Novel JAK inhibitors under investigation for systemic lupus erythematosus: - where are we now?

ABSTRACT

Introduction

Glucocorticoids and immunosuppressants are used to treat systemic lupus erythematosus (SLE). However, patients with SLE have poor long-term prognoses. This can be attributed to organ damage caused by flare-ups and drug toxicity due to the administration of nonspecific treatment. Therefore, SLE should be treated using therapeutic agents specific to its pathology. Janus kinase (JAK) inhibitors exert multitargeted effects by blocking the signaling of multiple cytokines. The use of JAK inhibitors has been approved to treat several inflammatory autoimmune diseases. Several clinical trials of JAK inhibitors for SLE treatment are ongoing.

Area covered

This review summarizes the basic and clinical significance of JAK inhibitors for treating SLE and the current status of the development of JAK inhibitors based on recent reports.

Expert opinion

SLE is a clinically and immunologically heterogeneous disease. Therefore, drugs targeting a single molecule require precision medicine to exert maximal therapeutic efficacy. JAK inhibitors can probably fine-tune the immune network via various mechanisms and broadly regulate complex immune-mediated pathologies in SLE. However, evidence is required to address some safety concerns associated with the use of JAK inhibitors in patients with SLE, including infections (particularly herpes zoster) and thromboembolism (particularly in the presence of concomitant antiphospholipid syndrome).

KEYWORDS:

• JAK inhibitor
• molecular targeted therapy
• T cell
• B cell
• systemic lupus erythematosu

1. Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies underlying multiorgan disorder [1,2]. In the treatment of SLE, the combined use of glucocorticoids and immunosuppressants has contributed to the improvement of organ disorders and acute-phase prognosis. However, the long-term prognosis of patients with SLE has not been improved sufficiently, and refractory SLE is often encountered in clinical practice. Deterioration in patients’ quality of life owing to repeated flare-ups and accumulation of drug-related organ damage is a problem in SLE [3].

The diagnosis of SLE is made using the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria published in 2019 [4]. The goal of SLE treatment is remission without flare-ups and organ disorders; minimization of drug toxicity and prevention of organ damage are imperative in achieving this goal [5]. Definition of remission in SLE (DORIS) is commonly used to define remission [6]. However, remission is difficult to achieve. Recently, lupus low disease activity state (LLDAS), the criteria for low disease activity proposed by the Asia-Pacific lupus collaboration (APLC) programme, has gained attention as a realistic treatment target [7]. Treat-to-target (T2T) recommendations for SLE include one that ‘lupus maintenance treatment should aim for the lowest glucocorticoid dosage needed to control the disease, and if possible, the complete withdrawal of glucocorticoids [5]. ’ However, complete withdrawal of glucocorticoids remains a very high bar in patients with SLE. Currently, new drugs targeting molecules involved in immunological abnormalities in SLE are being developed to eliminate the need for nonspecific therapeutic agents, such as glucocorticoids.

In the treatment of rheumatoid arthritis (RA), glucocorticoids have been used in a limited manner after the advent of biological disease-modifying antirheumatic drugs targeting tumor necrosis factor (TNF), interleukin (IL)-6, T-cell costimulatory molecules, and other molecules as well as molecular targeted drugs, such as Janus kinase (JAK) inhibitors [8]. There are growing expectations for molecular targeted drugs effective against SLE, and multiple clinical trials of such drugs are currently ongoing [9]. Cytokines such as type I IFNs, IL-12 and IL-23, which bridge the innate and adaptive immune systems, and IL-21, which activates T cell-B cell interactions, are promising targets for SLE treatment [10]. Activation of these cytokines requires signaling through the JAK. That is, type I IFNs transmit signals via JAK1/TYK2, IL-12 and IL-23 via JAK2/TYK2, and IL-21 via JAK1/JAK3. Therefore, JAK inhibitors exert multitargeted effects by blocking the signaling of multiple cytokines and represent a promising class of therapeutic agents for SLE with high immunological heterogeneity. This review summarizes the rationale for treatment of SLE with JAK inhibitors, the current status of the development of JAK inhibitors, and future prospects of JAK inhibitors.

2. Current status of new therapeutic agents for SLE

The pathological process of SLE involves a combination of genetic predisposition and epigenomic modifications triggered by environmental factors, resulting in a disruption of autoimmune tolerance [11]. The pathology of SLE comprises immunological abnormalities involving both innate and acquired immunity, such as excessive activation and abnormal differentiation of autoreactive T cells, increased differentiation of B cells into antibody-producing cells, and overproduction of type I interferons (IFNs) from dendritic cells via the recognition of immune complexes composed of self-nucleic acids and autoantibodies. Neutrophils, natural killer cells, macrophages, and their precursor monocytes, are also involved in the innate immune abnormalities in SLE. Antigens such as DNA, histone proteins and RNA proteins generated from these apoptotic cells lead to the production of autoantibodies from autoreactive B cells. On the other hand, neutrophil extracellular traps produced by activated neutrophils have been reported as antigens other than apoptotic cells. Therefore, specific therapeutic agents targeting specific molecules involved in these immunological abnormalities are being awaited.

B cells play a central role in the development and pathogenesis of SLE and other autoimmune diseases. In Europe and the United States, rituximab, a chimeric antibody targeting the B-cell surface molecule CD20, has been approved for treating RA and is being considered for clinical application to treat SLE. However, an international phase III trial of rituximab targeting CD20 on B cells failed to show significant differences in efficacy compared with a placebo [12]. Nevertheless, many clinicians are aware of the effectiveness of rituximab against refractory SLE in clinical practice. In Japan, a public knowledge-based application of rituximab for the treatment of refractory lupus nephritis has been approved and is covered by insurance. Meanwhile, phase III trials of ocrelizumab targeting CD20 [13] and epratuzumab targeting CD22 [14] were unsuccessful. Abatacept targeting T-cell costimulatory molecules also failed to meet the primary endpoint in a phase III trial for the treatment of Class III/IV lupus nephritis [NCT01714817]. Furthermore, a trial of ustekinumab targeting IL-12/23 was also unsuccessful [15]. To date, belimumab, an antibody against the representative B-cell costimulatory molecule BAFF (B cell-activating factor of the TNF family), and anifrolumab targeting the type I IFN receptor are the only molecular targeted agents approved for treating SLE [16–18].

New molecular-targeted agents for lupus nephritis are also being developed. However, to date, belimumab is the only drug that has shown significant results in phase III trials: in the BLISS-LN study, belimumab significantly improved renal primary response efficacy (PERR) at 104 weeks compared with placebo in patients with active lupus nephritis (43% in the belimumab group vs 32.3% in the placebo group) [19]. Other phase III trials are ongoing with anifrolumab, a type II CD20 antibody obinutuzumab, while many other drugs have failed, including the anti-BAFF/APRIL antibody atacicept and anti-CD40L antibody dapirolizumab. Rituximab also failed in the phase III LUNAR trial [20]; however as mentioned above, this drug was approved in Japan in September 2023 for the treatment of lupus nephritis with inadequate response to conventional therapy [21].

As summarized above, most clinical trials of many molecular targeted drugs have been unsuccessful. Various possible causes are conceivable for these disappointing results, one of which is the high heterogeneity of immunological abnormalities in SLE. This means that cells or molecules to be targeted in the treatment are diverse, and for this reason, any single molecular targeted drug may not be able to demonstrate consistent efficacy in a population. For example, anifrolumab showed a significantly higher efficacy in the subgroup of patients expressing a high level of IFN-related genes, and drugs can be effectively selected simply by classifying patients into two subpopulations [22]. Implementing precision medicine, in which molecular targeted drugs suitable for the pathology of each patient population are selected according to the heterogeneity of SLE, is a future challenge.

3. Mechanism of action of JAK inhibitors

When cytokines and cell surface molecules bind to their receptors, diverse intracellular signals are transmitted, which induces cellular functions or new cytokine transcription. Enzymes phosphorylating signaling molecules are called kinases. JAK is a family of intracellular tyrosine kinases constitutively binding immediately below the receptor and plays an important role as signal mediators for many cytokines and hormones. The JAK family of tyrosine kinases comprises four members (JAK1, JAK2, JAK3, TYK2), which mediate signal transduction of more than 50 cytokines [23–25]. A unique JAK binds to the cytokine receptor and phosphorylates JAK itself and the transcription factor called signal transducer and activator of transcription (STAT) when it receives extracellular stimuli via the receptor. The STAT family includes seven members (STAT1–4, 5a, 5b, 6). Phosphorylated STAT proteins form monomers/dimers and are transported to the nucleus, where they activate the transcription of cytokine-inducible genes [23,26,27] (Figure 1).

Figure 1. Jaks activated by cytokines and the selectivity of JAK inhibitors.

Four JAKs (JAK1, JAK2, JAK3, TYK2) control various signaling induced by different cytokines, and JAK inhibitors can simultaneously inhibit multiple cytokines.

Over the past three decades, multiple pieces of evidence have clearly defined the role of various JAKs and STATs in mediating the effects of cytokines using type I and type II cytokine receptors in immunoregulation, host defense, and immunopathology. For example, TYK2, JAK2, and STAT4 are essential for interleukin-12 (IL-12) signaling and Th1 and T follicular helper (Tfh) cell differentiation, whereas JAK1, JAK3, and STAT6 were critical for IL-4 signaling. JAK inhibition blocks various cytokine signals, which results in the regulation of immunity and inflammation. Therefore, high selectivity is important when JAK inhibitors are applied as therapeutic agents. Currently, the following JAK inhibitors have been approved in Japan: tofacitinib, which is relatively selective for JAK1/3, for RA and ulcerative colitis; baricitinib, which is selective for JAK1/2, for treating RA, atopic dermatitis, alopecia areata, and SARS-CoV-2 pneumonia; the pan-JAK inhibitor peficitinib for treating RA; upadacitinib for treating RA, psoriatic arthritis, axial spondyloarthritis, atopic dermatitis, and ulcerative colitis; filgotinib, which is selective for JAK1, for treating RA and ulcerative colitis; and ruxolitinib, which is highly selective for JAK1/2, for treating myelofibrosis and polycythemia vera.

4. Potential of JAK inhibitors in the treatment of SLE

Low-molecular-weight compounds capable of regulating many cytokines and inflammatory mediators via oral administration are also expected to be effective in the treatment of SLE. JAK inhibitors have attracted attention for this purpose. The activities of most cytokines involved in the pathogenesis of SLE depend on the JAK-STAT pathway. Of these, type I IFNs require JAK1/TYK2, type II IFNs require JAK1/JAK2, and IL-12 and IL-23 require JAK2/TYK2 as signal mediators (Figure 1).

The effects of JAK inhibition by tofacitinib and baricitinib on human immune systems in vitro have been studied [28–30]. With regard to effects on the innate immune system, analysis using human monocyte-derived dendritic cells revealed that the JAK inhibitors reduced the type I IFN-induced expression of costimulatory molecules (CD80 and CD86) and the production of type I IFNs from plasmablast-like dendritic cells. Furthermore, type I IFN signal blockade strongly inhibited IL-12- and IL-23-induced differentiation of Th1 cells, Tfh cells, and Th17 cells in addition to human B-cell differentiation and human T-cell proliferation.

SLE is a clinically and immunologically heterogeneous disease and requires precision medicine for effective treatment. We performed peripheral blood immunophenotyping of 143 patients with SLE using a standardized protocol for classification of human immune cell subsets proposed by the NIH/FOCIS according to their immune abnormalities [31]. The results showed high proportions of Treg and Tfh cells in SLE patients compared with normal subjects, and a strong correlation between increased differentiation of plasmablasts and disease activity. Furthermore, cluster analysis showed common B-cell differentiation abnormalities and we were able to divide the patients into three groups based on T-cell phenotyping: the T-cell-independent group characterized by poor T-cell differentiation and activation abnormalities; the Treg dominant group with increased number of memory Treg cells; and the Tfh dominant group with high number of Tfh cells and plasmablasts. In other words, patients with active SLE who share similar clinical features can be divided into three populations according to their T-cell phenotype. Based on this classification, the Tfh dominant group was resistant to conventional treatments, verifying that the functional B cell – Tfh cell association is important in the pathogenesis of SLE. Furthermore, Tfh/Th1-like cells with both Tfh and Th1 cell traits were observed to be increased characteristically in the peripheral blood of patients with SLE. The differentiation of Tfh/Th1-like cell is induced by IL-12-STAT1-STAT4 signal [32]. A recent genome-wide association study has identified IL-12B, TYK2, and STAT4 as SLE susceptibility genes, suggesting the involvement of abnormalities of the JAK-STAT signaling pathway in the development of SLE [32,33]. Particularly, a population carrying the STAT4 risk allele has been reported to be more prone to develop SLE in the presence of viral infection ***** [34,35]. Therefore, JAK inhibitors are attractive as a novel class of therapeutic agents for SLE.

5. Development status of JAK inhibitors in SLE

Clinical trials of multiple JAK inhibitors for the treatment of SLE are ongoing, as outlined below (Table 1).

Table 1. Clinical trials with JAK inhibitors in SLE.

Drugs	Target	Indication	Development stage	Trial number*
Tofacitinib	JAK1/3	SLE DLE/SLE CLE	Phase 1 Phase 1 Phase 1/2	NCT02535689 NCT03159936 NCT03288324
Baricitinib	JAK1/2	SLE	Phase 3 (failed)	NCT03616912 NCT03616964
Upadacitinib/Elsubrutinib	JAK1/BTK	SLE	Phase 2	NCT03978520 NCT04451772
Upadacitinib	JAK1	SLE	Phase 3	NCT05843643
Filgotinib	JAK1	CLE LMN	Phase 2 Phase 2	NCT03134222 NCT03285711
Deucravacitinib	TYK2	SLE LN SLE	Phase 2 Phase 2 Phase 3	NCT03252587 NCT03920267 NCT03943147 NCT05617677 NCT05620407
Brepocitinib	JAK1/TYK2	SLE	Phase 2	NCT03845517
Solcitinib	JAK1	SLE	Phase 2 (failed)	NCT01777256
Baracetinib	JAK1	LN	Phase 2	NCT05432531

*from https://clinicaltrials.gov/.

SLE: systemic lupus erythematosus, DLE: discoid lupus erythematosus, CLE: cutaneous lupus erythematosus, LMN: lupus membranous nephropathy, LN: lupus nephritis.

5.1. Tofacitinib

Tofacitinib inhibits JAK3 and JAK1, but it has limited affinity to JAK2 and TYK2 (Figure 1). To date, three clinical trials of tofacitinib have been conducted. A phase Ib trial to evaluate tofacitinib safety in patients with SLE was initiated in 2015 [NCT02535689] (Table 1). In this study, patients with SLE with mild to moderate disease activity were stratified according to the presence or absence of STAT4 risk alleles, and the safety and tolerability of tofacitinib in patients with SLE were evaluated by comparing the standard treatment plus tofacitinib 10 mg with the standard treatment plus a placebo. Most adverse events in the tofacitinib group were mild and moderate upper respiratory infections, which resolved spontaneously or after treatment with oral antibiotics. Neither reactivation of herpes zoster nor any venous thromboembolic events were reported [36]. As for the efficacy, the results have not been published, and further studies are necessary because the sample size was small (n = 30). Apart from this trial, two phase I/II trials in patients with discoid lupus erythematosus, cutaneous lupus erythematosus, and SLE with moderate-to-severe skin symptoms are ongoing [NCT03159936, NCT03288324] (Table 1).

5.2. Baricitinib

Baricitinib is an inhibitor selective for JAK1 and JAK2. In a phase 2b trial of baricitinib, a placebo or baricitinib 2 mg or 4 mg was combined with the standard treatment in 314 patients with SLE with high disease activity, including those with skin and joint symptoms, regardless of the standard treatment. Significantly more patients in the baricitinib 4 mg group achieved resolution of skin and joint symptoms at week 24 according to SLEDAI-2000 (odds ratio 1.8), meeting the primary endpoint; patients satisfying SRI-4 were also significantly higher [37].

Based on these results, two phase III trials (BRAVE-I and BRAVE-II) were conducted [NCT03616912, NCT03616964] (Table 1). In the BRAVE-I study, 760 patients with active SLE were randomized to receive baricitinib 4 mg (n = 252), baricitinib 2 mg (n = 255), or a placebo (n = 253) [38]. The SRI-4 response rate at week 52, which was the primary endpoint, was 57% in the baricitinib 4 mg group (n = 142; odds ratio 1.57 [95% CI 1.09～2.27]; difference from placebo 10.8 [2.0～19.6]; p = 0.016), which was significantly higher than 50% in the baricitinib 2 mg group (126; 1.14 [0.79～1.65]; 3.9 [−4.9～12.6]; p = 0.47) and 46% in the placebo group (n = 116). Meanwhile, in the BRAVE-II study, 775 patients with SLE receiving the standard treatment were randomized to receive baricitinib 4 mg (n = 258), baricitinib 2 mg (n = 261), or a placebo (n = 256) [39]. However, the SRI-4 response rate at week 52, which was the primary endpoint, did not differ between the baricitinib 4 mg group and the placebo group (4 mg group 121 [47%], odds ratio 1.07 [95% CI 0.75～1.53], difference from placebo 1.5 [95% CI −7.1～10.2]; 2 mg group 120 [46%], 1.05 [0.73 ～1.50], 0.8 [−7.9～9.4]; placebo group 116 [46%]). Serious adverse events were observed in 29 patients (11%) in the baricitinib 4 mg group, 35 patients (13%) in the baricitinib 2 mg group, and 22 patients (9%) in the placebo group. The safety profile of baricitinib in patients with SLE agreed with the known safety profile of baricitinib. No key secondary endpoints, such as the percentage of participants whose glucocorticoid dose was reduced gradually and the time to first severe flare-up, were achieved in either study. Based on these results, the development of baricitinib therapy for SLE was discontinued.

5.3. Upadacitinib

Upadacitinib is a selective JAK1 inhibitor. Phase II trials of upadacitinib without or with the Bruton’s tyrosine kinase inhibitor elsubrutinib (ABBV-599) were conducted in patients with moderate-to-severe SLE [NCT03978520, NCT04451772] (Table 1). In these studies, a total of 341 patients were enrolled and categorized into five treatment groups (upadacitinib 30 mg; upadacitinib 30 mg + elsubrutinib 60 mg; upadacitinib 15 mg + elsubrutinib 60 mg; elsubrutinib 60 mg; and a placebo). The rate of achieving both SRI-4 and steroid dose reduction to ≤10 mg prednisone equivalent once daily at week 24, which was the primary endpoint, was 54.8% in the upadacitinib 30 mg + elsubrutinib 60 mg group, which was statistically significant relative to the 37.3% in the placebo group (p = 0.28) [40]. In the upadacitinib 30 mg + elsubrutinib 60 mg group, the overall number of flare-ups was lower and the time to first flare-up was longer compared with those in the placebo group. The safety results in the upadacitinib 30 mg group in this study agreed with the known safety profile of upadacitinib, and no new safety signals were identified. Based on these results, a phase III trial of upadacitinib was initiated (Table 1) [NCT05843643].

5.4. Filgotinib

Filgotinib is a JAK inhibitor highly selective for JAK1. To date, a phase II trial to investigate the efficacies of filgotinib and lanraplenib (GS-9876, SYK inhibitor) in patients with SLE with moderate-to-severe skin symptoms has been conducted (filgotinib 17 patients, lanraplenib 19 patients, and placebo 9 patients). The improvement in the CLASI-A score at week 12, which was the primary endpoint, tended to be higher in the filgotinib group, but the difference was not of statistical significance [NCT03134222] (Table 1) [41]. A phase II trial to investigate the efficacy of filgotinib and lanraplenib in patients with lupus nephritis and membranous nephropathy (Class V alone or Class V in combination with Class II and a urine protein level of ≥1.5 g/day) is also ongoing [NCT03285711] [39] (Table 1). In this study, nine patients were randomized to receive filgotinib (n = 5) or lanraplenib (n = 4). Four patients in the filgotinib group and one patient in the lanraplenib group completed the assigned intervention up to week 16. The median 24-h urine protein level decreased by 50.7% after the 16-week treatment with filgotinib. Although a very limited number of patients were included, the results of this study may support future studies using filgotinib or other JAK inhibitors in patients with lupus nephritis [42].

5.5. Deucravacitinib

TYK2-dependent pathways (IL-23, IL-12, and type I IFNs) and cytokine networks under control thereof (e.g. IL-17, IL-22, and IFN-γ) are involved in the pathophysiology of multiple immune-mediated diseases, such as psoriasis, Crohn’s disease, SLE, and dermatomyositis [43,44]. Particularly, IL-12 and type I IFNs are important cytokines for the differentiation of Th1 and Tfh cells and are involved in the pathology of SLE [32,45]. Profiles of TYK2 inhibitors are considered to differ from those of inhibitors of other JAK family kinases as TYK2-dependent receptors are different from receptors dependent on other JAK members, such as those highly dependent on JAK1 or JAK3 (e.g. IL-2, IL-15, and IL-6 receptors) or receptors highly dependent on JAK2 (e.g. erythropoietin, thrombopoietin, and granulocyte – macrophage colony-stimulating factor receptors).

Deucravacitinib (BMS-986165) is an allosteric inhibitor with high specificity based on the structural features of the TYK2 pseudokinase domain. More specifically, deucravacitinib is expected to specifically inhibit signals of IL-12, IL-23, and type I IFNs, unlike nonselective JAK family kinase inhibitors that target the active site in the kinase domain [46]. In a phase II trial in patients with active SLE [NCT03252587], the SRI-4 response rate at week 32, which was the primary endpoint, was 34% in the placebo group, 58% in the group receiving deucravacitinib 3 mg twice daily (odds ratio [OR] 2.8 [95% confidence interval (95％CI) 1.5～5.1]; p < 0.001 vs placebo), 50% in the 6 mg twice daily group (OR 1.9 [95% CI 1.0～3.4]; p = 0.02 vs placebo), and 45% in the 12 mg once daily group (OR 1.6 [95% CI 0.8～2.9]; p = 0.08 vs placebo) (Table 1) [47]. The rates of achieving BICLA (British Isles Lupus Activity Group (BILAG)-based Combined Lupus Assessment), CLASI-50 (Cutaneous Lupus Erythematosus Disease Area and Severity Index), and LLDAS (Lupus Low Disease Activity State) in the deucravacitinib group were also significantly higher than those in the placebo group. The incidence rates of adverse events were similar between the groups, except for higher incidence rates of infection and skin events in the deucravacitinib group. The incidence of serious adverse events was also similar between the groups; no deaths, opportunistic infections, tuberculous infection, serious cardiovascular adverse events, or thrombotic events were reported. Phase III trials are currently ongoing (Table 1) [NCT05617677, NCT05620407]. Deucravacitinib has been demonstrated to regulate type I IFN-related genes. If the clinical trials of baricitinib were unsuccessful in part because of an inhibition of T regulatory cell differentiation owing to a blockade of the IL-2 signaling pathway by baricitinib, deucravacitinib may be effective because it preserves, rather than blocking, IL-2 signaling.

5.6. Brepocitinib (PF-06700841)

Brepocitinib (PF-06700841), a JAK1/TYK2 inhibitor, is currently being tested for the treatment of SLE in a phase 2 trial [NCT03845517] (Table 1).

5.7. Others

In addition to the drugs described above, those clinically tested for the treatment of SLE include the JAK1 inhibitors solcitinib (GSK2586184) and baracetinib. A phase II trial of solcitinib was conducted in patients with moderate-to-severe SLE; however, the efficacy was not established, and eight cases of serious adverse events occurred (six cases of impaired liver function and two cases of DRESS [drug rash with eosinophilia and systemic symptoms) syndrome]. Thus, the clinical trial was discontinued [48] [NCT01777256]. A phase II trial of baracetinib in patients with lupus nephritis is currently ongoing [NCT05432531].

6. Conclusion

SLE is a genetically and immunologically diverse autoimmune disease, and cells or molecules to be targeted in its treatment are diverse. Therefore, drugs targeting a single molecule may require precision medicine, in which appropriate molecular targeted drugs are selected for each patient. On the other hand, JAK inhibitors can exert broad immunomodulatory effects on highly heterogeneous immunological abnormalities in SLE by blocking signaling pathways of various cytokines. Therefore, JAK inhibitors may induce a paradigm shift in the SLE treatment strategy.

7. Expert opinion and five-year view

A priority in therapeutic strategies for SLE is to maintain a balance between efficacy and safety. Some adverse events have been predicted from mechanisms associated with the blockade of cytokines requiring JAK-STAT for signal transduction. Since JAK/STAT signaling is essential for numerous homeostatic processes, including hematopoiesis, immune cell differentiation, and organismal growth, it needs to be borne in mind in thinking about not only the effectiveness of JAK inhibitors but also adverse reactions. Furthermore, clinical trials of JAK inhibitors and biologics for SLE and lupus nephritis are being studied as an addition to standard treatments such as hydroxychloroquine, immunosuppressive agents (mycophenolate mofetil or intravenous cyclophosphamide) and glucocorticoids. Therefore, these combination therapies are the basic strategy and safety considerations, such as infection, need to be taken into account. Safety profiles of JAK inhibitors are increasingly being unveiled as a result of their use in clinical settings to date (Table 2). Herpes zoster is a common adverse event of JAK inhibitors; however, the risk may be even higher in patients with SLE, for whom the incidence of herpes zoster is already high. Thus, careful considerations are necessary to decide whether to administer JAK inhibitors to patients with SLE. Thromboembolism occurs relatively rarely in association with JAK inhibitors but is an unexpected and unexplained event [49–52]. Thrombosis has been reported to be more common in patients with SLE than in those with other immunological diseases [51]. While it is unclear whether activation of the coagulation – fibrinolysis system, platelets, or endothelial cells is involved in this phenomenon, effects of the thromboembolic events on SLE-associated antiphospholipid syndrome should be considered. Meanwhile, Hasni et al. have suggested that JAK inhibitors may alleviate cardiovascular risk and complications in SLE [36]. Thus, in these two contrasting aspects of JAK inhibition and its unknown positive or negative effects on cardiovascular diseases in SLE, there are unanswered questions that need to be clarified based on the findings of ongoing clinical trials. Furthermore, long-term safety studies on the development of infectious diseases and malignant tumors, such as lymphoma, are also necessary. As described above, deucravacitinib is highly selective for TYK2 and may leave the IL-2/IL-15 pathway intact, unlike when JAK1/3 is inhibited; thus, deucravacitinib may be advantageous in terms of malignant tumors. The answer is likely to be obtained from long-term studies, but drug development from such a perspective is also important. In September 2021, the U.S. Food and Drug Administration released an updated warning about increased risks of deaths, major cardiovascular events, malignant tumors, and thrombosis associated with JAK inhibitors compared with the risks associated with TNF inhibitors in patients with RA. Therefore, screening at the initiation of JAK inhibitor treatment and during monitoring may be important particularly in patients with SLE-associated antiphospholipid syndrome.

Table 2. Adverse events during treatment with JAK inhibitors.

Frequent adverse events observed under treatment with JAK inhibitors
Infections
Upper respiratory tract infections Nasopharyngitis Herpes zoster Herpes simplex infections
Abnormal laboratory findings
Increase in liver enzyme (AST, ALT) Increase in cholesterol, triglycerides Increase in creatine phosphokinase Decrease in hemoglobin Decrease in white blood cell count (neutropenia, lymphopenia)
Rare adverse events reported under treatment with JAK inhibitors
GI tract perforation Thromboembolic events Non-melanoma skin cancers Solid cancers Lymphoma

AST: aspartate aminotransferase, ALT: alanine aminotransferase, GI: gastrointestinal.

The candidate pathways targeted in SLE are very diverse, mainly inflammatory cytokines and their receptors, intracellular signaling, B cells or plasma cells, dendritic cells, costimulatory molecules, complement fraction, T cells, and various other immunological targets of interest. In addition to JAK inhibitors, the development of treatments using drugs that target dendritic cells (such as the anti-BDCA2 antibody litifilimab) and proteasome inhibitors (such as iberdomide) is also attracting significant attention. The ability to identify molecules that play a central role in the pathogenesis of SLE and select therapeutics that target these molecules is the result of recent revolutionary advances in science.

Whereas JAK inhibitors used in SLE trials are ATP-competitive inhibitors of JAK, deucravacitinib is an allosteric inhibitor that increases selectivity by binding to the pseudodomain and indirectly regulates the kinase domain. Furthermore, deuteration increases the binding activity of the pseudo-domain to the alanine pocket and inhibits nonspecific binding. In the future, the development of safe and effective drugs using novel compounds with such molecular structural design is also expected.

Article highlights

• Abnormalities in both innate and acquired immunity resulting from many cytokines are involved in the development of SLE.

• JAK is involved in various immunological abnormalities, and thus, it is an attractive therapeutic target for SLE.

• Multiple clinical trials on JAK inhibitors that differ in the selectivity for JAK family proteins for the treatment of SLE are being conducted.

Declaration of interest

S Nakayamada has received consulting fees, lecture fees, and/or honoraria from Bristol-Myers, GlaxoSmithKline, Chugai, Sanofi, Pfizer, Astellas, Asahi-kasei, Boehringer Ingelheim and has received research grants from Mitsubishi-Tanabe, Novartis, and MSD. Y Tanaka has received lecture fees and/or honoraria from Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, AbbVie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead, Janssen, research grants from AbbVie, Mitsubishi-Tanabe, Chugai, Asahi-Kasei, Eisai, Takeda, Daiichi-Sankyo and consultation fees from Eli Lilly, Daiichi-Sankyo, Taisho, Ayumi, Sanofi, GSK, AbbVie.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We thank Crimson Interactive Pvt. Ltd. (Ulatus) – www.ulatus.jp for their assistance in manuscript translation and editing.

Additional information

Funding

This work was supported in part by a Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number JP20K08815) and the University of Occupational and Environmental Health, Japan through an UOEH Grant for Advanced Research (grant number H30-905).