-
PDF
- Split View
-
Views
-
Cite
Cite
Hua Chen, Wenjie Zheng, Jinmei Su, Dong Xu, Qian Wang, Xiaomei Leng, Wen Zhang, Mengtao Li, Fulin Tang, Xuan Zhang, Xiaofeng Zeng, Yan Zhao, Fengchun Zhang, Low-dose rituximab therapy for refractory thrombocytopenia in patients with systemic lupus erythematosus—a prospective pilot study, Rheumatology, Volume 50, Issue 9, September 2011, Pages 1640–1644, https://doi.org/10.1093/rheumatology/ker176
Close -
Share
Abstract
Objectives. To evaluate the safety and efficacy of low-dose rituximab therapy for refractory thrombocytopenia in patients with SLE.
Methods. Ten adult SLE patients with severe refractory thrombocytopenia (mean platelet count 10.4 × 109/l) were enrolled in this prospective pilot study. All patients had failed traditional high-dose CSs and immunosuppressants including methylprednisolone pulse therapy. Patients were scheduled to receive i.v. rituximab at a dose of 100 mg once weekly for 4 weeks. Previous dose of CSs were gradually tapered, and immunosuppressants were withdrawn. Patients were followed at Weeks 4, 12, 24 and 36.
Results. All patients completed four courses of low-dose rituximab infusion. At Week 4, two (20%) patients achieved complete responses (CRs, platelet count >100 × 109/l). The CR rate increased to 60% (six patients) at Week 12, was maintained at Week 24 and began to drop at Week 36 (four patients, 40%). Overall response (OR, platelet count >50 × 109/l) was achieved in 5/10, 6/10, 7/10 and 5/10 patients at Weeks 4, 12, 24 and 36, respectively. Peripheral CD19+ B cells were depleted (<5 × 106/l) in all patients at Week 4, and gradually increased at Weeks 24 and 36. Serum C3, IgG, IgA and IgM levels did not change significantly (P < 0.05). Infusion reaction was observed in two patients. One patient developed pulmonary thrombosis at Week 14 and active tuberculosis at Week 25.
Conclusions. Low-dose rituximab therapy is effective in treating severe thrombocytopenia in SLE patients who do not respond to vigorous glucocorticoid plus immunosuppressants, and in most cases is safe.
Introduction
Autoimmune thrombocytopenia is a common manifestation of SLE. Rituximab, a chimeric mAb against the mature B-cell surface marker CD20, is an emerging new agent for the treatment of various autoimmune diseases [1–3], including SLE [4–8] and ITP [9, 10]. We and other groups reported that rituximab showed promising efficacy in treating refractory severe thrombocytopenia secondary to CTDs [5, 11]. However, the optimal treatment dosage of rituximab has not been explored. When treating CTD, rheumatologists used to adopt the treatment regimen from that used for B-cell lymphoma (375 mg/m2 once a week for consecutive 4 weeks) [12], though it is well realized that the B-cell load in patients with CTD is much less than that in patients with lymphoma and therefore a lower dosage of rituximab might be sufficient [13, 14]. Zaja et al. [15, 16] investigated the efficacy of lower dose rituximab (100 mg i.v. weekly for 4 weeks) in patients with ITP, and found that it had a similar response rate though the response was often slower. In our study, we performed a prospective clinical trial using low-dose rituximab (100 mg i.v. weekly for 4 weeks) to treat SLE patients with refractory thrombocytopenia.
Methods
Patients
From December 2008 to November 2009, 10 adult SLE inpatients with severe refractory thrombocytopenia at Peking Union Medical College Hospital were enrolled in the study. All patients fulfilled at least four of the 1997 ACR revised criteria for SLE [17]. Patients were excluded if they were pregnant, or had severe LN (urinary protein excretion >1.5 g/24 h or serum creatine >1.5 mg/dl), drug-induced thrombocytopenia, active infections (including Type B and C viral hepatitis) or malignant diseases.
All patients had severe thrombocytopenia (platelet count < 10 × 109/l or <30 × 109/l with bleeding propensity). All patients had failed at least one course of methylprednisolone pulse therapy (1 g/day for 3 consecutive days) and (or) IVIG (20 g/day for 3–5 consecutive days) and high-dose glucocorticoid in combination with immunosuppressants, including CYC (i.v. pulse 1000 mg every month or 100 mg/day orally), vincristine (1–2 mg, weekly) and CSA (3–5 mg/kg/day). One of them had failed recombinant human thrombopoietin (rhTPO) and one case had undergone splenectomy without improvement. The study was approved by the ethics committee of Peking Union Medical College Hospital. Written informed consent was obtained from all patients.
Treatment regimen
Rituximab (Roche, USA) at a dose of 100 mg was administered i.v. once weekly for a total of four infusions (Days 1, 8, 15 and 22) [15]. Intravenous CSs were not administered at the time of the rituximab infusions.
Previous doses of oral prednisone or prednisolone were continued and gradually tapered to minimal maintenance dose (prednisone ≤7.5 mg/day). All previous immunosuppressants were withdrawn. Patients were followed at Weeks 4, 12, 24 and 36 after the start of the first dose of rituximab.
Laboratory studies
Laboratory evaluation included: complete haemogram, serum chemistry profiles, ANAs (IIF test), anti-dsDNA antibody (IFF and ELISA tests), anti-ENA antibodies (ID and immunoblot tests) and aCL, anti-β2-glycoprotein-I (anti-β2-GP-I) antibody (ELISA test), LA (DRVVT test), direct and indirect Coombs test, lymphocyte subsets (CD19+ B cells, CD16+CD56+ NK cells, CD3+CD4+ Th cells and CD3+CD8+ Tc cells) and serum immunoglobulin (IgG, IgA and IgM) and complement levels.
Response criteria
Response criteria were defined as follow [9].
Complete response (CR): a rise in platelet count to >100 × 109/l.
Partial response (PR): a rise in platelet count to between 50 and 100 × 109/l.
No response (NR): those patients who did not have CR or PR.
Overall response (OR): patients with CR or PR.
Statistical analysis
Standard descriptive summary statistics on all parameters were carried out with SPSS software version 13.0 (SPSS, Chicago, IL, USA), including arithmetic mean, s.d., minimum value, lower quartile, median, upper quartile and maximum value. Wilcoxon signed-rank test was used for comparing parameters before treatment with those after treatment.
Results
The clinical and laboratory characteristics of the patients are summarized in Table 1. All patients were female, age ranged from 20 to 42 years [34.3 (9.5)], SLE disease duration 0.5–20 years [4.5 years; interquartile range (IQR), 1.4–7 years], duration of thrombocytopenia 0.5–10 years (1 year; IQR, 1–5 years) and the mean platelet count at baseline was 10.4 × 109/l (range 4–23 × 109/l). All patients completed four courses of low-dose rituximab infusion. At Week 4, two (20%) patients achieved CR. The CR rate increased to 60% (six patients) at Week 12, was maintained at Week 24 and began to drop at Week 36 (four patients, 40%). ORs were achieved in 5/10, 6/10, 7/10 and 5/10 patients at Weeks 4, 12, 24 and 36, respectively (Fig. 1A and B). The disease activity measured by SLEDAI [18] was markedly decreased in most patients (Table 1).
Platelet response and monitoring of laboratory parameters. (A) Each column represents response rate at a particular time point. Case 3 was lost to follow-up at Week 14 and was considered as NR at Weeks 24 and 36. (B) Platelet counts. (C) CD19+ B-cell counts. (D) Complement C3 level. (B and C) The central horizontal bold line is the median; the lower and upper box limits are the first and third quartiles, respectively. The whiskers extend to the most extreme data points. (D) Data are presented as mean (s.d.). Normal values are: CD19+ B cells, 180–350 × 106/l; C3, 0.60–1.50 g/l.
Basic characteristics, treatment response and adverse events of patients
| Case no. . | Sex . | Age, years . | Duration of SLE, years . | Duration of thrombocytopenia, years . | Medical history . | Auto-antibodies . | SLEDAI . | Platelet count, ×109/l . | Adverse events . | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 0 . | Week 24 . | Week 0 . | Week 4 . | Week 12 . | Week 24 . | Week 36 . | ||||||||
| 1 | F | 40 | 4 | 1 | Oral ulcers, arthritis, neurological disorder | ANA, anti-U1RNP, anti-β2-GP-I | 11 | 8 | 6 | 34 | 25 | 102 | 16 | None |
| 2 | F | 40 | 1 | 1 | Malar rash, oral ulcers | ANA, anti- SSA, LA | 5 | 0 | 9 | 95 | 108 | 132 | 158 | PE, TB |
| 3 | F | 42 | 20 | 5 | Arthritis, neurological disorder | ANA, anti-dsDNA, anti-U1RNP | 12 | N/A | 11 | 14 | 11 | N/A | N/A | None |
| 4 | F | 28 | 7 | 7 | Oral ulcers, arthritis | ANA, aCL | 3 | 1 | 11 | 30 | 14 | 10 | 22 | None |
| 5 | F | 31 | 0.5 | 0.5 | Oral ulcers, arthritis | ANA, anti-U1RNP | 3 | 0 | 14 | 63 | 171 | 186 | 215 | None |
| 6 | F | 29 | 0.5 | 0.5 | Photosensitivity, oral ulcers | ANA, anti-SSA | 3 | 0 | 4 | 75 | 106 | 193 | 144 | None |
| 7 | F | 53 | 10 | 10 | Nephritis, arthritis | ANA, anti-U1RNP | 7 | 5 | 10 | 26 | 119 | 44 | 39 | Infusion reaction |
| 8 | F | 20 | 7 | 1 | Malar rash, oral ulcers | ANA, anti-rRNP | 2 | 1 | 11 | 22 | 43 | 57 | 35 | None |
| 9 | F | 33 | 2.5 | 1 | Serositis, oral ulcers | ANA, anti-β2-GP-I, anti-dsDNA, anti-SSA | 5 | 0 | 5 | 157 | 120 | 121 | 92 | None |
| 10 | F | 27 | 5 | 5 | Malar rash, arthritis | ANA, anti-SSA | 3 | 0 | 23 | 135 | 193 | 143 | 136 | Infusion reaction |
| Case no. . | Sex . | Age, years . | Duration of SLE, years . | Duration of thrombocytopenia, years . | Medical history . | Auto-antibodies . | SLEDAI . | Platelet count, ×109/l . | Adverse events . | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 0 . | Week 24 . | Week 0 . | Week 4 . | Week 12 . | Week 24 . | Week 36 . | ||||||||
| 1 | F | 40 | 4 | 1 | Oral ulcers, arthritis, neurological disorder | ANA, anti-U1RNP, anti-β2-GP-I | 11 | 8 | 6 | 34 | 25 | 102 | 16 | None |
| 2 | F | 40 | 1 | 1 | Malar rash, oral ulcers | ANA, anti- SSA, LA | 5 | 0 | 9 | 95 | 108 | 132 | 158 | PE, TB |
| 3 | F | 42 | 20 | 5 | Arthritis, neurological disorder | ANA, anti-dsDNA, anti-U1RNP | 12 | N/A | 11 | 14 | 11 | N/A | N/A | None |
| 4 | F | 28 | 7 | 7 | Oral ulcers, arthritis | ANA, aCL | 3 | 1 | 11 | 30 | 14 | 10 | 22 | None |
| 5 | F | 31 | 0.5 | 0.5 | Oral ulcers, arthritis | ANA, anti-U1RNP | 3 | 0 | 14 | 63 | 171 | 186 | 215 | None |
| 6 | F | 29 | 0.5 | 0.5 | Photosensitivity, oral ulcers | ANA, anti-SSA | 3 | 0 | 4 | 75 | 106 | 193 | 144 | None |
| 7 | F | 53 | 10 | 10 | Nephritis, arthritis | ANA, anti-U1RNP | 7 | 5 | 10 | 26 | 119 | 44 | 39 | Infusion reaction |
| 8 | F | 20 | 7 | 1 | Malar rash, oral ulcers | ANA, anti-rRNP | 2 | 1 | 11 | 22 | 43 | 57 | 35 | None |
| 9 | F | 33 | 2.5 | 1 | Serositis, oral ulcers | ANA, anti-β2-GP-I, anti-dsDNA, anti-SSA | 5 | 0 | 5 | 157 | 120 | 121 | 92 | None |
| 10 | F | 27 | 5 | 5 | Malar rash, arthritis | ANA, anti-SSA | 3 | 0 | 23 | 135 | 193 | 143 | 136 | Infusion reaction |
PE: pulmonary embolism; TB: tuberculosis; F: female.
Basic characteristics, treatment response and adverse events of patients
| Case no. . | Sex . | Age, years . | Duration of SLE, years . | Duration of thrombocytopenia, years . | Medical history . | Auto-antibodies . | SLEDAI . | Platelet count, ×109/l . | Adverse events . | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 0 . | Week 24 . | Week 0 . | Week 4 . | Week 12 . | Week 24 . | Week 36 . | ||||||||
| 1 | F | 40 | 4 | 1 | Oral ulcers, arthritis, neurological disorder | ANA, anti-U1RNP, anti-β2-GP-I | 11 | 8 | 6 | 34 | 25 | 102 | 16 | None |
| 2 | F | 40 | 1 | 1 | Malar rash, oral ulcers | ANA, anti- SSA, LA | 5 | 0 | 9 | 95 | 108 | 132 | 158 | PE, TB |
| 3 | F | 42 | 20 | 5 | Arthritis, neurological disorder | ANA, anti-dsDNA, anti-U1RNP | 12 | N/A | 11 | 14 | 11 | N/A | N/A | None |
| 4 | F | 28 | 7 | 7 | Oral ulcers, arthritis | ANA, aCL | 3 | 1 | 11 | 30 | 14 | 10 | 22 | None |
| 5 | F | 31 | 0.5 | 0.5 | Oral ulcers, arthritis | ANA, anti-U1RNP | 3 | 0 | 14 | 63 | 171 | 186 | 215 | None |
| 6 | F | 29 | 0.5 | 0.5 | Photosensitivity, oral ulcers | ANA, anti-SSA | 3 | 0 | 4 | 75 | 106 | 193 | 144 | None |
| 7 | F | 53 | 10 | 10 | Nephritis, arthritis | ANA, anti-U1RNP | 7 | 5 | 10 | 26 | 119 | 44 | 39 | Infusion reaction |
| 8 | F | 20 | 7 | 1 | Malar rash, oral ulcers | ANA, anti-rRNP | 2 | 1 | 11 | 22 | 43 | 57 | 35 | None |
| 9 | F | 33 | 2.5 | 1 | Serositis, oral ulcers | ANA, anti-β2-GP-I, anti-dsDNA, anti-SSA | 5 | 0 | 5 | 157 | 120 | 121 | 92 | None |
| 10 | F | 27 | 5 | 5 | Malar rash, arthritis | ANA, anti-SSA | 3 | 0 | 23 | 135 | 193 | 143 | 136 | Infusion reaction |
| Case no. . | Sex . | Age, years . | Duration of SLE, years . | Duration of thrombocytopenia, years . | Medical history . | Auto-antibodies . | SLEDAI . | Platelet count, ×109/l . | Adverse events . | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Week 0 . | Week 24 . | Week 0 . | Week 4 . | Week 12 . | Week 24 . | Week 36 . | ||||||||
| 1 | F | 40 | 4 | 1 | Oral ulcers, arthritis, neurological disorder | ANA, anti-U1RNP, anti-β2-GP-I | 11 | 8 | 6 | 34 | 25 | 102 | 16 | None |
| 2 | F | 40 | 1 | 1 | Malar rash, oral ulcers | ANA, anti- SSA, LA | 5 | 0 | 9 | 95 | 108 | 132 | 158 | PE, TB |
| 3 | F | 42 | 20 | 5 | Arthritis, neurological disorder | ANA, anti-dsDNA, anti-U1RNP | 12 | N/A | 11 | 14 | 11 | N/A | N/A | None |
| 4 | F | 28 | 7 | 7 | Oral ulcers, arthritis | ANA, aCL | 3 | 1 | 11 | 30 | 14 | 10 | 22 | None |
| 5 | F | 31 | 0.5 | 0.5 | Oral ulcers, arthritis | ANA, anti-U1RNP | 3 | 0 | 14 | 63 | 171 | 186 | 215 | None |
| 6 | F | 29 | 0.5 | 0.5 | Photosensitivity, oral ulcers | ANA, anti-SSA | 3 | 0 | 4 | 75 | 106 | 193 | 144 | None |
| 7 | F | 53 | 10 | 10 | Nephritis, arthritis | ANA, anti-U1RNP | 7 | 5 | 10 | 26 | 119 | 44 | 39 | Infusion reaction |
| 8 | F | 20 | 7 | 1 | Malar rash, oral ulcers | ANA, anti-rRNP | 2 | 1 | 11 | 22 | 43 | 57 | 35 | None |
| 9 | F | 33 | 2.5 | 1 | Serositis, oral ulcers | ANA, anti-β2-GP-I, anti-dsDNA, anti-SSA | 5 | 0 | 5 | 157 | 120 | 121 | 92 | None |
| 10 | F | 27 | 5 | 5 | Malar rash, arthritis | ANA, anti-SSA | 3 | 0 | 23 | 135 | 193 | 143 | 136 | Infusion reaction |
PE: pulmonary embolism; TB: tuberculosis; F: female.
Monitoring of laboratory parameters
Peripheral CD19+ B cells, with a median baseline count of 226 × 106/l (range, 72–496 × 106/l), all dropped to depleted level (defined as <5 × 106/l) at Week 4, and remained at the depleted level in most patients (8/10, 80%) at Week 12, and gradually increased at Week 24 (7 × 106/l, IQR 6–42 × 106/l) and Week 36 (57 × 106/l, IQR 44–189 × 106/l) (Fig. 1C). Peripheral blood CD3+CD4+ Th cells, CD3+CD8+ cytotoxic T cells (Tc) cells, as well as CD16+CD56+ NK cells, remained stable throughout the study.
Serum C3 level was slightly increased (Fig. 1D), and serum immunoglobulin G (IgG), immunoglobulin A (IgA) and immunoglobulin M (IgM) levels were slightly decreased, but the changes did not reach statistical difference. Four out of 10 patients presented aPLs (Table 1). The titre of aCL and LA remained stable, while the titre of anti-β2-GP-I antibody decreased significantly after treatment.
Adverse events
Two patients (Cases 6 and 10) experienced mild infusion reaction during the first infusion. The reaction disappeared after adjustment of infusion rate. One patient (Case 2) developed pulmonary thrombosis at Week 14 and active tuberculosis at Week 25, and symptoms improved with anti-coagulant and anti-tuberculosis treatments. No viral or fungal infections were observed in these patients.
Discussion
In our prospective cohort study, low-dose rituximab was administered in 10 SLE patients with severe thrombocytopenia who did not respond to traditional treatment including methylprednisolone pulse therapy. The study found that 80% of the patients responded to low-dose rituximab, and the response could be as early as Week 4, in line with the depletion time of B cells. The mechanism of rituximab in treating autoimmune thrombocytopenia remains unclear. Rituximab depletes B cell and inhibits some B-cell pathologic functions, including autoantibody production, antigen presenting and cytokine secretion. B-cell depletion by rituximab may also revert the Th1/Th2 ratio as well as expression of Fas ligand, Bcl-2, Bax in Th cells in patients with ITP [19]. In our study, the response could be maintained throughout 24 weeks, despite concomitant glucocorticoids being gradually tapered, and patients discontinuing previous immunosuppressants. When followed at Week 36, thrombocytopenia began to flare in two patients, requiring retreatment with rituximab. Due to the small number in the study, it was impossible to extrapolate which parameter could be used to predict patient response, though as shown in Table 1, patients with longer duration of thrombocytopenia (>5 years) seem to respond less well to rituximab treatment.
It is not surprising to find that with the low-dose regimen, infusion reaction were rare and did not require discontinuation of treatment. During follow-up, one patient had active tuberculosis at Week 25. Despite the fact that it might not be justified to ascribe the tuberculosis episode solely to low-dose rituximab, as the patient had a very long history of SLE (20 years), and had been vigorously treated with glucocorticoid and immunosuppressants, we suggest cautious tuberculosis screening before rituximab treatment, because low-dose rituximab could also potently deplete B cells.
In our study, four patients had aPLs. Though thrombocytopenia in three of them responded to rituximab treatment, one patient developed thrombosis 14 weeks after the treatment. Suzuki et al. [20] reported two cases of thrombotic exacerbation in lupus patients with APS after retreatment with rituximab. Our study also suggests that in lupus patients with APS, though rituximab is an effective treatment for thrombocytopenia, it cannot effectively prevent patients from developing thromboembolism.
In conclusion, our study shows that low-dose rituximab therapy is promising in treating severe thrombocytopenia in SLE patients. A randomized, comparative study with standard and low-dose rituximab is warranted. In view of the paucity of effective treatment options and cost-effectiveness, low-dose rituximab should be considered in SLE patients with severe thrombocytopenia that do not respond to vigorous glucocorticoid plus immunosuppressants.

Acknowledgements
Funding: This work was supported by National Key Technology R&D Program (2008BAI59B03, 2008BAI59B02), New Century Excellent Talents Project, Ministry of Education of China (NCET04-0191), National Natural Science Foundation of China (30400410, 30972731) and National Program for Key Basic Research Project (2007CB512405 for Immunology), Ministry of Science and Technology, China.
Disclosure statement: The authors have declared no conflicts of interest.
References
- thrombosis
- churg-strauss syndrome
- immunosuppressive agents
- lung
- carotid sinus syncope
- b-lymphocytes
- systemic lupus erythematosus
- glucocorticoids
- adult
- cd19 antigens
- craniosynostosis
- lung compliance
- methylprednisolone
- platelet count measurement
- safety
- thrombocytopenia
- immunoglobulin a
- immunoglobulin g
- immunoglobulin m
- pulse
- rituximab
- infusion procedures
- active tuberculosis


Comments