Advances in the treatment of systemic lupus erythematosus: Biologicals, small-molecular agents, and cell-depleting therapies coming to the clinic.

General introduction

Systemic lupus erythematosus (SLE; lupus) is an uncommon but not rare multisystem autoimmune disease that can occur at all ages but disproportionately affects women of childbearing age [ 1 ]. It is highly heterogeneous in its clinical manifestations, potentially involving virtually all organ systems. Among the more frequent clinical manifestations are various types of skin inflammation, ranging from acute to chronic, arthritis and other musculoskeletal involvement, renal disease (lupus nephritis; LN), hematological manifestations, central nervous system (CNS) disease, and others (Fig. 1 ). Along with these organ‐specific inflammatory manifestations, patients may experience profound fatigue, cognitive difficulties, and general malaise. The clinical symptoms and signs of lupus are invariably accompanied by evidence of autoimmunity that usually takes the form of multiple autoantibodies [ 2 ]. Antinuclear antibodies are present in nearly all patients, whereas other more specific antibodies—such as anti‐DNA, anti‐RNP, anti‐Sm, anti‐Ro, anti‐La, anti‐nucleosome, and others—are seen in variable percentages of patients [ 3 ]. Along with these autoantibodies, low complement levels are frequently seen as the result of complement activation, which indirectly represents the presence of immune complexes [ 4 ]. In addition to these clinically available immunological tests, in lupus patients it is possible to demonstrate multiple abnormalities of various immunological parameters representing virtually all compartments of the immune system, both innate and adaptive [ 5 ]. Of particular interest is the finding, going back several decades, that the Type 1 interferon (IFN) system is overactive in many patients with lupus [ 6 , 7 ]. For clinical detection, the so‐called interferon signature has been employed—a test done on peripheral blood mononuclear cells that detects the upregulation of sets of genes that are controlled by Type 1 IFN, thereby indicating excessive activation of that system [ 8 ].

The treatment of lupus is challenging at many levels, and the responsibility for it is shared by many different specialists, depending on the presentation in each patient. For many patients, close interaction and collaboration between these specialists is needed. Treatment recommendations have been issued by large international organizations, including the European Alliance of Associations for Rheumatology [ 9 , 10 ] (summarized in Fig. 2 ) and the American College of Rheumatology [ 11 ]. Such recommendations, and many national and regional ones that have echoed them, have been cited extensively and commented upon [ 12 ]. They generally present both general treatment principles and more specific guidance as to the use of individual drugs for particular manifestations of lupus or for the disease as a whole.

The current therapeutic armamentarium and treatment recommendations

The treatments that are available to clinicians and patients with SLE fall roughly into four categories: antimalarials, glucocorticoids (GCs), conventional immunosuppressants, and biologicals (Table 1 ).

As all these drugs have been reviewed elsewhere, I will here merely give some brief comments in order to illustrate strengths and weaknesses, hoping to indicate where these may lead us in the future.

The first line of treatment is generally held to be the use of antimalarials , in particular hydroxychloroquine (HCQ). During the Korean War, predecessors to this drug were serendipitously discovered to have beneficial effects in patients with various rheumatic diseases, and over time HCQ emerged as the drug of choice among the antimalarials owing to its mostly favorable benefit–risk profile [ 22 ]. Its efficacy was demonstrated in some randomized trials of modest size [ 23 , 24 , 25 ], but its benefits were mostly demonstrated in long‐term observational studies, many of which have used advanced methodologies to allow accurate comparisons even in the absence of randomization, such as propensity matching [ 26 , 27 ]. Many authorities consider HCQ to be the mainstay of treatment for lupus. International recommendations support its use for all patients with SLE, if no contraindications exist, and lifelong treatment is the norm. Although the efficacy may be well‐established, it can also be recognized that HCQ is not a very strong drug and that many patients, while benefitting from its use, also suffer from persistent disease activity and/or flares despite it [ 28 ]. HCQ has a very slow onset of action, and in the long run it is rarely sufficient treatment for the patient with SLE. HCQ is considered a safe drug in most patients, having few limiting toxicities in the clinic. Particular concerns are the risks that are associated with long‐term cumulative dosage and that include retinopathy [ 29 , 30 ] and less frequently myocardial toxicity [ 31 ] and ototoxicity [ 32 ]. Although studied much less, other antimalarials, such as quinacrine, may also be effective in some patients, particularly those with cutaneous lupus [ 33 ].

GCs have a unique place in the treatment of lupus due to their very rapid clinical benefits that may provide relief for the patient with active lupus within a matter of hours or days. For most patients with SLE, treatment with GCs will sooner or later be necessary, usually in the setting of a flare of the disease. Unfortunately, the longer term use of GCs is problematic on account of cumulative toxicities, which have received more attention in recent years than was the case earlier. These are highly dose‐dependent, and there is general agreement that dosages of GCs for chronic use should be restricted to prednisone (or equivalent) at 5 mg/day or less, whereas it is also recognized that slightly higher dosages may at times be accepted. There are several distinct uses of GCs for SLE [ 34 , 35 ]. In the setting of a severe, organ‐ or life‐threatening flare, high‐dose GCs are given, sometimes in the form of intravenous pulse therapy (e.g., 1000 mg/day for 3 days [ 36 ]) and/or oral GCs at dosages of 0.5–1.0 mg/kg/day (prednisone equivalent). In view of long‐term risks and side effects, such high dosages are always followed by attempts to taper. For moderate flares, intermediate dosages of oral GCs are often used (15–20 mg/day), the main reason being rapidity of action. For long‐term disease control, it was long accepted that low‐dose GCs (e.g., 5 or 7.5 mg/day) was an acceptable option. Recent research has made it clear that the disadvantages of such dosages are not negligible, whereby the recommended maximum dosage for longer term use in most recommendations is now 5 mg/day, and increasingly more authorities recommend always attempting to taper to zero. Besides their systemic use, GCs maintain an important role as local (skin creams) or intralesional (intra‐articular) therapies.

Conventional immunosuppressives include primarily azathioprine, methotrexate, and mycophenolate mofetil (MMF), although older medications, such as cyclosporin A, are used rarely, and other immunosuppressants have mostly been used in specific disease manifestations, such as tacrolimus in LN. The conventional immunosuppressives share a number of features. None of them were specifically developed for lupus: They were either antineoplastic agents or used as immunosuppressives in transplant recipients. Because they entered the therapy area many decades ago, the evidence base for their effectiveness in lupus is less robust and more fragmented than for newer agents; MMF being the one among them that was studied the most [ 37 ]. On the other hand, because they are widely used in other diseases as well, our knowledge about their risks and side effects is quite considerable, and in experienced hands they can represent useful therapeutic options for many patients. These agents are all slowly acting medications, requiring at least 3 months and often more to achieve full efficacy. They are associated with risks that must be monitored through laboratory testing (primarily, hepatotoxicity and bone marrow suppression). Despite these drawbacks, the conventional immunosuppressives are widely used and recommended for patients with insufficient disease control on antimalarials and GCs, often being considered “steroid‐sparing agents.” In the end, their use is mostly limited by the occurrence of side effects and by incomplete responses in many patients.

Biologicals : In the past 15 years, two biologicals, belimumab and anifrolumab, have been approved for the treatment of SLE; recently, a third biological, obinutuzumab, was approved for LN. In addition, the biological rituximab (RTX) has been used quite widely for SLE despite never having been formally approved [ 20 ]. Some other unapproved biologicals are used very infrequently and will not be discussed here further.

Belimumab is a monoclonal antagonist of B‐cell activating factor (BAFF) (Blys), a B‐cell‐stimulating cytokine. It was approved on the strength of two large Phase III clinical trials that demonstrated its efficacy [ 14 , 15 , 16 ]. A subsequent pooled analysis showed that belimumab was particularly effective in patients with elevated anti‐DNA antibodies and low complement [ 38 ]. Besides achieving the primary outcome in its clinical trials, belimumab was also shown to reduce the frequency of flares, reduce GC requirements [ 39 ], and reduce long‐term damage [ 40 ]. Being a parenteral therapy, it can be given as monthly infusions or as weekly injections. The safety profile of belimumab has been very good; infections and psychiatric side effects appeared to increase in the trials and in a large non‐randomized comparator study, but at such low levels that the favorable benefit/risk ratio is still maintained. Both from studies and from practical experience it became clear that belimumab is a slow‐acting drug that requires 3–6 months to achieve full efficacy. In more recent years, it was also approved for the treatment of LN (see below).

Anifrolumab is a monoclonal antagonist of the Type 1 IFN receptor. The IFN system was shown to play a key role in the pathophysiology of SLE, with a demonstrable “interferon signature” in the majority of patients [ 6 ]. Anifrolumab was approved on the strength of two large Phase III clinical trials that demonstrated its efficacy [ 17 , 18 ]. A pooled analysis of these trials suggested that although anifrolumab was effective in patients with an IFN signature, its efficacy in those without it could not be demonstrated [ 41 ]. Besides overall efficacy in clinical trials, anifrolumab was also shown to reduce the frequency of flares and to reduce GC requirements. As a parenteral therapy, it is given as monthly infusions; a recent study supports its use as weekly injections, which must yet be fully evaluated [ 42 ]. The safety profile of anifrolumab has revealed few major concerns, the only infection with a clear overrepresentation upon treatment being varicella‐zoster virus recrudescence (herpes zoster), and the agent is, therefore, felt to have a favorable benefit/risk ratio. Both clinical studies and practical experience attest to the fact that anifrolumab is particularly beneficial for patients with cutaneous manifestations of lupus, and these benefits are often observed within weeks of starting the treatment [ 43 ]. Nonetheless, this drug may also require 3–6 months to achieve full efficacy.

RTX is an anti‐CD20 monoclonal antibody that depletes B‐cells from the peripheral blood. It was approved for rheumatoid arthritis and vasculitis and tested in two randomized trials for SLE; both were negative [ 44 , 45 ]. Nonetheless, many case series and observational studies suggest its efficacy, especially for more serious manifestations of lupus and/or nephritis [ 21 , 46 ]. RTX treatment can be associated with infusion reactions, hypogammaglobulinemia, and some risk for infections. During the COVID‐19 pandemic, it was clearly shown to worsen the prognosis for those infected [ 47 ], and it interferes with vaccine efficacy [ 48 ]. Nonetheless, its benefits are felt to outweigh its risks in many clinical situations. As an off‐label treatment, its use is constrained by non‐medical issues, but it has continued to be used in patients with severe and refractory disease.

New therapeutic strategies for lupus nephritis

For several reasons, LN is often dealt with separately when it comes to the treatment of SLE. In part, this reflects that, in patients with LN, the treatment of this organ manifestation frequently (but not always) takes precedence over treatment of other organ manifestations. It also reflects that there have been many trials investigating the appropriate treatment of LN, so our cumulative knowledge of such treatments is more robust than for other organ manifestations. In the case of LN, the stakes are high: Failure of treatment means loss of kidney function. Some aspects of LN may be amenable to treatment that would not be expected to benefit other manifestations, such as antiproteinuric agents.

For many years, the standard therapy for LN was based on the use of MMF, which in this case is considered to be both an induction [ 49 ] and a maintenance therapy [ 50 ], or cyclophosphamide, primarily in the form of the so‐called Euro‐lupus schedule as an induction therapy of six biweekly infusions of 500 mg followed by maintenance therapy with azathioprine [ 51 ]; the latter drug has often been replaced by MMF in recent years. Both of these therapies are combined with GCs in the initial phases, often as initial pulse treatment intravenously and high‐dose oral dosing followed by a taper.

In recent years, two biologicals and a small‐molecular agent have been approved specifically for the treatment of LN. Belimumab , already in wide‐spread use for SLE, was approved for LN on the basis of a single randomized clinical trial that demonstrated how it increased, when added to standard therapy, the likelihood of a renal response [ 15 ]. More recently, the B‐cell‐depleting agent obinutuzumab —an anti‐CD20 monoclonal that is different from RTX in some respects but not in its core mechanism—was approved on the basis of a trial showing that its addition improved outcomes [ 52 ]. It is used as a treatment course of two infusions, which are then repeated at 6 monthly intervals. In the pivotal trial, efficacy was seen in the course of the first few months following treatment, and the treatment was well tolerated by most patients. Infusion reactions were sometimes seen, along with an increase in infections, including some with COVID‐19. The calcineurin inhibitors (CNIs) may be expected to be effective in SLE and LN owing to their immunosuppressive properties, but they are also highly effective antiproteinuric agents due to a direct effect on podocytes. For this reason, their use in LN may be particularly beneficial. The older CNIs, cyclosporin A and tacrolimus, were never approved for use in SLE or LN but have been used off‐label in selected patients for decades. The newer CNI voclosporin was approved for LN in recent years. Voclosporin is thus a small‐molecular immunosuppressant with structural similarity to cyclosporin A. Indeed, a randomized clinical trial confirmed efficacy for voclosporin in the key outcomes of the trial [ 53 ]. Voclosporin is also well tolerated, and in contrast to cyclosporine, it does not appear to be associated with hypertension. The original CNI cyclosporin A is rarely used in LN because of its side effects: hypertension and renal fibrosis. There has been interest in the use of tacrolimus , and several studies primarily in Southeast Asia have compared it with MMF; in these studies, tacrolimus achieved higher rates of renal response [ 54 , 55 ]. The main potential side effects of tacrolimus are tremors and polyneuropathy.

Treatment strategies

The heterogeneous and unpredictable nature of SLE tends to influence clinicians into treating their patients reactively, basing decisions on the basis of the immediate needs of the patient. In some respects, this is natural and appropriate: A flare needs to be treated immediately and with the most effective therapy, which, in many cases, involves the use of GCs. Likewise, treatment‐related side effects must also be dealt with expeditiously and may prompt a change in treatment. However, in the more chronic management situation, the reactive mode is not ideal. Many patients do not become truly symptom‐free [ 56 ], and a focus on relieving short‐term symptoms may end up doing the patient a disservice by distracting from the longer term goals. For these reasons, the “treating to target (T2T)” approach for lupus has been advocated [ 57 ]. This treatment approach was demonstrated to be superior to standard care in many non‐rheumatological diseases (e.g., hypertension and diabetes) and also in rheumatoid arthritis [ 58 ] and psoriatic arthritis [ 59 ]. T2T entails several steps: First, a clear treatment goal must be articulated. The goal is often clinical remission but may also be formulated as the absence of flares or improved quality of life. Second, therapeutic steps must be taken to try to achieve that goal. Third, the success of this intervention must be assessed after a time interval that is appropriate for the intervention. Fourth, and perhaps most importantly, if the target was not achieved, other steps must be taken to try to achieve it. These four steps are illustrated in Fig. 3 [ 60 ].

A few important notes to the T2T approach must be made. The superiority of T2T over regular care is not (yet) formally proven for lupus, yet many organizations have recommended this strategy based on indirect evidence. Currently, a randomized trial is underway to demonstrate the efficacy of this approach [ 61 ]. The interventions chosen in steps (1) or (4) need not necessarily be the introduction of a new treatment; they could equally well be the adaptation of an existing treatment (changing the dosage), adding a non‐pharmacological intervention, or having a conversation to optimize adherence [ 62 ]. The most important principle is not to accept the status quo if it is manifestly not consistent with the expressly articulated target.

It is important for the patient to be an active partner in the T2T approach. Human nature being what it is, patients may well feel that a suboptimal disease state (say, a smoldering disease with flares every now and then) is acceptable because the alternative—a change in their treatment—may seem intimidating. Although the patient's choice in the end must be decisive, it is in this situation that a clear explanation of the longer term perspective is called for [ 63 ]. Moreover, to employ a T2T approach in clinical practice is challenging for the physician, placing an additional burden on an already complicated medical situation. It is, therefore, not surprising that the T2T strategy, while widely recommended, is not used as widely in practice. Recently, we published a web‐based application that may help the practicing physician to treat according to T2T in practice [ 64 ]; the app has also been beta‐tested in four clinical sites in the Amsterdam region and has met with approval from both physicians and patients [ 65 ]. Further studies and implementation of this device are planned.

Current developments: new treatments in late‐stage clinical development

Several new biologicals and small‐molecular targeted therapeutics are currently in late‐stage development for SLE and may, therefore, become part of the treatment armamentarium for this disease in the coming years (summarized in Table 2 ). Deucravacitinib (Sotyktu) is a small molecular blocker of the tyrosine kinase Tyk‐2, a member of the Janus kinase (JAK) family [ 66 ]. Dimers consisting of Tyk‐2 and either JAK1 or JAK2 are needed for transducing signals to the cell nucleus following binding to their cognate receptors by several cytokines of potential importance in the pathophysiology of lupus, most importantly Type 1 IFN. It was therefore not unexpected that efficacy was demonstrated in a robust Phase II clinical trial [ 67 ], and two large Phase III trials are currently underway. Deucravacitinib has been approved for use in psoriasis, and both the large clinical trials in that disease [ 68 ] and clinical experience [ 69 ] suggest that it is generally a well‐tolerated and safe drug. The occurrence of acne vulgaris has been noted as a specific side effect. Deucravacitinib is also tested for various other conditions. Litifilimab is a monoclonal antibody directed against the BCMA‐2 receptor that is found almost exclusively on plasmacytoid dendritic cells, a low‐frequency subtype of peripheral blood leukocytes that is considered one of the main producers of Type 1 IFNs, along with other cytokines [ 70 ]. Litifilimab does not deplete these cells, but after binding, it is internalized, and intracellularly, it disrupts the production of IFNs, resulting in diminished IFN levels and a rapid normalization of the IFN signature in a dose‐dependent manner [ 71 ]. Modestly sized earlier trials supported efficacy and good tolerability [ 72 , 73 ], and currently two large Phase III trials are ongoing. Litifilimab is developed both for the treatment of SLE and for the treatment of cutaneous lupus as a separate disease entity. Cenerimod is a small‐molecular antagonist of the sphingosine‐1‐phosphate receptor [ 74 ]. By blocking this receptor, lymphocyte efflux from lymph nodes and lymphocyte trafficking are reduced. Fingolimod was the first medication built on these mechanisms, and it was proven beneficial and approved for use in multiple sclerosis. Several other molecules in this class are also being used and/or tested in various indications. In a robust Phase II clinical trial, cenerimod was investigated as a treatment for SLE; although the primary endpoint was not met, secondary analyses suggested efficacy and good tolerability [ 75 ]. The drug is currently being investigated in two large Phase III trials. It would represent a new mechanism of action for SLE. Dapirolizumab pegol (DZP) is a biological construct based on the Fab fragment of an antibody directed against the CD40 ligand (CD40L), stabilized by the addition of polyethylene glycol (similar in construction to the antirheumatic drug certolizumab‐pegol) [ 76 ]. Thus, the molecule is expected to interfere with the CD40‐CD40L interaction that is important in T‐cell activation, whereas the lack of an Fc region ensures that it does not signal or cause downstream activation events. The latter is particularly important as earlier studies using anti‐CD40L led to thromboembolic complications through platelet activation. A smaller Phase II trial of DZP did not meet its primary endpoint [ 77 ], but a more recent Phase III trial was reported to have met primary and secondary endpoints [ 78 ]. An additional Phase III trial is currently ongoing, and the drug is also being evaluated for LN. As in the case of cenerimod, the importance of this development lies in the fact that it represents a different mechanism, adding the principle of T‐cell inhibition to the already existing options of B‐cell inhibition/depletion and IFN antagonism. The anti‐CD20 monoclonal obinutuzumab , discussed above, was investigated in a large Phase III clinical trial for general lupus. The results of this trial were recently announced in a press release ( https://www.roche.com/media/releases/med‐cor‐2025‐11‐03 ). It was stated that the trial met its primary and all secondary endpoints, but no specific figures were given, and that safety was in line with the known profile of the drug. Ianalumab is a monoclonal antibody directed against the BAFF‐receptor [ 79 ]. While originally intended as a cytokine antagonist, it has become clear that it depletes BAFF+ cells—that is, B‐cells. It may therefore be considered in the same group of agents as RTX or obinutuzumab, but the added contribution to efficacy by also blocking the BAFF receptor cannot yet be fully evaluated. In a modestly sized Phase II trial in SLE, efficacy was demonstrated [ 80 ], and currently two large Phase III trials in SLE and one in LN are underway. Importantly, this drug demonstrated efficacy in Sjogren's disease in two Phase III clinical trials and may, therefore, be approved for that indication while still being investigated for SLE. The oral JAK inhibitor upadacitinib is widely used for the treatment of rheumatoid arthritis and several other rheumatological and non‐rheumatological indications [ 81 ]. In a Phase II trial, it showed efficacy in SLE [ 82 ], and it is currently being investigated in two Phase III trials.

Anifrolumab , already approved for SLE, was tested in a modest‐size Phase II trial in LN [ 89 ]. The primary endpoint was not met, but positive signals [ 90 ] prompted the initiation of a currently ongoing Phase III trial.

Finally, telitacicept has a peculiar development history leading to an unusual global situation. It is a biological construct based on the naturally occurring TACI receptor (found on B‐cells) linked to an IgG framework (similar in construction to, e.g., etanercept) [ 87 ]. Because TACI is the receptor for both BAFF (Blys) and a proliferation‐inducing ligand (APRIL), telitacicept will block the activity of both these B‐cell cytokines. This distinguishes its mechanism from that of belimumab, which blocks BAFF but not APRIL. The expected result is a more profound down‐regulation of B‐cells that even includes down‐regulation of plasma cells. Lowered immunoglobulin level is an expected pharmacodynamic effect. Telitacicept was developed and tested in China, and authorities in that country granted preliminary approval of the drug for the treatment of lupus already in 2021 and a full approval in 2023. These results were based on a large Phase II trial followed by a Phase III trial [ 88 ], both done in China. Since then, more than 80,000 patients have been treated with it, making it one of the most widely used drugs for lupus in the world. Yet, in other parts of the world it is not available, and no trials for lupus are currently ongoing in Europe, North America, or elsewhere. Telitacicept is being developed for other autoimmune diseases besides lupus, including Sjogren's disease; the latter indication is being pursued worldwide.

Cellular therapies and other advanced approaches

Chimeric antigen receptor‐expressing autologous T cells (CAR‐T cells) are a novel, high‐tech treatment modality developed over the past decade, primarily for the treatment of hematological malignancies [ 91 ]. The principle of this approach is that the patient's T lymphocytes are harvested through a pheresis procedure and subsequently modified in vitro so as to express a specific T‐cell receptor. The construct may also involve ancillary molecules that play key roles in subsequent steps. These modified T cells, now called CAR‐T cells, are then reinfused into the patient, where they expand and kill cells that carry the ligand corresponding to the inserted T‐cell receptor. The entire procedure runs over the course of several weeks and is illustrated in Fig. 4 .

The most commonly used CAR‐T cells at the current time are those that have a T‐cell receptor targeting CD19, a pan‐B cell marker, or blood dendritic cell antigen, a marker for plasma cells. The result of treatment with anti‐CD19 CAR‐T cells is a profound B‐cell depletion, which, in contrast to that seen with monoclonals, may extend to B‐cells that are present deep in lymphoid tissues. Although CAR‐T cells have been approved for the treatment of hematological malignancies, such as B‐cell lymphomas, leukemias, and multiple myeloma, over the past several years, a number of case series and case reports have described patients who were treated with CAR‐T cells for autoimmune diseases, and among these, many had SLE and/or LN. By their very nature, these reports are scattered and differ widely in patient selection, the exact treatments used, and assessments. The most noted published reports of this therapy include a series of five lupus patients treated with anti‐CD19 CAR‐T cells in Erlangen, Germany [ 92 ], and a report from the same center describing 15 patients, including those first ones, but with longer follow‐up [ 93 ]. From this case series and additional cases and small series, the message that emerges is that many patients with severe disease responded very well to the treatment, and, perhaps most importantly, at least some of them were able to maintain a clinical remission for many months or years without the need for further treatment. Based on these reports, formal trials have also been started.

Many aspects of the CAR‐T cell therapies are unique to this approach and clearly distinguish it from the treatments that were discussed above, in part because technical details of the production of CAR‐T cells reflect the impressive complexity of molecular medicine. Moreover, early experience with CAR‐T cells in hematology showed that patients must be pre‐treated with cytotoxic agents in order for the CAR‐T cells to be able to expand in vivo after reinfusion into the patient. In hematology, the pre‐treatment of choice has evolved to consist of cyclophosphamide plus fludarabine. The former drug is of course known in rheumatology and was an essential treatment for severe lupus during many decades [ 94 ]; however, the dose used for pre‐treatment is higher than what was typically used for lupus and is given once, whereas cyclophosphamide for the treatment of lupus was typically given at lower dosages but for prolonged periods of time (6–24 months) rather than as a one‐off treatment. And fludarabine was never a standard treatment in the treatment of lupus. Thus, it is not easy to answer the question of what the expected clinical effects of this combination would be in patients with severe lupus. Most experts feel that the benefits seen in cases of lupus patients treated with CAR‐T cells cannot be attributed to the pre‐treatment. However, some side effects or negative consequences of such pre‐treatment, including potential effects on fertility, would have to be weighed carefully for patients with a nonlethal disease [ 95 ].

Having thus been pre‐treated, the subsequent CAR‐T cell treatment requires the patient to be free of immunosuppressants, as these would otherwise interfere with the effect of the CAR‐T cells. As a result, the early experiences with CAR‐T cells in lupus led to a situation where treatments were completely stopped and, thankfully, did not need to be restarted for long periods of time—in some cases for years [ 93 ]. This observation has generated a great deal of enthusiasm, as it suggests that a more permanent change in the nature of the autoimmune disease has been achieved [ 96 ]. That suggestion was further bolstered by studies that showed how the B‐cell compartment, as it was repopulated following the complete depletion, did not show typical autoimmune aspects any longer [ 97 , 98 ]. This has been described as an “immune reset” or an “immunological remission.” Although this is highly encouraging, it must be emphasized that testing the possibility of maintaining a remission without continuing the immunosuppressive regimen has not been a step in any of the large Phase III clinical trials conducted with modern agents. Clinicians do recognize that historically there have always been some patients who were fortunate enough to achieve a remission and maintain it without needing indefinite treatment [ 56 ]. There is a paucity of data on the frequency with which this desirable outcome is achieved, what types of patients are most likely to achieve it, or what treatments are most likely to bring it about. The SLE International Collaborating Clinics Network (SLICC group) has recently embarked on a large retrospective review (the long‐lasting remission in lupus study) in thousands of patients to determine the frequency with which such a state is seen in lupus patients treated with conventional means. A reasonable statement based on current observations is that this state—a long‐lasting treatment‐free remission—is achieved more readily by CAR‐T therapy than by other available treatments. In addition, although CAR‐T cell therapy is an accepted treatment in hematology and is appropriately being tested extensively and increasingly used as “rescue therapy,” it is nonetheless associated with clear risks as well as many practical disadvantages (Table 3 ). One of the main risks to consider is cytokine release syndrome (CRS), where the patient develops fever and other symptoms as the result of both the large‐scale in vivo activation of the CAR‐T cells and the massive lysis of target cells. CRS occurs at variable time intervals following the infusion of CAR‐T cells and is a rather common occurrence following CAR‐T cell therapy. In addition, although most cases are mild, there is a spectrum of severity that ranges all the way to life‐threatening complications in the inner organs. Treatment with GCs and especially with the interleukin (IL)‐6 inhibitors (tocilizumab and sarilumab) has proven very beneficial and able to prevent most serious downstream consequences [ 91 ]. CAR‐T cell therapy is also associated with the immune effector cell–associated neurotoxicity syndrome (ICANS), which is less common than CRS and emerges unpredictably at any point in time during the first weeks after CAR‐T cell infusion [ 91 ]. The etiology of ICANS is not understood. It is manifested by a great variety of neurological symptoms, ranging from mild and transient ones to life‐threatening involvement of the CNS. Established treatments are lacking, so management is often symptom‐based and supportive, whereas GCs and IL‐6 are also used. The unpredictable and potentially fatal nature of ICANS poses a serious concern for implementation of CAR‐T cell therapies in larger patient populations. CAR‐T cells can also give rise to i mmune treatment–associated hematological events (ICAHS): In a similar vein to ICANS but even more rarely, patients may experience hematological alterations, including cytopenias in any of the lines, following CAR‐T cell therapy. As is the case for ICANS, these events can occur at highly variable intervals after treatment, and they range in severity from mild to very severe [ 91 ]. As is to be expected, profound B‐cell depletion following cytotoxic premedication may increase the risk for infections, including opportunistic infections . Reports to date of CAR‐T cell therapy have generally not shown alarming frequencies of any infections. Yet it stands to reason that a treatment that brings about profound B‐cell depletion lasting for several months may yet be shown to increase the risk of these by a meaningful margin. It is remarkable that B‐cell‐depleting agents that are already in wide use for several diseases (RTX, ocrelizumab, ofatumumab, and others) are tolerated as well as they are. A key practical aspect of CAR‐T cell therapy that deserves mention is the fact that currently the standard is an inpatient stay of 1–3 weeks, mostly in order to monitor the patient for the development of CRS, ICANS, and other adverse events. The admission must be in a specialized hospital unit that is equipped to deal with these complications, and as such this requirement places a large burden on health care facilities. It is possible that inpatient stays for this procedure can be made shorter, but the late emergence of serious side effects is not easily circumvented.

Other advanced therapies

Excitement about the potential benefits of “deep” B‐cell depletion as seen with CAR‐T cells has prompted investigators and drug developers to examine the potential for other B‐cell‐depleting agents and approaches. Many of these developments are primarily intended for hematological indications, but interest in employing them for the treatment of autoimmune diseases, including SLE, has skyrocketed in the past few years (Table 4 ). It must be recognized that many of these approaches are at a relatively early stage of development and that technical challenges still may need to be overcome. As the list of technological possibilities and the number of approaches in preclinical and very early clinical testing are very large, I will here only discuss a few select ones that may come to fruition in the treatment of SLE over a 5–8‐year time frame.

Bi‐specific T‐cell engagers (TCEs) and related approaches

These are molecular constructs of varying degrees of complexity that share the property of binding both a target and an effector cell. This is made possible by the basic fact that antibody molecules have two “arms” (Fab domains) that normally bind the same target but can be modified to bind two different molecules, hence “bi‐specific.” For instance, blinatumomab is a monoclonal antibody with one arm that binds CD19 on B‐cells, the target, and one arm that binds CD3 on T‐cells [ 100 ]. The construct thereby brings the T‐cell into close proximity to the B‐cell, and by virtue of the signal provided by the monoclonal antibody, it will then kill the B‐cell, the end result of all this being profound B‐cell depletion akin to that seen with CAR‐T cell approaches. A dozen or so TCEs are already approved for use in hematology and oncology, with many more in development, and for many of these, autoimmune indications are also considered [ 101 , 102 , 110 ]. The case of lupus patients treated successfully with teclistamab (binding BCMA and CD3) was reported [ 110 ]. A small case series of blinatumomab in rheumatoid arthritis was published [ 102 ]. A key consideration with respect to this class of drugs is that although the therapeutic principle of “deep” B‐cell depletion is similar to that of CAR‐T cells, the practical implementation would be very different. On the one hand, the treatment would be considerably simpler, consisting of infusions or subcutaneous injections. Some monitoring following the treatment would be required (adverse events such as CRS and others do occur), but presumably for shorter periods of time. On the other hand, this would not be a “one‐off” treatment: In current indications, TCEs are given continuously or as repeated courses, and whether this could be different for autoimmune indications remains speculative.

Allogeneic CAR‐T cells

One of the main drawbacks of CAR‐T cell therapy is the fact that cells have to be harvested and molecularly modified before the treatment can be administered. This tedious, lengthy, and costly process could be circumvented if CAR‐T cells were made available on an “off‐the‐shelf” basis, and this is intended to be achieved with allogeneic CAR‐T cells. Thus, cells would be harvested from a donor and modified for use in potentially unlimited numbers of recipients. The main challenge here is, of course, to prevent rejection, as the donor cells are normally recognized as foreign by the recipient's immune system, and the allogeneic cells must therefore be modified before they can be used. Various molecular technologies can be harnessed to achieve this [ 103 , 111 ], and the first clinical tests with such allogeneic cells have already taken place [ 104 ]. Once again, these are intended first and foremost for use in hematology and oncology, but there is also great interest in the potential use for the treatment of autoimmune diseases, including lupus.

In vivo CAR‐T cells

Another highly advanced approach would be based on the idea that the reconstructed “CAR” could be infused into the patient, packaged in a manner that would guide it towards the patient's own T‐cells, thereby converting their own cells to CAR‐T cells inside the body. Early trials of this approach are underway [ 105 ].

Antigen‐specific CAAR‐T cells

Yet another highly sophisticated approach involves the generation of chimeric autoantigen‐specific T cells (CAAR‐T cells) that would selectively deplete the cells responsible for the production of pathophysiologically relevant autoantibodies [ 106 ]. This approach, which is still at a very early stage of development, would primarily be of interest in diseases where pathogenic autoantibodies are fully responsible for the disease, such as myasthenia gravis [ 107 ] or Graves’ disease, but may become relevant for SLE as well.

Treg‐harnessing approaches

The natural mechanism of controlling immunity by regulatory T cells (Treg cells) was put into the limelight by the 2025 Nobel Prize in Physiology or Medicine awarded to Brunkow, Ramsdell, and Sakaguchi—investigators who discovered this important part of our immune system. Various attempts have been made to harness this system to control autoimmune diseases, including a specific monoclonal intended to stimulate Tregs [ 109 ], the use of low‐dose interleukin‐2 to do so [ 112 ], and others. Currently, no clear path forward has emerged, but hope remains that this will become a possibility in the future.

Regulatory aspects, definitions, terminology

In general, it is clear that extraordinary claims (this treatment brings about an immunological reset) must be supported by extraordinary data, but, in turn, it is also true that if such claims are proven, they must be followed by commensurate regulatory approvals. Thus, important discussions are taking place to determine what level of evidence is needed for such therapies to be approved, in light of the clear difficulty of conducting studies of this treatment in a double‐blinded manner. How this will play out in coming years is far from certain, but many large initiatives are being employed to support such developments, including the Lupus Accelerating Breakthroughs Consortium [ 99 , 113 ] (Table 5 ).

Likewise, along with changes in the therapeutic options for lupus and the many trials that are ongoing, there have been significant reevaluations of the terminologies, outcomes, and definitions that are used to describe these. The importance of having accurate descriptors is present both in clinical practice and in research but may be particularly urgent in the regulatory context, where the approval of a new treatment may hinge on having the correct interpretation of the right outcomes in a trial. Several of these developments deserve special mention. Thus, the primary outcomes in RCTs for lupus over the past two decades have been the SLE response index and the British Isles Lupus Assessment Group–based Composite Lupus Assessment, two instruments with regulatory support but rightly criticized for being highly complex and nonintuitive. For this reason, and with full support from the main regulatory agencies, a large international consortium has set out to develop a better clinical trial endpoint entitled trial response measure for SLE [ 114 ]. This large‐scale project, which has been underway for the past several years, is nearing completion in the coming years. Meanwhile, remission in lupus was, for many years, a concept used widely but not defined accurately. The definition of remission in SLE (DORIS) from 2021 succeeded in unifying the field, and this definition of clinical remission has been used very widely since then [ 115 ]. However, the results seen in some patients with CAR‐T cells have prompted the search for a definition of the more profound state that is characterized by having not just a clinical remission but also immunological quiescence, a longer duration, and the absence of the need for treatment. This state, tentatively named DORIS+, is currently being defined by the international DORIS Task Force. In parallel, severe lupus —while intuitive to the clinician and the patient—has not been accurately defined. As increasingly more trials are done or designed that are specifically targeting those patients, a definition of this patient subset is needed. The international ENDORSED initiative aims to achieve that.

New therapeutic strategies for SLE: some predictions

The dynamics of therapeutic developments for SLE are at an unprecedented level of intensity. It invites one to speculate what the future will bring but makes it commensurately harder to do so. A large number of late‐stage clinical trials are currently in progress, and each of these may succeed or fail. The more advanced therapies discussed above are in earlier phase development where the full spectrum of benefits and side effects still remains to be determined. Some very exciting but preliminary approaches are still at the level where technical and practical aspects need to be resolved. Interrelated with this are initiatives to reexamine outcomes, endpoints, and regulatory requirements and scientific studies to bring about further characterization of patients who, despite having the common diagnostic label of “SLE,” may have different pathophysiologies that overlap with those in patients carrying other diagnoses. All this makes predicting hard, but here I will try to make a few predictions on how the treatment of SLE will evolve in the coming years (Table 6 ).

Short term: 1–3 years

With the recent announcement of a positive Phase III trial of obinutuzumab, it is likely that this drug—already approved for the treatment of LN—will also receive regulatory approval for SLE in general. Meanwhile, in the coming 2 years we will see the completion of several Phase III clinical trial programs (deucravacitinib [ 67 ], litifilimab [ 72 ], cenerimod [ 75 ], dapirolizumab [ 77 ], upadacitinib [ 85 ], and ianalumab [ 80 ]). Each of these trials (or pairs of trials in some cases) is intended to support the registration of the drug for the indication of SLE in general. I expect several of these trials to be successful and therefore at least three or four new therapies for lupus to have been approved by regulators by 2028. For clinicians, this will mean additional treatment options (which, needless to say, may be constrained by reimbursement issues), and for patients with poorly controlled disease, it means hope for a better life. These approvals may include small molecular oral therapeutics, providing a level of convenience and increasing the versatility of treatment, and some entirely new therapeutic mechanisms, which is particularly relevant for those patients whose disease has been truly refractory to the currently available therapies. The expanded choice of therapeutics will, however, place a burden on physicians and particularly on those specialists who are primarily responsible for prescribing them in SLE; in most health care settings, that would be rheumatologists.

Medium term: 3–5 years

In the somewhat longer perspective, CAR‐T cells may be approved for the treatment of SLE. It is expected to be a tightly circumscribed approval, perhaps requiring previous failure of multiple therapies and/or organ‐ or life‐threatening disease manifestations. It can be hoped that by that time, health care providers will have created the necessary infrastructure for providing CAR‐T cell therapy to an ever expanding number of patients, whereas it may also be hoped that improvements in technology, healthy competition, and volumes will lead to lower prices for this procedure.

Longer term: 5–10 years

The development of more practical alternatives, such as allogeneic CAR‐T cells, or more sophisticated options (CAAR‐T cells and Tregs) will lead to clinically applicable products in the years thereafter, so that by 2032 the options for lupus patients will have multiplied considerably. Moreover, parallel developments will have taken place for many other autoimmune diseases, and health care will increasingly be organized around the “theme”—in this case, autoimmunity—rather than around the organ system. By that time the current nomenclature of autoimmune diseases, based mostly on clinical manifestations, may be well on its way to being replaced by a more pathophysiology‐based nomenclature, even as the older names will also be maintained.

In summary, the treatment of SLE has undergone significant changes over the past decade, but all ongoing activities suggest that the changes in the coming decade will be even greater. For physicians and health care systems as a whole, these developments may pose significant challenges, but for our patients they spell hope and the expectation of a brighter future.

Author contributions

Ronald van Vollenhoven : Conceptualization; writing—review and editing; writing—original draft.

Conflict of interest statement

Research and educational support (institutional grants): Alfasigma, AstraZeneca, BMS, Cabaletta, Galapagos, MSD, Novartis, Pfizer, Remegen, Roche, Sanofi, and UCB. Consultancy and/or speaker: AbbVie, AstraZeneca, Biogen, BMS, Cabaletta, Galapagos, GSK, Janssen, Kyowakirin, Pfizer, RemeGen, Sanofi, UCB, and Vorbio.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Associated Data

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.