FormalPara Key Points

The type I interferons (IFN) are a family of cytokines with a key role in innate immune responses, especially to viral infections. Activation of IFNs has emerged as a key characteristic of multiple autoimmune diseases, especially systemic lupus erythematosus (SLE).

The production of IFN, IFN proteins themselves, and IFN signalling have each been targeted in clinical trials in SLE. A monoclonal antibody to the common type I IFN receptor, anifrolumab, has been approved for the treatment of SLE, while multiple other agents are in advanced clinical trial stages.

The lack of success of several IFN-targeting trials, despite robust pre-clinical data, highlight the multiple challenges in SLE drug development and provide lessons to improve outcomes for SLE therapeutics in the future.

1 Introduction

Systemic lupus erythematosus (SLE, lupus) is a complex and highly clinically heterogenous condition in which the immune system mounts an unprogrammed response to host cells and tissues. As we recently summarized [1], SLE is best considered as a clinically assigned label for a spectrum of health states that have in common autoimmune reactivity to nucleic acids in the form of anti-nuclear antibodies and clinical manifestations related to autoimmunity-driven inflammation. A key characteristic of SLE is the potential for it to manifest in virtually any organ system, but in an unpredictable sequence, such that patients are highly clinically heterogeneous. This creates challenges with measuring changes in disease activity in response to treatment in the setting of a trial. In addition, approaches such as genome-wide transcriptomics have made it clear that biological profiles of patients with SLE are also highly heterogeneous, meaning that in unstratified patients highly targeted therapies may ‘miss the mark’ in substantial subsets. Together these issues have meant that multiple clinical trials of medicines for SLE have failed. Compared with other autoimmune rheumatic diseases such as rheumatoid arthritis in which outcomes have been transformed by the use of targeted biological and small molecule therapies, patients with SLE have high morbidity, low quality of life, and reduced life expectancy.

Despite the clinical and biological heterogeneity of SLE, evidence of aberrant activation of type I interferons (IFN) is highly reproducible across diverse cohorts of patients with SLE, even those with variation in other biomarkers and in clinical profile. This suggests an important role for this family of cytokines in SLE pathogenesis but also that IFN could be a transformative therapeutic target in this disease. Clinical trials of early anti-IFN pathway therapies were encouraging, and despite a clinical development program characterized by inconsistent trial results driven by issues such as those listed above, the anti-IFN receptor monoclonal antibody anifrolumab has received regulatory approval, providing the opportunity to intervene directly on this pathway in patients with SLE. In this article we will review the journey towards approval of IFN-targeting therapies for SLE and consider how this story exemplifies the opportunities and hurdles in SLE drug development.

2 Pathophysiological Rationale for Targeting Type I Interferons (IFN) in Systemic Lupus Erythematosus (SLE)

Unravelling the intricacies of SLE pathogenesis is an active and ever-evolving field of research, but understanding the role of type I IFN provides a chance to explore the complexity inherent in the disease. Diverse inflammatory sensor pathways converge on induction of IFN production and initiate multiple pathogenic outcomes, and understanding what is on either side of this bow-shaped concept (Fig. 1) is key to understanding the processes that underlie disease. Of course, type I IFNs are not the sole factors at play, and this concept extends to other effectors in lupus; we delineate a pathway for the selection of new drug targets in SLE later in this review.

The earliest stages of inflammation in SLE involve the activation of the innate immune system, triggered by cellular and nuclear debris. This response is linked to the modification and exposure of normally intracellular antigens, associated with a breakdown of immune self-tolerance to these antigens depending on an individual's genetic and epigenetic background. Clearance of exposed self-antigens to protect against immune auto-activation is facilitated in health by the complement system [2, 3], as well as DNASE1L3, an enzyme crucial for digesting chromatin from apoptotic cells [4,5,6]. Neutrophil extracellular traps (NETs), released during cell death, represent another way through which intracellular molecules are externalized [7], particularly in a subset of neutrophils known as low-density granulocytes, contributing to inflammatory responses and tissue damage [8,9,10].

The exposed intracellular proteins, either alone or bound to autoantibodies in immune complexes, are processed and presented to T cells by dendritic cells, macrophages, and other antigen-presenting cells, initiating adaptive immune responses to intracellular autoantigens resulting in the classical autoantibodies that characterize SLE. In parallel, dysfunction in the innate immune system, particularly dysregulated type I IFN responses, is crucial in SLE initiation and perpetuation. Nucleic acids recognized through endosomal Toll-like receptors (TLRs) and cytosolic DNA and RNA sensors are potent inducers of inflammatory responses. TLRs, particularly TLR7 and TLR9, and the cytosolic nucleic acid recognition system, including the cGAS/STING pathway [11,12,13], converge to stimulate type I IFN production. Type I IFNs are in fact a family of diverse proteins that signal through a common receptor complex [14]. Various cell types, including plasmacytoid dendritic cells (pDCs) [14,15,16,17,18], monocytes/macrophages, follicular dendritic cells, and keratinocytes [19,20,21,22,23], have been implicated as potential sources of excess type I IFN activity in SLE, as we reviewed elsewhere [1]. Exaggerated type I IFN responses are reproducibly observed in SLE patients, with elevated circulating IFN levels and IFN gene expression signatures associated with disease severity [24]. As well as having direct effects on immune cells and target tissues, type I IFN impedes glucocorticoid effectiveness [25,26,27], and targeting IFN therefore potentially provides a critically needed opportunity to reduce glucocorticoid use in SLE, in line with the latest treatment guidelines [28].

Ongoing investigations aim to uncover whether the different origins of innate immune overactivation correlate with the diverse clinical phenotypes within the broad SLE diagnostic category, potentially leading to distinct therapeutic approaches. Regardless, the success of targeting type I IFN in lupus serves as a prime example of how heeding patient data can steer the development of new therapeutics that offer the most advantage to the most patients. While acknowledging that this approach may not be universally effective, it still stands as the most beneficial strategy to have emerged in decades. Indeed, a suite of new drugs targeting type I IFN is now in development after a prolonged hiatus in the landscape of lupus treatment.

Fig. 1
figure 1

The ‘bow-shaped’ concept of type I interferon production and action in systemic lupus erythematosus. Multiple sources result in the availability of ligands, especially nucleic acids, for cell surface and cytoplasmic sensors that detect innate immune system activating stimuli. These converge by inducing the expression and release of type I interferons by several cell types, but especially plasmacytoid dendritic cells. The many type I interferon family proteins signal through a common receptor, that is in turn expressed on a wide range of immune and resident cells, resulting in a wide range of downstream effects. DCs dendritic cells, IFN interferon, NK natural killer, PMN polymorphonuclear leukocytes, TLR Toll-like receptor

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3 Pharmacological Routes Attempted and Early Clinical Trial Results

Multiple points along the IFN pathway can potentially be targeted therapeutically, including IFN production, IFN proteins themselves, and IFN signalling (Fig. 2). In the following sections we address each of these opportunities and the results of interventions designed to impact on them.

Fig. 2
figure 2

Points of intervention on the interferon (IFN) pathway in systemic lupus erythematosus (SLE). The type I IFN pathway can be addressed therapeutically at multiple levels, including (i) at the level of production through antibodies to BDCA2 found on the surface of plasmacytoid dendritic cells (pDCs), or small molecules that inhibit signalling through Toll-like receptors (TLRs) 7 and 8; (ii) at the level of IFN cytokine proteins themselves through therapeutic monoclonal antibodies or endogenous antibodies induced by vaccination, or (iii) at the level of signalling by IFN in target cells via blockade of the common IFN receptor (IFNAR) or the kinases such as TYK2 and JAK1 involved in IFNAR signalling

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3.1 Targeting the Production of IFN

The encouraging but ultimately negative results of IFN-alpha targeting (see below) were followed by approaches which sought instead to address the source of IFN. In fact, debate continues as to whether the classically considered primary source of IFN-alpha, the pDC, is indeed the primary source of type I IFNs in SLE [14]. Nonetheless, targeting pDCs directly with antibodies against the cell surface marker BDCA2 has been the subject of clinical trials. The non-depleting monoclonal anti-BDCA2 antibody litifilimab, formerly known as BIIB059, was shown in a phase I study to suppress peripheral blood IFN signatures and IFN-induced proteins in cutaneous lupus lesions [18]. Two subsequent phase II trials with primary endpoints in cutaneous lupus [16] and lupus arthritis [17] were positive (Table 1), and a phase III program is underway (Table 2). An alternative approach to targeting pDCs is via CD123, the receptor for interleukin (IL)-3, a cell surface marker for pDCs and eosinophils. A depleting anti-CD123 antibody showed encouraging suppression of IFN pathway activation in ex vivo studies of human SLE patient cells stimulated with immune complexes [29, 30].

Table 1 Completed clinical trials of agents targeting interferon (IFN) pathways in systemic lupus erythematosus
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Table 2 Ongoing phase II and III clinical trials of agents targeting interferon (IFN) pathways in SLE
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An alternative to targeting cells that produce IFN is to target mechanisms involved in IFN production, an approach potentially addressable with small molecules. As we noted earlier, there are many pathways which can entrain IFN production, but evidence including convincing genetic associations and even monogenic index cases based on TLR7 polymorphisms strongly suggest this pathway as a candidate [31]. As well as activating IFN, TLR7 signalling results in the production of multiple other pro-inflammatory cytokines, and impacts on an important subset of double-negative effector B cells that may be involved in aberrant autoantibody production in SLE [32]. Although clinical trials are yet to report, the small molecule TLR7/8 inhibitor enpatoran has been shown to have efficacy in vitro and in murine lupus models [33]; importantly, given evidence mentioned earlier that IFN in general and TLR7 in particular is involved in glucocorticoid resistance [27], enpatoran was shown to increase glucocorticoid sensitivity both in vitro and in vivo [33].

3.2 Targeting IFN Proteins Directly

Direct targeting of cytokines using monoclonal antibodies is an approach that has yielded enormous benefit in other diseases; consider the broad efficacy and safety of anti-TNF antibodies in rheumatic disease, inflammatory bowel disease, and psoriatic disease. Not surprisingly, early efforts at targeting type I IFN focused on antibodies to IFN-alpha. After a successful phase I trial which showed well-tolerated suppression of peripheral blood IFN signatures in SLE patients [34], the anti-IFN-alpha antibody sifalimumab was the subject of a phase II trial [35]. Increased herpes zoster, a not unexpected adverse event that has been observed in many subsequent IFN-targeting studies, was observed but otherwise treatment was relatively well tolerated. The trial confirmed suppression of the peripheral blood IFN signature, but was a negative trial in terms of the primary outcome of reduction in disease activity (Table 1). Analysis after adjustment for protocol violating glucocorticoid use were consistent with efficacy, a finding that was even more persuasive when analysis was restricted to the patients with a high IFN signature at baseline [35]. As we shall see, these considerations impacted on the outcome of other trials in SLE.

In contrast to these encouraging findings, a trial of another antibody to IFN-alpha, rontalizumab, was not only negative but also perplexing [36]. After a phase I study in which suppression of IFN signatures by rontalizumab was demonstrated [37], the phase II trial in SLE patients with active disease, ~ 75% of whom had baseline high IFN gene signatures, showed no difference in efficacy between rontalizumab and placebo [36] and in fact suggested superior efficacy in IFN signature negative patients, a finding that remains unexplained. It is important to consider that while gene expression signatures of IFN activation are highly reproducible overall across diverse cohorts of SLE patients [14], no common standard for measurement has been agreed upon [38], and variations in measurement and in the genes that comprise the signatures used in different studies make direct comparison challenging. It is also conceivable that the unconvincing efficacy of antibodies to IFN-alpha imply important contributions from other members of the type I IFN cytokine family.

A fascinating alternative approach to the use of antibodies to target type I IFN arose from a vaccination approach based on an ‘IFN-kinoid’ molecule which induced endogenous anti-IFN antibodies that neutralized IFN gene signatures [39]. A phase II trial of IFN kinoid was negative for the primary endpoint (Table 1), but positive for several secondary endpoints including glucocorticoid tapering and the key treat-to-target endpoint known as the lupus low disease activity state (LLDAS) [39]. Development has not been further pursued, and subsequent evidence that endogenous anti-IFN antibodies and other defects in IFN biology are associated with worse outcomes in patients with COVID-19 [40, 41] may give pause to future developments of such ‘permanent’ approaches.

3.3 Targeting IFN Signalling

3.3.1 IFNAR

All type I IFN family members signal through a common receptor complex known as IFNAR1, which in fact categorizes this cytokine family. Targeting the receptor presents the opportunity to block all type I IFNs, avoiding the potential limitations of targeting only IFN-alpha [35, 36]. Initial in vitro studies demonstrated that targeting IFNAR1 interrupted the positive feedback loop entrained by IFN-alpha as well as IFN gene signature expression induced by SLE patient serum [42]. As the clinical trials of anifrolumab to target IFNAR led to its approval, we will deal with it in detail in a subsequent section, but note here that the ability of IFNAR blockade to prevent signalling by all type I IFN cytokines, and the effect of this to shut positive pro-inflammatory feedback loops entrained by IFNs, may have contributed to the ultimately successful clinical development of anifrolumab. Side-by-side biomarker studies of blocking IFNAR versus individual IFN family cytokines would be extremely informative in this regard, but are unlikely to be done.

3.3.2 TYK2 and JAK1

Signalling through IFNAR is transduced via the receptor kinases TYK2 and JAK1, which in turn phosphorylate STAT1 and STAT2 resulting in direct effects on gene transcription through STAT binding sites in gene regulatory and promoter regions. Although not specific to the IFN pathway, the JAK1/2 inhibitor baricitinib (which is approved in several other inflammatory disease indications) showed clinical effects in a phase II trial that were encouraging [43]. These clinical results were supported by post-hoc biomarker studies showing convincing inhibition of pathways activated by IFN [44]. However, these findings did not translate to convincing results in two subsequent large phase III trials, with one trial positive and another negative for the primary outcome [45, 46] (Table 1), and with neither showing evidence of benefit in secondary outcome measures. Importantly, these trials did not include mandatory glucocorticoid tapering, an approach suggested by some of the earliest IFN targeting trial data as noted earlier [35], and the development of baricitinib in SLE has been abandoned. Another JAK inhibitor, upadacitinib, has had positive phase II trial results reported in abstract form only [47] (Table 1) but has proceeded into phase III trials (Table 2). Interestingly, in that study, upadacitinib was studied both alone and in comparison with and in combination with the Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib, which appeared to have no effect either alone or in combination [47].

TYK2 transduces signalling by type I IFN, IL-12, IL-23, and IL-10, a set of signals distinct from those transduced by JAK1, JAK2, and JAK3 [48]. Polymorphisms in TKY2 have been associated with SLE and other autoimmune diseases [49]; in addition, TYK2 is not involved in growth factor signalling, suggesting the potential for a safety profile differentiated from that of JAK inhibitors. An oral small molecule TYK2 inhibitor, deucravacitinib, has been approved for the treatment of psoriasis, and a phase II clinical trial in SLE was positive with suppression of IFN gene signature accompanied by significant responses across multiple endpoints including LLDAS for the 3-mg twice-daily dose [50] (Table 1). As for litifilimab, confirmation of the efficacy in SLE of deucravacitinib in phase III is required, and while this is ongoing it is challenging as we discuss below.

4 Clinical Development of Anifrolumab

As noted above, anifrolumab is a human monoclonal antibody to IFNAR1, the receptor for all type I IFNs. After in vitro studies demonstrating comprehensive blockade of INFAR signalling, anifrolumab was first tested in phase I studies in systemic sclerosis [51]. The phase II ‘MUSE’ trial in SLE compared two doses of anifrolumab, 300 mg and 1000 mg, both administered intravenously on a monthly basis, in a study using a primary outcome measure that required glucocorticoid tapering as well as reduced disease activity [52]. This trial showed a significant difference in efficacy between anifrolumab and placebo for this outcome measure (Table 1), as well as for other secondary measures including the SLE responder index (SRI) and BILAG-based composite lupus assessment (BICLA), while post-hoc analysis also showed higher attainment of LLDAS with anifrolumab treatment [53]. These findings led to two phase III trials of anifrolumab 300 mg/month, and here ‘the plot thickens’. The first trial to report, TULIP-1, was negative, with similar numbers of patients achieving SRI response with anifrolumab and placebo [54]. In this trial, concomitant medication rules were found to have been applied to the analysis in a way that did not reflect the clinical intent; for example, over-the-counter NSAID use for an intercurrent headache could result in non-responder classification, although post-hoc analysis altering these rules did not affect the primary outcome. Although not formally analysed because the primary outcome measure was negative, odds ratios and confidence intervals for endpoints other than the primary outcome measure appeared positive, especially the BICLA endpoint which had also been positive in the phase II trial [52].

As a result, and with prior approval from regulatory agencies and prior to database lock, the primary endpoint for TULIP-2 was changed from SRI to BICLA and the revised medication rules applied. TULIP-2 was positive, with multiple secondary outcome measures also positive [55]. Despite one of the pivotal trials being formally negative, regulators have approved anifrolumab as add-on therapy for moderate to severe active SLE, presumably on the basis of the totality of evidence. Since then, numerous post-hoc analyses have been reported, showing evidence of benefit in skin, joint, and haematological domains of lupus [56], supporting a glucocorticoid-sparing effect [57], reducing flares [58], demonstrating increased attainment of LLDAS and remission [59], and demonstrating acceptable safety [60]. Importantly, increased rates of herpes zoster reactivation, first noted in the first IFN targeting studies nearly 10 years earlier, were observed in anifrolumab-treated patients. A total of 34 patients had herpes zoster-related adverse events in the two TULIP trials; two patients ceased therapy, one of whom had confirmed herpes zoster transverse myelitis. All other events were of mild or moderate severity, all responded to antiviral therapy, and patients continued therapy. Anifrolumab was also associated with increased vial respiratory infections but was otherwise well tolerated [60]. Most recently, a 3-year long-term extension study, which, unusually, was placebo controlled, showed enduring effects of anifrolumab on disease activity and glucocorticoid reduction, and acceptable safety with lower rates of herpes zoster reactivation in years 2–4 [61]. Several cases of COVID-19 were reported in anifrolumab-treated patients; the study was mostly completed in the pre-vaccination era and no cases were reported in vaccinated subjects [61].

Development of anifrolumab in lupus nephritis is at an earlier stage. A phase II trial in lupus nephritis was completed, yielding a negative result for the primary outcome in the 300-mg/month dose group but showing more encouraging results for a regimen including 900-mg doses in the first 3 months [62]. A long-term analysis of data from this study suggested that this anifrolumab regimen was associated with higher rates of both complete renal response and glucocorticoid tapering at year 2 [63]; these data provided the rationale for a phase III trial in LN which is underway (Table 2).

5 Lessons Learned

Although the journey to approval of any new medicine is long and complex, the approval of a new class of medicine for SLE after a long hiatus provides the opportunity to reflect on what can be learnt from that journey. First, we believe the efficacy of anifrolumab makes it clear that IFN is important in the pathogenesis of SLE, with a ‘Koch’s postulate’ triad of evidence including the presence of IFN in disease, induction of disease by exogenous IFN in humans [64, 65], and the benefit of targeting IFN therapeutically. Case reports have begun to emerge of impressive clinical responses to anifrolumab even in patients resistant to B-cell–targeting therapies such as rituximab or belimumab [66, 67]. Although responses to IFNAR blockade are clearly superior to placebo, attainment of validated treat-to-target states such as low disease activity [68] and remission [69] are less than optimal, with post-hoc analysis of the two phase III trials showing that only around one third of patients achieve either state [59]. That this is the case despite clear suppression of IFN activity, as evidenced in IFN gene signatures, is a reminder that pathways which are independent of IFN remain important in SLE and that alternative approaches are still needed. Nonetheless, consideration of IFN blockade with anifrolumab is recommended in the recently updated European treatment guidelines for all SLE patients other than those with mild disease responsive to antimalarials and low-dose glucocorticoids [28].

In relation to IFN gene signatures, a further question is posed but the lessons to be learnt are unclear. Each of the IFN-targeting drugs we have reviewed here apart from upadacitinib had been reported to have suppressive effects on peripheral blood IFN gene signature expression in SLE patients. Direct comparison between agents studied in different trials and responses measured using different combinations of genes is not possible, but it may be that blockade of all type I IFN signalling via targeting the common receptor is more powerfully suppressive of IFN signatures; without a head-to-head comparison it is not possible to definitively conclude that this explains the overall positive results of clinical trials of anifrolumab that led to its approval. A recent review has highlighted the many issues that need to be addressed before IFN signature testing can become routine practice [70]. In the case of anifrolumab, the difference between response to drug and placebo was greater in IFN signature ‘high’ patients than in IFN ‘low’ patients, but this was driven by higher placebo responses in IFN ‘low’ patients while responses to anifrolumab were similar [71]. In our centre, IFN signature testing is not used in clinical practice and it is not generally recommended in recently updated SLE management guidelines [28].

Thirdly, the long list of negative or conflicting phase II and III trials of SLE treatments continues to signify that drug development in this disease is challenging; witness the discordant baricitinib phase III trial results [45, 46] and the ‘narrow escape’ for anifrolumab approval. What are the factors that lead to these discordant outcomes in parallel phase III trials in essentially identical study cohorts? Biological heterogeneity among patients classified clinically has having SLE is well described; notably, the SLE classification criteria, revised in 2019, do not refer to any biological concepts [72], meaning different biologies resulting in similar clusters of clinical manifestations are currently classified together. In turn, this means that therapies that specifically target a given biology may fail to impact on many patients in a given trial, and even large cohort sizes may be insufficient to balance this heterogeneity between studies. Parallel phase III trials are often performed in non-overlapping countries or centres, and the well described variation in SLE phenotype between ancestries [73], and even between countries of different national wealth [74], may impact on trial outcomes too.

Finally, we have come to understand that alongside biological heterogeneity, negative, discordant, or difficult-to-interpret trials are likely also due to a combination of issues relating to patient selection, study design, and outcome measures. Patients need us to be better at these human-assigned aspects of testing the efficacy of drugs in SLE in clinical trials; indeed, the Lupus Foundation of America has identified better outcome measures as a critical need in improving the lives of patients with SLE [75]. We recently reviewed the many issues with current outcome measures that contribute to these challenges [76]. As one example, the use of SRI as a primary outcome measure dictates the use of the SLE disease activity index (SLEDAI) as the disease activity measure, despite SLEDAI not being designed to measure responses to therapy. Spurred by these issues, a major global effort supported by academia, industry, and patient organizations has launched a project to develop a novel primary outcome measure for SLE trials, adhering to contemporary measurement and regulatory principles [77]. In that program, a ‘clean slate’ approach is being taken, beginning with enumerating the domains of disease involvement that are important to patients and then planning novel ways to assess response to therapy in each domain, for example using continuous variables and individual patient baselines, to ultimately yield a multi-domain instrument which can characterize individual patient responses across the heterogeneity of disease.

6 Future Drug Selection in SLE

Advancements in our understanding of SLE continue to reveal the cellular and molecular mechanisms underlying the disease. Such discoveries are made by immunologists, geneticists or clinicians, but synergize when multidisciplinary teams collaborate with a singular focus. The development of type I IFN-targeting therapies showcases the effectiveness of collaboration between basic and translational researchers, clinicians, and industry partners to advance transcriptional and biological observations in humans into treatments that are now utilized in the clinic.

Innovative technologies change the nature and speed at which these advancements are made. Genomic studies unveil genetic variants that can offer insights into potentially aberrant pathways in individual patients [31], guiding the selection for therapeutic strategies in a stride towards personalized medicine for lupus. Beyond the genome, transcriptomic and proteomic studies can identify gene expression signatures, revealing biomarkers, novel pathogenic or protective biological mechanisms, and potential drug targets. SLE lacks biomarkers that are reliable indicators of disease activity, severity, and organ involvement, or could guide treatment selection, predict response, and influence novel target candidate identification. However, the identification of the type I IFN signature was a notable exception, sparking comprehensive enquiries into the contribution of IFN to SLE pathogenesis and facilitating the development of the suite of therapeutics targeting this pathway, as reviewed here.

Novel candidate identification can be expedited using emerging massively parallel techniques such as high-throughput CRISPR screening. This allows identification of key cellular pathways involved in a specific customizable readout, to generate a short list for validation and further experimental testing. Circling back to fundamental biological studies is crucial in this process, as is exploring connections between candidates and clinical phenotypes through in-depth analysis of large gene and protein expression datasets. This is particularly advantageous when clinical data are detailed, allowing for multivariate analyses to pinpoint correlations of the gene expression with disease activity. Machine learning will be especially convenient for this type of study.

As was exemplified for the type I IFN pathways, candidate targets need rigorous validation studies in vitro and in vivo using animal models or preferably ex vivo patient samples. In parallel, the feasibility of selectively modulating candidate targets can be assessed and an appropriate modality chosen, such as small molecules, monoclonal antibodies or nanobodies, gene or cell therapies. The cost, treatment method, and distribution considerations of these modalities vary substantially and dictate future market access, together with safety and efficacy. Multidisciplinary scientific teams working with industry partners from an early point to advise and share knowledge can increase the likelihood that the biology has a pathway towards translation and commercialization, speeding the pathway to market. Likewise, engagement with patient groups leads to incorporation of their perspectives and priorities, a crucial element in the drug development process. Finally, improvements in the way treatment responses are measured, biomarker-based patient selection, and close attention to critical success factors such as glucocorticoid tapering, are needed to ensure that high late-clinical trial failure rates in SLE are a thing of the past [76].

We believe this comprehensive approach, integrating diverse disciplines and perspectives from the outset, offers the most effective strategy to develop more therapies for SLE beyond anifrolumab. As we fill and progress the therapeutic pipeline, it is imperative to learn from the collaborative success exemplified by targeting IFN in lupus and expedite it, mirroring the accelerated approach witnessed in the development of therapeutics and vaccines during the COVID era. Lupus patients have waited long enough—while upholding rigorous standards for safety and efficacy, let us not delay the delivery of innovative therapies.