Systemic lupus erythematosus (SLE) is associated with diverse clinical manifestations, from skin lesions and arthritis, to damage to vital systems such as the blood and kidney. The management of SLE is based on the type and severity of organ involvement. Patients with SLE are treated with nonsteroidal anti-inflammatory drugs, corticosteroids, antimalarial agents, and immunosuppressive agents including cyclophosphamide, azathioprine, and mycophenolate mofetil, according to their disease activity and the extent of vital organ involvement [
B-cell depletion therapy has been shown to be clinically effective in rheumatoid arthritis (RA) [
Given these roles of B-cells in SLE pathogenesis, B-cell-targeted therapy has been recently introduced for SLE therapy. The chimeric anti-CD20 antibody, rituximab (RTX) has been reported to be a promising treatment option in several case series and off-label trials in patients with refractory SLE [
Here we report a multicenter retrospective study investigating the effectiveness and safety of RTX in Korean patients with refractory SLE.
Thirty-nine SLE patients refractory to conventional therapies received RTX, who were enrolled from eight tertiary rheumatology clinics in Korea. The patients were all native Koreans and satisfied the American College of Rheumatology 1997 revised criteria for SLE [
The clinical and response data for all patients were collected retrospectively by rheumatologists using a uniform format. The responses to treatment were determined by comparing disease activity before RTX and at 3, 6, 12, 24, and 36 months after RTX infusion using response criteria specific to the organ involved. Overall disease activity was assessed using the SLE Disease Activity Index (SLEDAI) [
For nephritis, complete response was defined as a decrease in proteinuria to <500 mg/day, disappearance of hematuria and cellular casts, and normal estimated glomerular filtration rate (eGFR), and partial response as >50% improvement in renal parameters (proteinuria and eGFR) from pretreatment values [
Dosing of RTX differed depending on the decision of rheumatologists or disease severity. Twenty-three (59.0%) patients received two 500 mg doses of RTX 2 weeks apart, five (12.8%) received 375 mg/m2/week for 4 weeks, and four (10.3%) received two 1000 mg doses of RTX 2 weeks apart (Table
Characteristics of the 39 SLE patients receiving rituximab.
Age, mean ± SD years |
|
Female, % | 92.1 |
Disease duration, mean ± SD years |
|
Major organ involved, % ( |
|
Nephritis | 43.6 (17) |
Hematologic | 33.3 (13) |
Arthritis | 7.8 (3) |
Myositis | 7.8 (3) |
Vasculitis | 5.1 (2) |
Enteritis | 2.6 (1) |
Disease activity before rituximab | |
SLEDAI score, mean ± SD years |
|
Anti-DNA antibody, % ( |
48.7 (19) |
C3, mean ± SD g/dL |
|
C4, mean ± SD g/dL |
|
Rituximab administration, % ( |
|
500 mg × 2 infusions | 59.0 (23) |
1000 mg × 2 infusions | 10.3 (4) |
375 mg/m2 × 4 infusions | 12.8 (5) |
500 mg × 1 infusion | 7.7 (3) |
Other regimen | 10.2 (4) |
| |
Previous immunosuppressive agents, % ( |
|
Mycophenolate mofetil | 48.7 (19) |
Cyclophosphamide | 43.6 (17) |
Azathioprine | 33.3 (13) |
Cyclosporine | 23.1 (9) |
IV immunoglobulin | 17.9 (7) |
Methotrexate | 7.7 (3) |
Tacrolimus | 2.6 (1) |
TNF blocker | 2.6 (1) |
Others | 5.1 (2) |
Number of immunosuppressive agents, mean ± SD |
|
Rituximab-concomitant immunosuppressive agents, % ( |
|
Glucocorticoids | 87.2 (34) |
Dosage, mean ± SD mg/day |
|
Hydroxychloroquine | 84.6 (33) |
Azathioprine | 59.0 (23) |
Cyclosporine | 28.2 (11) |
Mycophenolate mofetil | 23.1 (9) |
Cyclophosphamide | 2.6 (1) |
Number of immunosuppressive agents, mean ± SD |
|
*Values are % (number) of patients. SLEDAI: systemic lupus erythematosus disease activity index.
The Chi-square test was used to compare responders and nonresponders. Differences in continuous variables were analyzed using the Mann-Whitney
Thirty-nine patients with refractory SLE treated with RTX were included from 8 centers in Korea and did not have previously received RTX (Table
In patients with lupus nephritis, mean proteinuria was
Previous conventional treatment failure was defined as at least one course (mean ± SD,
Concomitant immunosuppressive agents used with RTX are summarized in Table
Data on the 37 patients with 6-month followup or more were analyzed for effectiveness of RTX.
Complete or partial response to RTX after 6 months was found in 28 (75.6%) patients: 11 (64.7%) lupus nephritis (0 complete and 11 partial response), 10 (90.1%) hematologic disorder (3 complete and 7 partial response), 3 (100%) arthritis (0 complete and 3 partial response), 2 (66.7%) myositis (0 complete and 2 partial response), and 2 (66.7%) others (0 complete and 2 partial response) (see Figure
Comparison of responders and nonresponders at 6 months after rituximab administration (
Nonresponders ( |
Responders ( |
| |
---|---|---|---|
Age, mean ± SD | 36.6 ± 8.8 | 30.8 ± 8.7 | 0.11 |
Female, % | 77.8 | 96.3 | 0.06 |
Disease duration, mean ± SD | 4.1 ± 3.1 | 4.9 ± 3.6 | 0.61 |
Rituximab dose, mean ± SD | 1062 ± 417 | 1285 ± 460 | 0.22 |
Response at 6 months after RTX treatment in patients with refractory SLE.
The total SLEDAI score was decreased from
SLEDAI score after RTX treatment in patients with refractory SLE. *
Among the 28 clinical responders after the first course of RTX, 4 patients (1 lupus nephritis, 3 thrombocytopenia) experienced a relapse of disease at
Adverse events were observed in 7 of 39 patients receiving RTX (17.9%). Four patients experienced mild infusion reactions (rash or myalgia) (10.3%), but severe infusion reactions such as anaphylactic shock or hypotension were not noted (Table
Adverse events in 39 SLE patients receiving rituximab.
Total adverse events, % ( |
17.9 (7) |
Infusion reaction (rash, fever, myalgia) | 10.3 (4) |
Infection (pneumonia, tuberculosis, abscess) | 7.7 (3) |
Death due to severe infection, % ( |
2.7 (1) |
*Values are % (number) of patients.
Infections were observed in 3 patients (7.7%) who developed pneumonia, tuberculosis, and an abscess after RTX therapy. Among them, one patient died of septic shock due to a multifocal abscess in the muscles of the hip.
In the present multicenter study, RTX was effective in 75.6% of patients (28/37) with refractory SLE who had responded poorly to conventional immunosuppressive treatment. The SLEDAI score was significantly lower after RTX than at baseline and remained so after 3 years. RTX infusion was relatively well tolerated in this study, with only 17.9% of patients experiencing adverse events. These findings are in keeping with those of previous open-label studies of RTX in SLE [
Two RCTs of RTX in SLE patients without lupus nephritis (Exploratory Phase II/III SLE Evaluation of Rituximab [EXPLORER]) [
The EXPLORER trial [
In the LUNAR trial [
The optimal dosing regimen for RTX in SLE remains unclear. In RCT studies, RTX 1,000 mg × 2 infusions were used and responders had a lower B-cell counts. In the present study, responders received a higher RTX dose (
It is important to note that our study differs from the LUNAR trial in that all patients with lupus nephritis included in our study were refractory to cyclophosphamide and/or mycophenolate mofetil. Two trials [
The limitations of our study include its relatively small population size, retrospective and observational design, and missing immunological data such as B-cell counts (CD19, CD20) or RTX human antichimeric antibody. In addition, the SLEDAI scores do not record improving or worsening, and may be not sensitive to small changes of disease activity after treatment. Further studies are needed to confirm RTX dose and concomitant immunosuppressive therapy.
In summary, RTX might not be recommendable as first-line treatment for patients with SLE who have potential to respond well to the conventional treatment. However, many studies including the present Korean multicenter retrospective study supported that RTX could be effective and relatively safe therapeutic option in patients with severe refractory SLE until new novel B-cell depletion therapy is widely available. Further randomized controlled trials in patients with refractory SLE are needed.
The authors declare that they have no conflict of interests.
This study was supported in part by a Grant from the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A080588).