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This study aimed to determine the effect and safety of telitacicept, an antagonist of BLyS/APRIL-mediated B cell activation, in patients with systemic lupus erythematosus (SLE) who failed treatment with belimumab and in whom telitacicept was administered combined with conventional therapy. A review of published reports on telitacicept for SLE was also performed.
Methods
A retrospective review was performed of the records of patients seen in the Department of Rheumatology at the Wuhan Hospital of Chinese and Western Medicine, Wuhan, China, with refractory SLE who had failed treatment with belimumab. The terms “systemic lupus erythematosus” and “telitacicept” were used to identify patients reported in the English medical literature.
Results
Identified were 14 refractory SLE patients, 3 males (21%) and 11 females (79%). The median age was 32.9 years. The median disease duration was 8.9 years. Patients in this cohort received telitacicept for an average of 34.1 weeks (17–62 weeks) and the total SLE responder index 4 (SRI-4) response rate was 78.9% (n = 11). The mean SLE Disease Activity Index (SLEDAI) score declined from 8.6 at baseline (95% confidence interval [CI] 7.87–9.28) to 4.29 at the endpoint (95% CI 3.4–5.16). All cases (100%) had hypocomplementemia at baseline, and 7 cases (50%) reported normal C3 and C4 levels at the follow-up endpoint. At the observation endpoint, the 24‑h urinary protein value of the 13 cases with proteinuria (baseline 24‑h urinary protein > 0.5 g/d) displayed a reduction, and 3 values turned negative. Although some patients had low serum total immunoglobulin (Ig) levels, subnormal IgG levels, and absolute counts of peripheral blood lymphocytes after treatment, no serious infection was reported. One case was refractory lupus hepatitis confirmed by liver pathology, and upon change to change to telitacicept treatment, liver function returned to normal.
Conclusion
This is the first case series in SLE patients who accepted telitacicept treatment after failed treatment with belimumab. Our case series and review of the literature show that telitacicept combined with the original standard treatment may significantly improve disease activity while reducing prednisone use. No major safety issues were seen in this group of patients. Telitacicept may be a promising drug for the treatment of refractory lupus hepatitis.
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Introduction
Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease characterized clinically by multiple system involvement and multiple positive autoantibodies, and symptoms that range from mild to severe and even life threatening [1]. The treatment drugs for SLE are constantly being updated and replaced, are not universally effective, and produce severe adverse effects [2]. Therefore, safe and effective new treatments for SLE are urgently needed.
At present, the pathogenesis of SLE is still unknown. Moreover, its clinical manifestations are highly heterogeneous, and no single mediator or approach can account for the complex pathogenesis. A number of studies have suggested that immune dysfunction at the level of B cells, T cells, cytokines, and macrophages is closely related to SLE pathogenesis [3]. B cells play a very important role in the generation of disease via disruption of immune balance and the production of a variety of autoantibodies, which provides a theoretical basis for the study of new therapeutic targets [4‐7].
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It is well known that levels of B lymphocyte stimulator (BlyS) and a proliferation-inducing ligand (APRIL) are elevated in patients with SLE. Telitacicept is a new kind of dual BLyS/APRIL inhibitor that effectively blocks proliferation of activated B lymphocytes. These results indicate that blockade of BLyS alone by belimumab may be worse than dual blockade by telitacicept. Telitacicept not only inhibits activated B cells, but also has the advantage of targeting long-lived plasma cells [8]. Based on past efficacy and safety data, telitacicept has been approved in China to treat patients with active SLE [4].
To date, there are no reported real-world data on application of telitacicept in SLE patients who have failed treatment with belimumab, either in China or in other countries. In this study, we aimed to explore the efficacy and safety of telitacicept in patients with SLE who failed belimumab treatment.
Methods
The records of all patients diagnosed with SLE in the Department of Rheumatology at the Wuhan Hospital of Chinese and Western Medicine, Wuhan, China, from March 2022 to July 2023 were reviewed. The course of their illness until July 2023 or their last visit was noted. All patients fulfilled the American College of Rheumatology (ACR) criteria for SLE [9]. The extracted patient information was deidentified to ensure anonymity, and the study adhered to the tenets of the Declaration of Helsinki. Demographic data and age at administration of telitacicept in SLE patients were recorded. The use of immunosuppressive drugs or glucocorticoids, course of disease, and duration of follow-up after treatment with telitacicept were recorded.
All patients were administered telitacicept combined with standard treatment (glucocorticoids and/or immunosuppressants mycophenolate mofetil, cyclophosphamide, tacrolimus, cyclosporin, etc., and/or antimalarials). Telitacicept was subcutaneously injected once a week on the basis of standard treatment with 80 mg or 160 mg, and the choice of dosage was based on the severity of disease and financial situation of the patient. The SLE responder index 4 (SRI-4) was assessed monthly. Patients were enrolled at different starting points, but all were observed at the same endpoint (July 01, 2023).
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Results
Case series of patients
A total of 14 patients had used telitacicept after failing treatment with belimumab combined with conventional therapy. The demographic data, clinical manifestations, and treatment at the time of the first telitacicept administration are shown in Table 1. The endpoint of follow-up for all cases was 17–62 weeks. Among the 14 cases of SLE, three were males (21%) and 11 were females (79%). Median age was 32.9 years. The median duration of disease was 8.9 years. All cases were refractory SLE, among which 12 cases were patients with lupus nephritis. Prior to injection of telitacicept, 5 patients had received ≥ 2 immunosuppressants, and all patients had terminated belimumab treatment at least 6 months prior. These immunosuppressive drugs included mycophenolate mofetil (n = 7), azathioprine (n = 1), calcineurin inhibitors (n = 8), and leflunomide (n = 2). The median length of the disease course was 8.9 (1–18) years, and the median Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was 8.6 (8–12) points. Among all 14 patients, the decision to inject telitacicept was due to persistent and recurrent conditions and difficulty in reducing glucocorticoids. Patients received medication at a dose of 160 mg (n = 7) or 80 mg (n = 7) every week. The specific values of 24‑h urine protein before and after treatment with belimumab are shown in Table 1.
Table 1
The baseline conditions of systemic lupus erythematosus patients before treatment with telitacicept
Case
Age (years)
Gender
Disease duration (years)
Belimumab (10 mg/kg), number of times
Before belimumab, 24‑h urinary protein (mg/24 h)
After belimumab, 24‑h urinary protein (mg/24 h)
Low complement level
Prior to telitacicept treatment
Glucocorticoids(mg)
Immunosuppressant
1
24
Female
6
8
300
350
Yes
14a
Aza 50 mg bid + HCQ
2
26
Male
14
8
3600
2027.2
Yes
10a
MMF + FK + HCQ
3
33
Male
6
8
3675
4409
Yes
20b
MMF + FK
4
26
Female
3
10
1208
1085.4
Yes
17.5b
FK + HCQ
5
28
Female
6
9
1807
1534.5
Yes
15b
MMF + HCQ
6
45
Female
12
8
1890
1550
Yes
20b
MMF + HCQ
7
35
Female
5
8
2306
2202.5
Yes
10a
LEF + FK
8
16
Female
9
11
1200
1025.6
Yes
15b
CsA
9
39
Female
9
8
4008.6
4985.5
Yes
20b
FK + HCQ
10
19
Male
1
8
1560
1061
Yes
14a
MMF + HCQ
11
46
Female
9
13
1205.8
896
Yes
8a
HCQ + HCQ
12
49
Female
18
8
1823.8
1500
Yes
20b
LEF + CsA + HCQ
13
32
Female
10
10
8345.6
9560.5
Yes
17.5b
MMF + FK + HCQ
14
43
Female
17
10
4367.2
5455.9
Yes
20b
MMF
LEF leflunomide, MMF mycophenolate mofetil, CsA cyclosporine A, FK tacrolimus, Aza azathioprine, HCQ hydroxychloroquine
amethylprednisolone
bprednisone acetate
Primary outcome
Telitacicept was given for at least 17 weeks in all 14 cases. At the endpoint of observation, patients in the cohort had received telitacicept for an average of 34.1 weeks (17–62 weeks), and the total SRI‑4 response rate was 78.9% (n = 11). The response rate was 100% (3/3) in the 160-mg group. The mean SLEDAI score declined from 8.6 at baseline (95% confidence interval [CI] 7.9–9.3) to 4.3 at the endpoint (95% CI 3.4–5.2). In terms of the British Isles Lupus Assessment Group (BILAG) index, 14 cases (100%) achieved no additional organ reaching BILAG grade A or no more than one additional organ elevating to grade B. The Physician Global Assessment (PGA) did not increase ≥ 0.3 in any of the 14 patients (100%), indicating either stable or improving with no deterioration (Table 2).
Table 2
Primary outcome of telitacicept treatment in systemic lupus erythematosus patients
SRI‑4
SLEDAI score
BILAG1
PGA score
Case
Dose (mg), frequency, number of weeks
Endpoint n = 14
Pretreatment n = 14
Posttreatment n = 14
Posttreatment n = 14
Pretreatment n = 14
Posttreatment n = 14
1
160, qw × 62
Response
8
2
YES
1.5
0.5
2
160, qw × 61
Response
8
4
YES
1.2
0.8
3
160, qw × 55
Response
8
2
YES
1.5
0.8
4
160, qw × 43
Response
12
4
YES
1.5
0.5
5
160, qw × 31
Response
8
4
YES
1.5
0.8
6
160, qw × 39
Response
8
4
YES
1.2
0.8
7
160, qw × 35
Response
10
4
YES
1.2
0.8
8
80, qw × 31
No response
8
8
YES
1
0.8
9
80, qw × 27
No response
8
6
YES
1
0.8
10
80, qw × 23
Response
8
4
YES
1
0.8
11
80, qw × 19
No-response
8
6
YES
1.5
1.2
12
80, qw × 18
Response
10
4
YES
1.5
0.5
13
80, qw × 17
Response
8
4
YES
1.5
0.8
14
80, qw × 17
Response
8
4
YES
1
0.8
SLEDAI Systemic Lupus Erythematosus Disease Activity Index, BILAG British Isles Lupus Assessment Group PGA Physician Global Assessment, qw weekly
Secondary outcome
Twelve of the remaining 14 cases achieved a reduction in glucocorticoid administration by > 25% or a maintenance dose of ≤ 7.5 mg daily, of which 4 cases maintained a prednisolone dose ≤ 7.5 mg/d, and no cases increased glucocorticoid dosage. Fourteen cases had both C3 and C4 reexamined, and all cases showed either a stable or upwards trend; among them, all cases (100%) had hypocomplementemia at baseline, and 7 cases (50%) reported normal C3 and C4 levels at the end of follow-up. At the observation endpoint, the median 24‑h urinary protein value of the 13 cases with proteinuria (baseline 24‑h urinary protein > 0.5 g/d) showed a reduction, and 3 of them became negative. Among the 14 cases with hypoalbuminemia, plasma albumin increased to normal levels in four cases, and one case was not reexamined. Seven cases were subjected to reexamination of the anti-dsDNA antibody titer at the endpoint, and the antibody had become negative in 3 of these cases (Table 3). Between baseline and the endpoint, serum total immunoglobulin decreased in 9 patients, serum IgG decreased in 4 patients, and peripheral blood lymphocytes decreased in 6 patients, among whom 2 patients had a serum IgG level < 4.5 g/L, and there was no statistical difference in the above indicators (p = 0.403, p = 0.148, p = 0.285; Fig. 1). No serious infection was reported. Case 1 was a refractory patient with lupus hepatitis confirmed by liver pathology. Belimumab combined with the standard treatment was ineffective for 6 months, but after changing to telitacicept treatment, the liver function returned to normal.
Table 3
Secondary outcome of telitacicept in systemic lupus erythematosus
Case
Glucocorticoid reduction
Decreased anti-ds DNA antibody titerc
C3 (pre/post; g/L)
C4 (pre/post; g/L)
24‑h urinary protein (mg/24 h)
Plasma albumin (change trend)
Before (mg)
After (mg)
1
14a
6a
Negative
Low/N
N/N
N
Rise
2
10a
10a
Negative
Low/N
N/N
N
Risee
3
20b
7.5b
Negative
Low/N
Low/N
Low
Rise
4
17.5b
7.5b
Yes
Low/rise
Low/low
N
Risee
5
15b
10b
Yesd
Low/N
N/N
Low
Rise
6
20b
10b
Negative
Low/rise
N/N
Low
Rise
7
10a
8a
Negative
Low/rise
Low/N
Low
Rise
8
15b
10b
No
Low/low
N/N
Low
Descend
9
20b
10b
Negative
Low/rise
N/N
Low
Rise
10
14a
4a
No
Low/rise
N/N
N
Risee
11
8a
6a
No
Low/N
N/N
Low
Rise
12
20b
10b
Yesd
Low/N
N/N
Low
Risee
13
17.5b
10b
Yesd
Low/rise
N/N
Low
Rise
14
20b
10b
Negative
Low/N
N/N
Low
Rise
N normal
amethylprednisolone
bprednisone acetate
cthe anti-dsDNA antibody changes from positive to negative, or the titer of anti-dsDNA antibody decreases compared with that of the baseline
danti-dsDNA antibody turned negative
eplasma albumin turned negative
Fig. 1
Secondary outcome of telitacicept in systemic lupus erythematosus
All patients were still on treatment at the end of follow-up. One case of urinary tract infection and one case of pneumonia were reported. Both were classified as moderate, and both recovered after systemic treatment. No deaths were reported.
Discussion
Systemic lupus erythematosus is a chronic inflammatory relapsing autoimmune disease with multiple clinical manifestations and positive autoantibodies [12]. Patients with SLE suffer from chronic organ injury due to both active disease and multidrug toxicity [10]. While the prognosis of SLE has greatly improved over the past 40 years, there is still an urgent need for a safer and more effective treatment, particularly in patients with recurrent disease or difficulty with glucocorticoid reduction [14].
Belimumab, an anti-BAFF monoclonal antibody, was approved by the United States Food and Drug Administration (FDA) for use in treating SLE. Belimumab has recently been widely used for treatment of SLE involving various organs [15].
Telitacicept (tradename: Tai’ai) is a fusion protein comprising a recombinant transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) receptor fused to the fragment crystallizable (Fc) domain of human immunoglobulin G (IgG). Atacicept is also a soluble, fully human, recombinant fusion protein that inhibits the B cell-stimulating factors APRIL and BLyS and reduces B lymphocyte numbers and immunoglobulin levels in some studies. However, one study was terminated after enrollment of 6 patients due to an unexpected decline in serum IgG and occurrence of serious infections [13]. In the current study, some patients had decreased IgG levels after treatment, and IgM levels also slightly decreased; no cases of severe infection occurred. The level of immunoglobulin may be a reliable indicator for assessing the level of immunosuppression and adjusting the telitacicept dose, and further research is needed.
It was discovered in the current study that in the 14 patients with refractory SLE, disease activity could be relieved or controlled within a short period of time after administration of telitacicept. The drug retention rate of the 14 SLE cases was 100% during the observation period. There was no self-discontinuation caused by difficulties in administration or adverse reactions. A real-life observational study of 20 cases of SLE showed that telitacicept is a potential treatment option for patients with SLE, especially for lupus nephritis [13]. Consistent with the above report, in the present study, 13 of 14 cases had experienced repeated albuminuria before accepting telitacicept treatment, and urinary protein was relieved to varying degrees in 12 patients. As mentioned previously, reducing the glucocorticoid dose is a key treatment goal in SLE [11]. Similar to other literature reports [14, 15], a key finding of this study was the reduction in corticosteroids and no cases of upregulated glucocorticoid dosages. From case 1, it was found that telitacicept may be a promising drug for treatment of refractory lupus hepatitis, but this still needs to be confirmed in a large-sample study.
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In contrast to other studies, telitacicept was well tolerated: adverse events were mild to moderate, and all resolved after symptomatic treatment, with one case of urinary tract infection and one case of pneumonia reported [16]. The study has some limitations. First, in this observational study of SLE, the number of subjects was small. The second possible bias of this study is the relatively short median observation time, which was only 7–53 weeks. The third possible bias is that belimumab may have enhanced the effect of telitacicept. In this study, all patients terminated treatment with belimumab and started using telitacicept 5 weeks later, and a pharmacokinetic study on belimumab showed that in the intravenous group, the mean serum belimumab concentration progressively decreased to 15.7% at 672 h (day 29) and to 3% at 1680 h (day 71) [17]. The estimated population terminal half-life was 19.4 days. Therefore, after 5 weeks there was very little residual belimumab, which likely did not have an impact on the subsequent evaluation of the efficacy of telitacicept, although further research is needed. Despite these limitations, the study provides valuable information about the effect of telitacicept treatment in patients with active autoantibody-positive SLE. Despite these limitations, to the best of the authors’ knowledge, this is the first observational study in patients with SLE who have failed treatment with belimumab.
In conclusion, this study found that telitacicept is a potential treatment option for patients with SLE, especially in lupus nephritis, with a significantly increased SRI‑4 response rate and reduced glucocorticoid use.
Declarations
Conflict of interest
Q. Fan, H. Yang, and Y. Liu declare that they have no competing interests.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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