Rituximab induction therapy for systemic lupus erythematosus works, so what about as maintenance therapy? Research courier

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This study prospectively evaluated the efficacy and safety
of rituximab (RTX) in induction of post-remission maintenance therapy in patients with recurrent or refractory systemic lupus erythematosus (SLE).
The results showed that the RTX group had a higher recurrence-free survival rate
compared with the immunosuppressant (ISA) group for maintenance therapy for 12 months (p=0.
029) or 24 months (p=0.
015).
In terms of safety, there was no significant difference in serious adverse events (SAEs) between the RTX and ISA groups (16.
2 vs 12.
1 SAEs/100 patient-years).

It can be seen that RTX maintenance therapy has good efficacy and acceptable safety
.

SLE is a chronic systemic autoimmune disease
involving multiple systems.
Corticosteroids, antimalarial drugs, and ISAs are standard treatments for SLE, but are not effective
in all patients.
Targeted B-cell therapies in biologics are of increasing concern, in which RTX can significantly improve abnormalities in B-cell homeostasis, possibly inducing long-term remission in patients with SLE
.
Several guidelines recommend the use of RTX for the treatment of recurrent and refractory SLE, but there is still insufficient evidence
on whether RTX can be used for maintenance therapy with SLE.

To compare the efficacy and safety of RTX and traditional ISAs in maintenance therapy for patients with relapsed or refractory SLE after RTX-induced remission, and to explore the predictors of SLE recurrence, Dr.
Chen Xiaotou and others at the Second Affiliated Hospital of Zhejiang University School of Medicine conducted a prospective study recently published in Rheumatology (Oxford) (Impact Factor 7.
046).

Study the design

Patients with SLE who were included in relapsed or refractory SLE and who received at least one course of RTX induction therapy, were admitted to the maintenance therapy period after 6 months of treatment with a standard dose of RTX (2×375 mg/^m2 at intervals) or a low dose (375 mg/m²+400 mg at intervals or 400 mg at 1 week interval) during the induction of remission, and the included patients with a clinical response entered the maintenance treatment period, RTX or ISA therapy is given separately with glucocorticoids, and HCQ is given in patients without contraindications to hydroxychloroquine (HCQ
).
To assess efficacy (no recurrence rate), safety, and predictors of SLE recurrence
.
The results of the clinical response assessment are as follows:

➤ Primary clinical response (MCR): 6 months with a C or better index (BILAG) score for all organs of Lupus Anglos with no recurrence in the first 6 months

➤ Partial clinical response (PCR): ≤ 1 organ BILAG score B at 6 months, or ≥ organ BILAG score A or B compared to baseline

➤ No clinical response (NCR): the definition of MCR or PCR is not met at 6 months

Results of the study

A total of 82 patients were enrolled in the study, 73 (89.
0%) were female, the median age (quartile difference [IQR]) was 32.
0 (25.
0-43.
3) years, and the median course (IQR) was 5.
5 (3.
0-11.
0) years
.

Induction therapy period

At 6 months of RTX induction therapy, 67 patients (81.
7%) had a clinical response (MCR 57.
3%, PCR 24.
4%), and 15 patients (18.
3%) had no clinical response (NCR), the former had a decrease in daily prednisone dose, BILAG, SLEDAI, and the median dose (IQR) of prednisone decreased from 45 (25-75) mg/d to 7.
5 (6-10) mg/d
.

Maintenance treatment period

The 67 patients with clinical response were divided into 2 treatment groups, 34 (50.
7%) in the RTX treatment group and 33 patients (49.
3%)
in the ISA treatment group.
The median follow-up time (IQR) was 24 (18-36) months
.
At baseline, the median dose (IQR) of prednisone was 50 (35-100) mg/day in the RTX group and 30 (25-50) mg/day in the ISA group, with a significant difference between the two groups (p=0.
044), but there was no significant difference
in the median dose of prednisone in the two groups during maintenance therapy.

During the follow-up period, 13 patients (19.
4%) relapsed, including 3 in the RTX group and 10 in
the ISA group.
The median recurrence time (IQR) was 18 (12-23) months
.
Three of the 13 patients who received RTX switched to ISA maintenance therapy for 12 to 24 months and continued to remission
after treatment.
The recurrence rate was lower in patients treated with standard dose RTX than in patients treated with low dose RTX (9.
1% vs.
29.
4%, p=0.
035).

The RTX group had a higher relapse-free survival rate than the ISA group, either within 12 months of maintenance therapy (p=0.
029) or within 24 months (p=0.
015) (Figure 1).

Figure 1 Patient-free recurrence rate during maintenance therapy in the RTX and ISA groups

A: maintenance therapy for 12 months, B: maintenance therapy for 24 months

Predictors of recurrence

Multivariate analysis showed that HCQ use (risk ratio [OR] 0.
067, 95% confidence interval [CI] 0.
010-0.
463, p=0.
006), RTX maintenance therapy (OR 0.
088, 95% CI 0.
012-0.
636, p=0.
016), and hematologic involvement (OR 0.
124, 95% CI 0.
021-0.
744, p=0.
022) were independent predictors of sustained remission in patients with SLE
。

security

At the median follow-up of 24 months throughout the study, 48 patients (58.
5%) had no adverse drug reactions (ADRs), 8 (9.
8%) had mild ADRs, 26 (31.
7%) had SAEs, and 6 patients had discontinued RTX due to SAEs with no malignant events
.
A total of 43 SAEs occurred, mainly infections (33/43, 76.
7%), of which 24 (55.
8%) occurred within
6 months of induction therapy.
There was no significant difference in SAEs between the RTX and ISA groups during maintenance therapy (16.
2 vs 12.
1 SAEs/100 patient-years
).

Research conclusions and discussion

This study prospectively assessed the efficacy and safety of RTX for induction post-remission maintenance therapy in patients with relapsed or refractory SLE
.
The results showed that the RTX group had a higher recurrence-free survival rate
compared with the ISA group for 12 months (p=0.
029) or 24 months (p=0.
015) of maintenance therapy.
In terms of safety, there was no significant difference in SAEs between the RTX and ISA groups (16.
2 vs 12.
1 SAEs/100 patient-years).

It was also found that treatment with RTX significantly reduced the dose of glucocorticoids used by patients, which is more pronounced
in RTX maintenance therapy.
This finding is important because higher glucocorticoid dose accumulation increases the risk of organ damage, and the combination of the two may lead to relapse
in patients.

Previous studies have shown that the longer the duration of B cell reduction after RTX induction therapy, the better
the disease prognosis.
In this study, the RTX and ISA groups had similar recurrence rates within 12 months after induction; After 12 months, the recurrence rate in the ISA group continued to increase and was significantly higher than in the RTX group, which may be related
to the gradual recovery of B cell activity.
A large multicenter retrospective study found that RTX maintenance therapy helped maintain the efficacy of glucocorticoids and ISAs while stabilizing disease activity
.
The results of this study also show that RTX maintenance therapy is one of
the independent predictors of sustained remission in patients with SLE.

HCQ use and haematologic involvement are also independent predictors of persistent remission of SLE
.
Studies have shown that reduction/discontinuation of HCQ increases the risk of SLE recurrence, and this study also supports the effectiveness
of continued use of HCQ in patients treated with RTX.
In addition, patients with hematologic involvement are more
likely to achieve sustained remission with RTX therapy than in patients with renal and neurologic involvement.

There were no RTX treatment-related deaths in this study, and there was no significant difference in SAEs between the RTX and ISA groups, suggesting that the safety of RTX maintenance therapy is acceptable compared to ISA
.
Moreover, more than half of SAEs occur in the induction of remission, in addition to the effects of RTX therapy, are also associated
with patients with high disease activity and simultaneous use of high-dose glucocorticoids.

Despite the lack of evidence from randomized controlled trials, RTX is widely used in induction therapy in patients with recurrent and refractory SLE
.
This study provides strong evidence that long-term RTX maintenance therapy has a good efficacy and acceptable safety profile
in patients with relapsed or refractory SLE who have a clinical response to RTX induction therapy.
The details of using RTX still need to be further investigated
.

References: Chen X, Shi X, Xue H, et al.
Rituximab as maintenance therapy following remission induction in relapsing or refractory systemic lupus erythematosus.
Rheumatology (Oxford).
2022 Aug 17:keac471.
doi: 10.
1093/rheumatology/keac471.
Epub ahead of print.
PMID: 35976105.