|Year : 2023 | Volume
| Issue : 1 | Page : 6-10
Outcome of rituximab therapy in patients with systemic lupus erythematosus
Mufaddal Adil Alaithan1, Hussein Halabi2, Maryam Mohammed Shamaa2, Rawan Naser Alharbi3, Nuwar Ibrahim Aljoma3, Hanan Al Rayes1
1 Department of Medicine, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
2 Department of Rheumatology, King Faisal Specialist Hospital, Jeddah, Saudi Arabia
3 Department of Internal Medicine, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
|Date of Submission||12-May-2022|
|Date of Decision||28-Oct-2022|
|Date of Acceptance||29-Oct-2022|
|Date of Web Publication||31-Mar-2023|
Dr. Hanan Al Rayes
Department of Medicine, Prince Sultan Military Medical City, Riyadh
Source of Support: None, Conflict of Interest: None
Purpose: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs. Rituximab (RTX) is an anti-CD20 monoclonal antibody that is an approved treatment for various autoimmune diseases. However, no randomized controlled trial (RCT) has proved the benefit of RTX for patients with lupus nephritis (LN). We conducted a retrospective study to evaluate the effectiveness of RTX as an immunosuppressive treatment for SLE and LN. Methods: Subjects were selected by reviewing medical records from January 2004 to July 2020 in the rheumatology departments of two hospitals in Saudi Arabia. Patients were included if they were >16 years of age with a diagnosis of SLE that fulfilled the 2019 European League Against Rheumatism and the American College of Rheumatology criteria and had received RTX for SLE. Clinical and laboratory data, SLE disease activity index (SLEDAI) score and adverse events before and 3, 6, and 12 months after starting RTX were collected. Statistical analysis was conducted comparing median baseline values with those at various times after starting RTX. Results: 40 patients with SLE were included in the study. The indications for RTX were arthritis (37.5%) and LN (32.5%), with LN varying in severity. Over the 12 months from starting RTX, there were significant improvements in SLEDAI score, and anti-dsDNA antibody, C3, and C4 levels (P<0.001, P=0.048, P<0.001, and P=0.005, respectively). Steroid dose was also significantly reduced (P<0.001) post-RTX. Meanwhile, serum creatinine at 6 and 12 months did not differ significantly from the baseline. Proteinuria in patients receiving RTX for LN showed a significant reduction from median baseline value to that at 12 months (P=0.028). Conclusions: RTX effectively controlled multiple manifestations of SLE in a Saudi population and exhibited a steroid-sparing effect in this population. Larger RCTs should be conducted to determine the patients that could benefit from such treatment.
Keywords: Lupus erythematosus, lupus nephritis, rituximab, systemic
|How to cite this article:|
Alaithan MA, Halabi H, Shamaa MM, Alharbi RN, Aljoma NI, Al Rayes H. Outcome of rituximab therapy in patients with systemic lupus erythematosus. Ann Rheumatol Autoimmun 2023;3:6-10
|How to cite this URL:|
Alaithan MA, Halabi H, Shamaa MM, Alharbi RN, Aljoma NI, Al Rayes H. Outcome of rituximab therapy in patients with systemic lupus erythematosus. Ann Rheumatol Autoimmun [serial online] 2023 [cited 2023 Jun 7];3:6-10. Available from: https://www.arajournal.org//text.asp?2023/3/1/6/373349
| Introduction|| |
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of many cytokines and autoantibodies, which cause multisystemic inflammation with variable clinical manifestations and laboratory abnormalities. Females are more commonly affected than males. In addition, the incidence of SLE is higher among people of African American descent compared with Caucasians in the United States. Hispanics and Asians also had a higher incidence and prevalence of SLE compared with Caucasians, and the incidence of SLE among Arab Americans was twice that of Caucasians.
The immunogenesis mechanism of SLE plays an important role in inflammation pathways that lead to dysregulation of the adaptive immune system via the production of multiple cytokines and the triggering of cell signal transduction processes, which culminate in inappropriate recruitment and activation of B cells and DCs to inflammatory sites. The role of B cells in lupus is variable. In SLE, auto-reactive B cells produce numerous pathogenic autoantibodies that bind to self-antigens. Different signals acquired from other immune cells enhance and maintain survival and differentiation of B cells into antibody-producing plasma cells at varying levels. Toll-like receptor 7 (TLR7) and TLR9 recognition of immune complexes by plasmacytoid dendritic cells (pDCs) stimulates the synthesis of IFNs in the pDCs, which increases B-cell activating factor (BAFF) production by myeloid dendritic cells (mDCs). BAFF increases survival, proliferation and differentiation of B cells into plasma cells after binding to its three receptors, BAFF-R, TACI and BCMA, which are all expressed on B cells. Another cytokine required for plasma-cell differentiation is interleukin 6 (IL-6). T cells and mDCs release IL-6, with T cells connecting with B cells via CD40:CD40L and cognate MHC-II: TCR interactions. After activation, B cells also release IL-6, resulting in an autocrine positive feedback loop that amplifies the stimulatory impact. B-cells-targeted treatments are based on techniques that disrupt B-cell survival and differentiation. Most subsets of B cells express CD19 and CD20 at various phases of development, and anti-CD20 antibodies, such as rituximab (RTX), are used to deplete B cells.
SLE can affect all organs in the body. Lupus nephritis (LN) is a serious manifestation of SLE and this renal involvement results from glomerular, tubule-interstitial and vascular lesions. Approximately 40% of patients with SLE experience LN, often within five years of diagnosis with SLE, and progression to end-stage renal disease is 4.3%–10.1%. RTX, which is an approved treatment for various autoimmune diseases, has been reported as a therapeutic option in patients with LN where standard treatment failed. Through targeting of B cells, RTX was effective at controlling SLE in many observational studies. For example, evaluation of open-label RTX in 24 patients found benefits regarding LN. A retrospective study of 45 patients with SLE found RTX was effective at controlling disease; 89% of patients achieved either complete or partial remission after administration of RTX despite having a history of poor responsiveness or nonresponsiveness to conventional therapy. However, in contrast, two randomized controlled trials (RCTs) for nonrenal and renal SLE (EXPLORER and LUNAR, respectively) did not meet the primary endpoint and prove the superiority of RTX over placebo when used in addition to standard therapy. Given the varied findings of previous studies, we aimed to evaluate the effectiveness of RTX as an immunosuppressive treatment for LN.
| Methods|| |
The research was conducted in Prince Sultan Military Medical City in Riyadh and King Faisal Specialist Hospital and Research Center in Jeddah, Saudi Arabia. Medical records from January 2004 to July 2020 in the Rheumatology Departments of the two hospitals were reviewed to select subjects for the study. Patients were included if they were >16 years of age with a diagnosis of SLE that fulfilled the 2017 ACR/EULAR criteria and had received RTX for SLE at the discretion of their primary physician. Patients were excluded if they had received RTX for any other indication or had any rheumatic disease other than SLE. The date and exact indication for starting RTX was assessed for each patient. Clinical and laboratory data before and 3, 6, and 12 months after starting RTX were collated and assessed, including: presence or absence of nephritis, mucocutaneous manifestations, and arthritis; levels of 24-hour urinary protein and complement C3 and C4; anti-dsDNA levels (determined by immunofluorescence method); complete blood count; renal function; SLE disease activity index (SLEDAI) score; and adverse events (allergic reactions or infections). Only one patient had received previous immunosuppressive therapy (belimumab) [Table 1], and the indication for RTX was variable between arthritis, hematological disorders and renal symptoms [Table 2]. For patients with LN, induction was with cyclophosphamide but did not achieve complete renal response; therefore RTX was administered and maintained throughout the follow-up period.
|Table 2: Indications for rituximab and classification of lupus nephritis|
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Efficacy was determined to be reached based on the following parameters: a reduction of 3 points of more in the SLEDAI score; a ≥50% reduction in proteinuria or serum creatinine if abnormal at baseline was regarded as a partial renal response; proteinuria <500 mg/day and a normal serum creatinine were counted as a complete renal response; hemoglobin >10 g/dL or an increase by 2 g/dL from baseline in cases of hemolytic anemia; and a platelet count >100 × 109/L for a complete response or >50 × 109/L for a partial response, for patients with thrombocytopenia.
Data were analyzed using IBM SPSS 28.0. Frequencies and percentages are reported for qualitative variables. Data with means are reported ± standard deviation (SD). A one-sample Kolmogorov–Smirnov (KS) test was applied to assess the normality of quantitative variables, and as the quantitative variables were not normally distributed, they are presented as median (25th–75th quartile). Wilcoxon signed-rank test was applied to compare the clinical parameters at baseline and 12 months, while the Friedman test was applied to compare various clinical parameters at baseline, 3 months and 6 months. Post hoc analysis with Wilcoxon signed-rank tests was conducted with a Bonferroni correction applied. A P < 0.05 was considered statistically significant for all statistical tests.
| Results|| |
A total of 40 patients with SLE were included in the study; 34 patients (85%) were female. The mean age was 39.22 ± 12.55 years and the mean age at diagnosis was 29.87 ± 12.51 years. Most patients had arthritis (83%) and skin rash (70%), and some had alopecia (37.5%). An overview of the demographics and characteristics of the patients is presented in [Table 1]. The most common indications for RTX were arthritis (37.5%) and LN (32.5%). Two patients received RTX for combined manifestations—one for LN with arthritis and another for LN with autoimmune hemolytic anemia. The severity of LN varied; 10% of patients had LN class VI, 10% had class IV + V, 2.5% had class III, 5% had class III + V, and 10% had no biopsies to determine the class of LN. A list of indications for RTX along with the manifestations of SLE is shown in [Table 2].
Over a period of 12 months, the SLEDAI score improved significantly from a median of 9 at baseline, to 4 and 2 at 6 and 12 months, respectively (P < 0.001). The anti-dsDNA titer improved significantly from 628 IU/mL at baseline to 256.5 IU/mL and 187 IU/mL at 6 and 12 months, respectively (P = 0.048). Complement C3 also increased significantly from a baseline median of 0.69 g/L–0.78 g/L and 0.91 g/L at 6 and 12 months, respectively (P < 0.001). Complement C4 showed similar results with improvement from a median of 0.10 g/L at baseline to 0.17 g/L and 0.19 g/L at 6 and 12 months, respectively (P = 0.005). In contrast, serum creatinine did not differ significantly from baseline to 6 and 12 months, with median values of 62.5 μmol/L, 60.5 μmol/L and 62 μmol/L, respectively. An observed reduction in proteinuria was not significant when comparing median values at baseline (0.39 g/day), 6 months (0.25 g/day) and 12 months (0.24 g/day) (P = 0.233). However, subgroup analysis of proteinuria in patients receiving RTX for LN showed a significant reduction from a baseline median of 1.47 g/day to 0.24 g/day at 12 months, (P = 0.028). [Table 3] and [Table 4] summarize these data on response and efficacy of RTX.
|Table 4: Assessment of proteinuria at baseline and 12 months postrituximab|
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To further clarify the efficacy of RTX, a post hoc analysis was conducted comparing the effect of baseline to 6 and 12 months, as well as 6 months to 12 months [Figure 1]. The SLEDAI score had a significant reduction from baseline to 6 months (P < 0.001) and from baseline to 12 months (P < 0.001), but there was no significant difference in SLEDAI score from 6 to 12 months (P = 0.290). Anti-dsDNA antibody levels were significantly reduced from baseline to 12 months (P < 0.001), but there was no significant reduction from baseline to 6 months (P = 0.056) or between 6 and 12 months (P = 0.314). Complement C3 showed a significant difference from baseline to 6 months (P = 0.018) and from baseline to 12 months (P < 0.001), but there was no significant difference from 6 months to 12 months (P = 0.630). Complement C4 levels also showed a significant difference from baseline to 6 months (P < 0.001) and from baseline to 12 months (P < 0.001), with no significant difference from 6 months to 12 months (P = 0.768).
There was a marked steroid-sparing effect seen post-RTX. The overall steroid dose was significantly reduced from a median of 10mg prednisolone at baseline to a median of 5 mg at 12 months (P < 0.001). Post hoc analysis showed that the steroid dose had a significant reduction from baseline to 6 months (P = 0.019) and from baseline to 12 months (P < 0.001); however, no statistical difference was observed when comparing steroid doses for 6 and 12 months (P = 0.305).
To determine the infection rate in the patients, we reviewed all cultures performed because of a suspicion of infection during the RTX treatment period of each patient. A total of 78 blood cultures, 15 urine cultures and 38 sputum cultures were recorded, and of these, 10 (12.82%), 2 (13.33%) and 10 (26.31%), respectively, were positive cultures. In addition, one patient had a positive stool test for Clostridium difficile toxins and another patient had a positive COVID-19 swab.
Only one patient had a severe allergic reaction to RTX, while two other patients experienced mild to moderate allergic reactions but were able to continue with RTX.
| Discussion|| |
RTX effectively controlled various manifestations of SLE in our cohort of patients. RTX was significantly effective in controlling disease activity in general as evidenced by the reduction in SLEDAI score. This confirms the efficacy of RTX on articular and hematologic manifestations of SLE in our population. The lack of a significant effect of RTX on renal function, i. e. creatinine level, could be secondary to the fact that most patients had normal creatinine levels. However, a subgroup analysis of patients who received RTX for LN showed a significant reduction of proteinuria at 12 months from baseline. Our results are consistent with previous publications that reported the efficacy of RTX for SLE in multiple cohorts and retrospective studies. We found meta-analysis done in Saudi Arabia emphasized the effectiveness of RTX therapy in refractory SLE and LN with a favorable safety outcome; however, larger RCTs, like LUNAR and EXPLORER, have failed to demonstrate efficacy.,
The analysis of infections was limited in the present study owing to difficulties in retrieving outpatient data for infections. Consequently, the frequency of infections in patients undergoing RTX therapy may be underestimated in this study. Only one patient tested positive for COVID-19, therefore it was not possible to gauge the effect of RTX on the outcome of COVID-19 in our study.
Most patients tolerated treatment with RTX. A few patients experienced allergic reactions but were treated with antihistamines and hydrocortisone and RTX therapy was continued. This suggests that allergic reactions, while present, were not a major safety concern in most of the patients.
Our post hoc analysis showed that the SLEDAI score improved within 6 months of starting RTX, along with significant steroid-sparing effect. However, improvements in anti-dsDNA levels took longer, up to 12 months to show significance.
The study does have some limitations. The retrospective design is a source of bias and the sample size was small. In addition, all patients were of one ethnic background, which might limit the applicability of the findings for people from different ethnic backgrounds.
| Conclusion|| |
In summary, RTX effectively controlled multiple manifestations of SLE in a Saudi population and showed a favorable steroid-sparing effect in the population. However, larger RCTs should be conducted to determine the patients that could benefit from such treatment.
We acknowledge the support by the Saudi Society of Rheumatology.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]