Current treatment of systemic lupus erythematosus: a clinician's perspective

The treatment of autoimmune diseases with antimalarials has a long history, and chloroquine (CQ) and hydroxychloroquine (HCQ) are still used to treat patients with SLE. The main effects of antimalarial drugs are the inhibition of lysosomal activity and autophagy, inhibition of pro-inflammatory cytokine signaling and secretion, inhibition of T-cell proliferation, and blocking of Toll-like receptors [11‐13].

The activity of SLE and the accrual of organ damage can be significantly reduced with chronic HCQ treatment, provided that the patient's blood HCQ concentration remains at 800–1000 ng/ml [14, 15]. HCQ also delays the appearance of disease flares [16, 17]. However, the expected clinical results are difficult to achieve due to poor patient compliance; 7–29% of patients treated with this drug had HCQ < 200 ng/ml [18]. This observation demonstrates the need to monitor patients' adherence to HCQ therapy. In lupus nephritis (LN), a severe phenotype of lupus, antimalarials reduce the risk of renal flare, ESRD, and death [19, 20]. Other benefits of using antimalarial drugs include prolonged survival and reduction of damage accrual [21‐23]. In the context of organ protection, it is important that antimalarials use allows reduction of GC dose [24]. HCQ has also been shown to have a beneficial effect on lipid profile and glycemic control. It can improve endothelial function and inhibit platelet aggregation and arachidonic acid release. The other benefit of antimalarial therapy is diminishing the risk of developing cardiovascular disease by reducing the number of thrombotic events. HCQ has also protective effects against severe bacterial and viral infections and their complications [25, 26]. HCQ treatment is recommended as the background therapy for all patients with SLE without contraindications to this drug [8]. These contraindications are limited to retinopathy and cardiomyopathy and relate to high doses of HCQ. Therefore, in SLE, a dose of HCQ > 5 mg/kg body mass (corresponding to an HCQ cumulative dose of > 1000 g) is not recommended [27]. Maculopathy develops in 2% and 0.1% of patients with SLE within 10 years of CQ or HCQ treatment, respectively. To detect asymptomatic, early, and reversible retinopathy, careful monitoring of patients undergoing this therapy is necessary [28]. HCQ can be administered to reduce the rates of lupus flares in pregnant women [29]; however, the scarcity of data on pharmacokinetics and posology of this drug in pregnant women does not allow for indication of recommended HCQ dosage [30].

Quinacrine, used to treat skin lesions in SLE, does not increase retinopathy risk. This drug inhibits the production of TNF-α and INF-α by dendritic cells and monocytes [31]. A synergistic effect of HCQ and quinacrine on the improvement of cutaneous lupus erythematosus has been reported [32].

Glucocorticoids can rapidly control SLE activity and remain the cornerstone of SLE therapy. The potency of GCs in dampening inflammation is associated with a broad spectrum of effects on the immune system; GCs reduce the expression of cytokines and adhesion molecules, inhibit leucocyte traffic, and their access to inflammation sites, and interfere with leucocyte, fibroblast, and endothelial cell functions [33]. Observational studies indicate that up to 88% of patients with SLE are treated with GCs, and more than half continue this therapy for a long time [34, 35]. A significant proportion of the early and late damage during disease treatment could be attributed to GC therapy [35, 36]. These findings are of great importance because irreversible organ damage has been reported to be a predictor of morbidity and mortality in SLE [37]. Therefore, using GCs more restrictively should help prevent serious complications in patients with SLE. According to the current recommendations, the use of CGs should be limited or completely discontinued depending on the activity of the disease, the duration of treatment, and the desired effects of GC treatment [5].

After diffusion into the cell, GCs can activate transcription factors either directly (via the genomic pathway) or indirectly (via the non-genomic pathway) [38]. In the genomic pathway, GC binds to the cytosolic receptor (GR), thereby becoming activated. The GC-GR complex then translocates to the cell nucleus, where it induces the transcription of genes encoding anti-inflammatory mediators. The effect of the genomic pathway is evident hours or days after its activation. However, the clinical effects of GC may be faster as high systemic doses of methylprednisolone can quickly alleviate the symptoms of a flare. The rapid effects of GCs are related to the activation of the non-genomic pathway. In this mechanism, GC binding allows the GR to interact with intracellular proteins as well, leading to rapid inhibition of inflammatory mediators such as arachidonic acid. The recruitment potential of a given pathway depends on the type and dose of GC. Compared to other steroids, methylprednisolone or dexamethasone are 10–15 and 20 times more potent in inducing a non-genomic pathway, respectively [39]. When using a dose above 30–100 mg/day of prednisone equivalent, the saturation of the cytosolic GR is ~ 100%, and the genomic pathway is fully operational. In contrast, the non-genomic pathway operates at clinically relevant levels at doses of > 100 mg/day of prednisone equivalent [40]. The usual dose of 1 mg/kg/day for treating SLE exacerbations is empirical and is currently not recommended since it was observed that the resulting response rates after using high initial prednisone doses of 1 mg/kg/day did not differ significantly from those obtained for pulse methylprednisolone in lower doses (0.3 and 0.5 mg/kg day), whether CYC or MMF was used [40]. This is an important observation as it has recently been shown that many side effects are related to the dose of GC used and the activation of the genomic pathway. Serious toxicity begins at 7.5 mg/day of prednisone equivalent, which is the borderline between low and medium pharmacological doses. Data from observational and clinical studies have shown that low-dose methylprednisolone pulses (125–500 mg daily) are potent treatments for severe acute lupus exacerbations with few associated side effects [41, 42]. However, even with low GC doses, the risk of cataracts, ischemic heart disease, osteoporosis, and fractures in long-term GC treatment may increase [43]. Therefore, lower GC doses (i.e., < 5 mg/day of prednisone equivalent) should be considered when it is not possible to discontinue long-term GC therapy. Concomitant use of antimalarial and immunosuppressive drugs may help to maintain a low GC dose or even to withdraw it [44, 45].

It should be noted that the definition of remission also considers the dose of GC the patient is taking; the use of GC in a daily dose of above 5 mg excludes the occurrence of remission of SLE in a patient [5]. According to recommendations of the European Renal Association-European Dialysis and Transplant Association for LN, withdrawal of GCs is suggested in patients being in remission for 3 years [46]. However, in real life, clinicians prefer to withdraw GC after 5 years of sustained remission while maintaining immunosuppressive therapy, particularly when the disease has a relapsing–remitting course with severe organ involvement [34]. The greatest concern for clinicians prior to discontinuing GC therapy in patients with inactive SLE is the risk of disease exacerbation. A recent meta-analysis of 738 lupus patients after discontinuation of GC revealed an increased risk of clinical flare (although not a major flare) and less organ damage assessed by the SLICC/ACR damage index [47]. Other recently published data indicate that gradual withdrawal of GC is safe in clinically inactive SLE and is associated with fewer disease flares and less damage accrual [48]. In the case of prolonged exposure of patients to GCs, an increase in the frequency of infections should be taken into account [26, 49].

Non-corticosteroid immunosuppressants target different B-cell populations. Cyclophosphamide (CYC) preferentially depletes less mature B-cells (naïve and pre-switching memory B-cells), while mycophenolate mofetil (MMF) depletes circulating plasmablasts. Azathioprine (AZA) is less potent in suppressing naïve and memory B-cells than MMF [50]. Non-corticosteroid immunosuppressants constitute the basic therapy for reducing SLE activity. They are used to initiate and maintain therapy. The type and dose of immunosuppressants should be adapted to the activity of lupus, the type, and the severity of the organ involved or manifestations. The most commonly used non-corticosteroid immunosuppressants in SLE are AZA, calcineurin inhibitors, methotrexate (MTX), and MMF. Life-threatening involvement of organs and systems, such as in LN and neuropsychiatric lupus, requires more aggressive parenteral treatment with CYC or MMF in combination with GCs. The teratogenic properties of CYC, MMF, and MTX should be considered when treating young women with maternity plans [29].

CYC interferes with DNA and blocks replication in proliferating cells, including B-cells. High doses of intravenous CYC in combination with GC are used as first-line therapy to induce remission in proliferative LN. Data from the Euro-Lupus Nephritis Trial show that remission-inducing treatment with a low dose of CYC gives clinical results comparable to those obtained with high-dose treatment but has a better safety profile [51]. These observations may influence the management of other difficult-to-treat cases of SLE, such as patients with vasculitis, and may reduce mortality. However, other randomized clinical trials of proliferative LN have shown little to no difference in complete remission rate in patients treated with intravenous CYC or MMF as induction therapy [52].

MMF, an orally administered prodrug, is metabolized in the liver to the active mycophenolic acid molecule. Mycophenolic acid is a potent, reversible inhibitor of inosine-5′-monophosphate dehydrogenase, an enzyme essential for the de novo synthesis of guanosine-5′-monophosphate. The use of MMF to inhibit DNA replication affects especially T cells and B cells, as they rely almost exclusively on de novo purine synthesis. MMF is recommended for the treatment of patients with LN. This drug is effective in inducing remission and as a long-term maintenance therapy. Compared to CYC, the use of MMF may lead to complete renal remission more frequently with a more favorable side effect profile [52]. In maintenance therapy, MMF was shown to be superior to AZA in preventing relapse in LN [52]. However, recent data suggest that the risk of LN relapse may be related to changes in B cell subpopulations and different B cell signatures in patients [50].

Calcineurin inhibitors affect B cells indirectly by inhibiting the activity of T cells. These drugs bind to the cytosolic protein cyclophilin and inhibit calcineurin, which prevents the activation of the NF-AT transcription factor. The traditional drug from this group is cyclosporin A (CSA), which has a beneficial effect and a good safety profile in pregnant women with SLE. Voclosporin (already registered in the US and EU) is a novel calcineurin inhibitor that, when combined with MMF and GC, allows a better complete renal response rate than MMF and GC alone in patients with active LN. The advantage of using voclosporin is fewer side effects, such as hypertension, increased mortality, and worsening renal function [53, 54]. Tacrolimus is another calcineurin inhibitor that is used in severe LN. Long-term data of a randomized controlled trial confirmed non-inferiority of tacrolimus to MMF as induction therapy of LN assessed by response rate to treatment and rate of flares [55].

AZA is mainly used as maintenance therapy for moderate-to-severe lupus. AZA is a prodrug that converts into 6-mercaptopurine and interferes with DNA replication and purine synthesis in lymphocytes. Animal studies have shown that the immunosuppressive effects of AZA are dose-dependent. Higher doses of AZA are needed for the effective suppression of humoral immunity than for the suppression of cellular immunity [56, 57]. According to a systemic analysis of nine studies, maintenance treatment of proliferative LN with AZA may increase the relapse rate compared to MMF (MMF risk ratio 1.75, 95% CI 1.20 to AZA 2.55) [52]. It was shown that the depletion of B-cells at an earlier stage of their development results in better treatment outcomes which may explain the stronger immunosuppressive effect of MMF than AZA [50]. AZA can be continued during pregnancy [29].

MTX may be effective when the musculoskeletal and mucocutaneous domains are involved in mild-to-severe SLE [9]. Results of the study involving 41 patients with cutaneous disease indicate that MTX may be superior to placebo in terms of complete clinical response (absence of malar/discoid rash) at 6 months of follow-up [58].

The biologics approved for treating patients with SLE are belimumab and anifrolumab. Rituximab (RTX) is used off-label, and many other biological drugs are evaluated in clinical trials. Biologics should be considered in persistently active or recurrent SLE (Fig. 1).

Resistance to conventional treatment with GCs and non-corticoid immunosuppressants is common among patients with SLE [88]. Biologics have become an alternative and are being assessed in clinical trials in patients whose disease is not sufficiently controlled by conventional drugs. Sequential therapy can help improve the effectiveness of B cell depletion. Treatment with RTX and CYC, followed by belimumab, was evaluated in the CALIBRATE study in refractory or recurrent LN. This treatment strategy prevented autoreactive B-cell re-emergence but did not lead to sufficient clinical improvement [89]. However, in another phase II clinical trial, treatment with belimumab followed by RTX significantly reduced levels of serum anti-dsDNA antibodies and the risk of severe flare in patients with SLE who were refractory to conventional therapy [90]. A randomized, controlled phase III trial of SynBioSe-2 is ongoing to investigate the long-term clinical and immunological efficacy of the combination of belimumab followed by RTX in LN. Interestingly, belimumab was also used as maintenance therapy in two SLE cases with refractory renal and pulmonary manifestations rescued by bortezomib as induction of remission [91].

The emergence of low-molecular-weight compounds in the treatment armamentarium allowed researchers to interfere directly with the intracellular cytokine signaling pathways.

Interaction of the proinflammatory cytokine with its membrane receptor triggers intracellular signaling that leads to gene transcription and inflammatory mediators’ production. Intracellular signal transmission depends on the activity of enzymes—kinases that phosphorylate signaling molecules [92]. In treating rheumatic diseases, 4 members of the Janus kinases family (JAK1, JAK2, JAK3, and tyrosine kinase-2; TYK2) and their 7 downstream signal transducers and activators of transcription (STATs) are currently of greatest interest. JAK inhibitors (JAKi) bind to the enzymatically active domain of JAK, thereby blocking its activity and cytokine-induced signal transduction. Baricitinib is an oral JAK1 and JAK2 inhibitor approved for the treatment of RA. In the phase IIb randomized multicenter placebo-controlled trial, baricitinib significantly improved the arthritis symptoms and resolved skin rash in patients with active SLE with skin or joint manifestations. Phase III of the clinical trial of baricitinib in SLE is ongoing [93]. TYK2 mediates the functional responses to IL-23, IL-12, and type I IFN stimulation. Selective TYK2 inhibitors might benefit patients with PS, PsA, inflammatory bowel disease (IBD), and SLE [94]. The TYK2 inhibitor, deucravacitinib, was effective in reducing SLE activity and tender and swollen joint counts in patients in an international, randomized, double-blind, placebo-controlled phase II clinical trial [95] and warrants further phase III research trials.

Bruton's tyrosine kinase (BTK) is a cytoplasmic signaling molecule involved in the development, survival, and activation of B cells. Fenobrutinib is an orally highly selective BTK inhibitor that reversibly binds its target. It was effective in reducing CD19-positive B cells and antibody production but was not sufficiently effective in randomized, placebo-controlled phase II trials in moderate-to-severe SLE [96].

Proteasomes are protein complexes that degrade unnecessary or damaged proteins by proteolysis. They are crucial for the survival and function of plasma cells, which anti-CD20 antibodies cannot eliminate due to the lack of surface CD20 [97]. Bortezomib is an N-protected dipeptide that binds to the catalytic site of the 26S proteasome. It is approved for the treatment of multiple myeloma. In Japan, studies are ongoing to investigate bortezomib in a multicenter, double-blind, randomized controlled trial in patients with refractory SLE [98].