalarials

ACR:

American College of Rheumatology

APRIL:

A proliferation-inducing ligand

AZA:

Azathioprine

BAFF:

B-cell activating factor

BCMA:

B cell maturation antigen

BICLA:

BILAG-Based Composite Lupus Assessment

BID:

Twice daily

BILAG:

British Isles Lupus Assessment Group

BlyS:

B-lymphocyte stimulator

CYC:

Cyclophosphamide

eGFR:

Estimated glomerular filtration rate (measured in ml per minute per 1.73 m2)

EULAR:

European League Against Rheumatism

HPF:

High powered field

IFN:

Interferon

IV:

Intravenous

JAK:

Janus kinase

MMF:

Mycophenolate mofetil

MFS:

Mycophenolate sodium

MTX:

Methotrexate

NSAIDS:

Nonsteroidal anti inflammatory drugs

QD:

Once daily

RPGN:

Rapidly progressing glomerulonephritis

RBC:

Red blood cell

SC:

Subcutaneous

SLE:

Systemic lupus erythromatosus

SLEDAI:

Systemic Lupus Erythematosus Disease Activity Index

SLICC:

Systemic Lupus International Collaborating Clinics

SRI:

Systemic Lupus Erythematosus Responder Index

TACI:

Transmembrane activator and calcium modulator and cySM101clophylin ligand interactor

UPCR:

Urine protein to creatinine ratio

WBC:

White blood cell

References

  1. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010;69:20–8.

    Article  CAS  PubMed  Google Scholar 

  2. Merrill JT, Burgos-Vargas R, Westhovens R, et al. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62:3077–87.

    Article  CAS  PubMed  Google Scholar 

  3. Furie R, Nicholls K, Cheng T-T, et al. Efficacy and safety of Abatacept in lupus nephritis: a twelve-month, randomized, double-blind study: Abatacept in lupus nephritis. Arthritis Rheumatol. 2014;66:379–89.

    Article  CAS  PubMed  Google Scholar 

  4. The ACCESS Trial Group. Treatment of lupus nephritis with Abatacept: the Abatacept and cyclophosphamide combination efficacy and safety study: Abatacept in lupus nephritis. Arthritis Rheumatol. 2014;66:3096–104.

    Article  PubMed Central  Google Scholar 

  5. Furie R, Dooley MA, Wofsy D, et al. OP0253 A phase iii randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of abatacept or placebo on standard of care in patients with active class iii or iv lupus nephritis. Ann Rheum Dis. 2018;77:176–7.

    Google Scholar 

  6. Furie R, Khamashta M, Merrill JT, et al. Anifrolumab, an Anti-Interferon-α Receptor Monoclonal Antibody, in moderate-to-severe systemic lupus erythematosus: Anifrolumab in moderate-to-severe SLE. Arthritis Rheumatol. 2017;69:376–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Furie RA, Morand EF, Bruce IN, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2019;1:e208–19.

    Article  Google Scholar 

  8. Morand EF, Furie R, Tanaka Y, et al. Trial of Anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2020;382:211–21.

    Article  CAS  PubMed  Google Scholar 

  9. Kalunian KC, Merrill JT, Maciuca R, et al. A phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-α) in patients with systemic lupus erythematosus (ROSE). Ann Rheum Dis. 2016;75:196–202.

    Article  PubMed  Google Scholar 

  10. Khamashta M, Merrill JT, Werth VP, et al. Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016;75:1909–16.

    Article  CAS  PubMed  Google Scholar 

  11. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Care Res. 2009;61:1168–78.

    Article  CAS  Google Scholar 

  12. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of Belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011;63:3918–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of Belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet. 2011;377:721–31.

    Article  CAS  PubMed  Google Scholar 

  14. Stohl W, Schwarting A, Okada M, et al. Efficacy and safety of subcutaneous Belimumab in systemic lupus erythematosus: a fifty-two–week randomized, double-blind placebo-controlled study. Arthritis Rheumatol. 2017;69:1016–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang F, Bae S-C, Bass D, et al. A pivotal phase III, randomised, placebo-controlled study of belimumab in patients with systemic lupus erythematosus located in China, Japan and South Korea. Ann Rheum Dis. 2018;77:355–63.

    Article  CAS  PubMed  Google Scholar 

  16. Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of Belimumab in lupus nephritis. N Engl J Med. 2020;383:1117–28.

    Article  CAS  PubMed  Google Scholar 

  17. Atisha-Fregoso Y, Malkiel S, Harris KM, et al. Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. Arthritis Rheumatol Hoboken NJ. https://doi.org/10.1002/art.41466. Epub ahead of print 4 August 2020.

  18. Furie RA, Leon G, Thomas M, et al. A phase 2, randomised, placebo-controlled clinical trial of blisibimod, an inhibitor of B cell activating factor, in patients with moderate-to-severe systemic lupus erythematosus, the PEARL-SC study. Ann Rheum Dis. 2015;74:1667–75.

    Article  CAS  PubMed  Google Scholar 

  19. Merrill JT, Shanahan WR, Scheinberg M, et al. Phase III trial results with blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2018;77:883–9.

    Article  CAS  PubMed  Google Scholar 

  20. Isenberg DA, Petri M, Kalunian K, et al. Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE-1, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016;75:323–31.

    Article  CAS  PubMed  Google Scholar 

  21. Merrill JT, van Vollenhoven RF, Buyon JP, et al. Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016;75:332–40.

    Article  CAS  PubMed  Google Scholar 

  22. Isenberg D, Gordon C, Licu D, et al. Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). Ann Rheum Dis. 2015;74:2006–15.

    Article  CAS  PubMed  Google Scholar 

  23. Merrill JT, Wallace DJ, Wax S, et al. Efficacy and safety of Atacicept in patients with systemic lupus erythematosus: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm Phase IIb Study. Arthritis Rheumatol. 2018;70:266–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. RemeGen Co., Ltd. A Phase 2, Randomized, Double-Blind, Multicenter Study of Telitacicept for Injection (RC18) in Subjects With IgA Nephropathy. 2021. Clinical Trial Registration NCT04905212, clinicaltrials.gov, https://clinicaltrials.gov/ct2/show/NCT04905212. Accessed 1 Nov 2021.

  25. A Phase II Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Obinutuzumab or Placebo in Combination with Mycophenolate Mofetil in Patients with Active Class III or IV Lupus Nephritis. ACR Meeting Abstracts, https://acrabstracts.org/abstract/a-phase-ii-randomized-double-blind-placebo-controlled-study-to-evaluate-the-efficacy-and-safety-of-obinutuzumab-or-placebo-in-combination-with-mycophenolate-mofetil-in-patients-with-active-class-iii/. Accessed 27 Aug 2021.

  26. Mysler EF, Spindler AJ, Guzman R, et al. Efficacy and safety of Ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study: Ocrelizumab in lupus nephritis. Arthritis Rheum. 2013;65:2368–79.

    Article  CAS  PubMed  Google Scholar 

  27. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: The randomized, double-blind, phase ii/iii systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010;62:222–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: The lupus nephritis assessment with rituximab study. Arthritis Rheum. 2012;64:1215–26.

    Article  CAS  PubMed  Google Scholar 

  29. van Vollenhoven RF, Hahn BH, Tsokos GC, et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet Lond Engl. 2018;392:1330–9.

    Article  Google Scholar 

  30. Cardiel MH, Tumlin JA, Furie RA, et al. Abetimus sodium for renal flare in systemic lupus erythematosus: results of a randomized, controlled phase III trial. Arthritis Rheum. 2008;58:2470–80.

    Article  CAS  PubMed  Google Scholar 

  31. Wallace DJ, Furie RA, Tanaka Y, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. The Lancet. 2018;392:222–31.

    Article  CAS  Google Scholar 

  32. Wallace DJ, Martin EC, Ona V, et al. 212 Phase 2, randomized, double-blind, placebo-controlled, dose-finding study, evaluating the Bruton’s tyrosine kinase inhibitor evobrutinib in patients with systemic lupus erythematosus: study design. Lupus Sci Med. 6. https://doi.org/10.1136/lupus-2019-lsm.212. Epub ahead of print 1 April 2019.

  33. Isenberg D, Furie R, Jones NS, et al. Efficacy, Safety, and Pharmacodynamic Effects of the Bruton’s Tyrosine Kinase Inhibitor, Fenebrutinib (GDC-0853), in Systemic Lupus Erythematosus. Arthritis Rheumatol. https://doi.org/10.1002/art.41811.

  34. Gaudy A, Ye Y, Korish S, et al. SAT0225 Cereblon modulator CC-220 decreases naÏve and memory B cells and plasmacytoid dendritic cells in systemic lupus erythematosus (SLE) patients: exposure-response results from a phase 2A proof of concept study. In: Poster Presentations. BMJ Publishing Group Ltd and European League Against Rheumatism, p. 858.2–859. https://doi.org/10.1136/annrheumdis-2017-eular.3036.

  35. Efficacy and Safety of Iberdomide in Patients with Active Systemic Lupus Erythematosus: 24-Week Results of a Phase 2, Randomized, Placebo-Controlled Study - ACR Meeting Abstracts, https://acrabstracts.org/abstract/efficacy-and-safety-of-iberdomide-in-patients-with-active-systemic-lupus-erythematosus-24-week-results-of-a-phase-2-randomized-placebo-controlled-study/. Accessed 27 Aug 2021.

  36. Urowitz MB, Isenberg DA, Wallace DJ. Safety and efficacy of hCDR1 (Edratide) in patients with active systemic lupus erythematosus: results of phase II study. Lupus Sci Med. 2015;2: e000104.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Wallace DJ, Gordon C, Strand V, et al. Efficacy and safety of epratuzumab in patients with moderate/severe flaring systemic lupus erythematosus: results from two randomized, double-blind, placebo-controlled, multicentre studies (ALLEVIATE) and follow-up. Rheumatology. 2013;52:1313–22.

    Article  CAS  PubMed  Google Scholar 

  38. Wallace DJ, Kalunian K, Petri MA, et al. Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study. Ann Rheum Dis. 2014;73:183–90.

    Article  CAS  PubMed  Google Scholar 

  39. Clowse MEB, Wallace DJ, Furie RA, et al. Efficacy and safety of epratuzumab in moderately to severely active systemic lupus erythematosus: results from two phase III randomized, double-blind, placebo-controlled trials: efficacy and safety of Epratuzumab in SLE. Arthritis Rheumatol. 2017;69:362–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wallace DJ, Strand V, Merrill JT, et al. Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial. Ann Rheum Dis. 2017;76:534–42.

    Article  CAS  PubMed  Google Scholar 

  41. Ablynx. A Phase II Multicenter, Randomized, Double-blind, Placebo Controlled, Dose-range Finding Study to Evaluate the Safety and Efficacy of ALX-0061 Administered Subcutaneously in Subjects With Moderate to Severe Active Systemic Lupus Erythematosus. 2019. Clinical Trial Registration NCT02437890, clinicaltrials.gov, https://clinicaltrials.gov/ct2/show/NCT02437890. Accessed 15 June 2021.

  42. Biotest. A Prospective, Double-blind, Randomized, Placebo-controlled, Repeated Dose, Multicentre Phase IIa Proof-of-Concept Study With BT063 in Subjects With Systemic Lupus Erythematosus. 2020. Clinical Trial Registration study/NCT02554019, clinicaltrials.gov, https://clinicaltrials.gov/ct2/show/study/NCT02554019. Accessed 15 June 2021.

  43. Zimmer R, Scherbarth HR, Rillo OL, et al. Lupuzor/P140 peptide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled phase IIb clinical trial. Ann Rheum Dis. 2013;72:1830–5.

    Article  CAS  PubMed  Google Scholar 

  44. Tillmanns S. SM101, a Novel Recombinant, Soluble, Human FcγIIB Receptor, in the Treatment of Systemic Lupus Erythematosus: Results of a Double-Blind, Placebo-Controlled Multicenter Study. ACR Meeting Abstracts, https://acrabstracts.org/abstract/sm101-a-novel-recombinant-soluble-human-fcγiib-receptor-in-the-treatment-of-systemic-lupus-erythematosus-results-of-a-double-blind-placebo-controlled-multicenter-study/. Accessed 28 Aug 2021.

  45. van Vollenhoven RF, Kalunian KC, Dörner T, et al. Phase 3, multicentre, randomised, placebo-controlled study evaluating the efficacy and safety of ustekinumab in patients with systemic lupus erythematosus. Ann Rheum Dis. 2022;81:1556–63.

    Article  PubMed  Google Scholar 

  46. Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021;397:2070–80.

    Article  CAS  PubMed  Google Scholar 

  47. Ohmura K. Which is the best SLE activity index for clinical trials? Mod Rheumatol. 2021;31:20–8.

    Article  CAS  PubMed  Google Scholar 

  48. Oon S, Huq M, Godfrey T, et al. Systematic review, and meta-analysis of steroid-sparing effect, of biologic agents in randomized, placebo-controlled phase 3 trials for systemic lupus erythematosus. Semin Arthritis Rheum. 2018;48:221–39.

    Article  PubMed  Google Scholar 

  49. Borba HHL, Wiens A, de Souza TT, et al. Efficacy and safety of biologic therapies for systemic lupus erythematosus treatment: systematic review and meta-analysis. BioDrugs Clin Immunother Biopharm Gene Ther. 2014;28:211–28.

    CAS  Google Scholar 

  50. Singh JA, Shah NP, Mudano AS. Belimumab for systemic lupus erythematosus. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD010668.pub2. Epub ahead of print 2021.

  51. Sciascia S, Radin M, Yazdany J, et al. Efficacy of belimumab on renal outcomes in patients with systemic lupus erythematosus: A systematic review. Autoimmun Rev. 2017;16:287–93.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

The authors did not receive any funding for this review.

Author information

Authors and Affiliations

  1. John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia

    Justin Chan, Giles D. Walters & Simon H. Jiang

  2. Department of Renal Medicine, Canberra Hospital, Canberra, Australian Capital Territory, Australia

    Justin Chan, Giles D. Walters & Simon H. Jiang

  3. Department of Nephrology, Royal Brisbane and Woman’s Hospital Health Service District, Herston, QLD, Australia

    Prianka Puri

Authors
  1. Justin Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giles D. Walters
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Prianka Puri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simon H. Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PP and JC reviewed existing literature and designed the review with input from GW and SJ. JC undertook the role of lead author for this review. GW and SJ reviewed and verified statistical data and the writing of this review. The manuscript was approved by all authors.

Corresponding author

Correspondence to Justin Chan.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chan, J., Walters, G.D., Puri, P. et al. Safety and efficacy of biological agents in the treatment of Systemic Lupus Erythematosus (SLE). BMC Rheumatol 7, 37 (2023). https://doi.org/10.1186/s41927-023-00358-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s41927-023-00358-3

Keywords

BMC Rheumatology

ISSN: 2520-1026

Contact us