Abstract
Aims
To characterise patients with refractory SLE receiving rituximab biosimilar (CT-P10) and to explore short-term efficacy and safety associated with rituximab biosimilar use.
Methods
We retrospectively analysed data from the medical records of patients with refractory SLE who received CT-P10 in Ramathibodi Hospital, Mahidol University, Thailand. Baseline characteristics, disease activity (modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)), response to treatment at 6 months after CT-P10 and infection over 6 months were recorded.
Results
Thirty-two patients with SLE received CT-P10 from April 2018 to June 2019. Of these, 29 (90.6%) were female and the mean±SD age was 36.8±15.2 years. The median (IQR) disease duration was 9.5 (1.3–13.0) years. All patients received glucocorticoid treatment and used 1.7±0.1 immunosuppressive agents at baseline, excluding antimalarial drugs. Baseline Systemic Lupus International Collaborating Clinics Damage Index score was 0.5 (0.0–1.0). Overall response, which was defined as a reduction in the modified SLEDAI score of ≥4, was achieved in 25.0% of patients at 6 months. The modified SLEDAI score reduced from 4 (1.3–8.0) at baseline to 1 (0.0–5.8) at 6 months (p=0.005). Response by active organ involvement was 71.8%. Serious infection occurred in four patients (12.5%), resulting in one death. The median time of onset of infection after CT-P10 infusion was 35.5 (17.0–72.5) days.
Conclusion
Rituximab biosimilar is associated with improvement in active organ involvement in patients with refractory SLE. Infection occurred early after rituximab biosimilar infusion.
Keywords: biological products, lupus erythematosus, systemic, outcome assessment, health care
Introduction
Polyclonal B cell hyper-reactivity has been well described in SLE, and B cells have been considered a potential therapeutic target.1 Rituximab (RTX) is a chimeric monoclonal antibody that depletes CD20+ B cells. Two randomised, placebo-controlled trials of RTX failed to reach their primary endpoints.2 3 However, other observational studies of RTX use in patients with SLE and refractory lupus are promising.4–11
Preclinical and clinical data have demonstrated the equivalence and similarity of RTX biosimilar, CT-P10, to RTX originator.12 In this retrospective cohort, our primary objective was to characterise patients with refractory lupus receiving CT-P10 and to explore its short-term efficacy and safety.
Patients and methods
We retrospectively analysed data of patients with refractory SLE who commenced RTX biosimilar therapy in Ramathibodi Hospital, Mahidol University, Thailand, between April 2018 and June 2019.
Patients with SLE, classified according to the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria, aged above 16, refractory to treatment (failure of at least one immunosuppressant), commenced a new biologic therapy with CT-P10 and with follow-up up to 6 months were included. We also included patients who expired before 6 months. Patients who previously received any biologic agent within 1 year or were diagnosed overlapping with other rheumatic diseases were excluded from the study.
Demographic data, disease duration, comorbidities and SLICC Damage Index (SDI) score were collected at baseline. Disease activity (modified SLEDAI13), laboratory data and immunosuppressive agents use were recorded at baseline and 6 months after the first infusion of CT-P10.
Efficacy analysis
Overall response was defined as a reduction in the modified SLEDAI-2K score of ≥4. Disease flare was defined as an increase in the modified SLEDAI-2K score of ≥4. Response by specific organ was defined as ≥50% improvement of that organ according to SLEDAI-2K Responder Index-50 (SRI-50) definitions.14 For a specific organ that was not mentioned in SRI-50, response was defined as a significant improvement (≥50%) of initial disease, based on clinical judgement. Complete renal response was defined as normal kidney function (within 10% of normal GFR) and proteinuria <0.5 g/day. Partial renal response was defined as near-normal GFR and ≥50% reduction of proteinuria to subnephrotic levels.
Safety analysis
Immediate infusion reaction (within 48 hours) was recorded. Serious infections were defined as any infection requiring hospitalisation and/or intravenous antibiotics or resulting in disability or death.
Statistical analysis
Paired t-test and Wilcoxon test were used to compare paired continuous variables with normal distribution and non-normal distribution, respectively. P values less than 0.05 were considered statistically significant. Data were analysed using SPSS V.22.0 software.
Results
Patient characteristics
A total of 32 patients were enrolled in this study. Of these, 29 (90.6%) were female and the mean±SD age was 36.8±15.2 years. The median (IQR) disease duration was 9.5 (1.3–13.0) years. The median SDI and modified SLEDAI-2K scores were 0.5 (0.0–1.0) and 4.0 (1.3–8.0), respectively (table 1). The most common organ involvement during RTX biosimilar administration was lupus nephritis (n=13). Six patients had more than one organ involvement.
Table 1.
Characteristics of 32 patients with SLE receiving rituximab biosimilar
| Characteristics | n (%) |
| Female | 29 (90.62) |
| Age (at first RTX biosimilar infusion), mean±SD, years | 36.75±15.22 |
| Disease duration, median (IQR), years | 9.50 (1.25–13.00) |
| 2012 SLICC classification criteria | |
| Clinical criteria | |
| Acute cutaneous lupus | 10 (31.25) |
| Chronic cutaneous lupus | 8 (25.00) |
| Oral ulcers | 5 (15.62) |
| Non-scarring alopecia | 8 (25.00) |
| Synovitis | 16 (50.00) |
| Serositis | 3 (9.38) |
| Renal | 16 (50.00) |
| Neurological | 9 (28.13) |
| Haemolytic anaemia | 6 (18.75) |
| Leucopenia | 14 (43.75) |
| Thrombocytopaenia | 15 (46.88) |
| Immunological criteria | |
| ANA level above laboratory reference range | 32 (100.00) |
| Anti-dsDNA antibody level above laboratory reference range | 18 (56.25) |
| Anti-Sm | 3 (9.38) |
| Antiphospholipid antibody positivity | 8 (25.00) |
| Low complement | 27 (84.38) |
| Direct Coombs test in the absence of haemolytic anaemia | 0 (0.00) |
| Comorbidity and damage | |
| Chronic HBV infection | 2 (6.25) |
| Hypertension | 8 (25.00) |
| Dyslipidaemia | 8 (25.00) |
| End-stage renal disease | 3 (9.38) |
| SLICC Damage Index, median (IQR) | 0.50 (0.00–1.00) |
| RTX biosimilar administration | |
| 1 g × 2 infusions per 2 weeks | 13 (40.63) |
| 500 mg × 2 infusions per 2 weeks | 10 (31.25) |
| 1 g × 1 infusion | 5 (15.63) |
| 500 mg × 1 infusion | 1 (3.13) |
| Other regimen | 3 (9.38) |
| RTX biosimilar-associated treatment (prior/concurrent) | |
| Glucocorticoids | 32 (100.00) |
| Oral | 32 (100.00) |
| Intravenous | 13 (40.63) |
| Immunosuppressive agents | |
| Intravenous cyclophosphamide | 12 (37.50) |
| Oral cyclophosphamide | 2 (6.25) |
| Mycophenolate mofetil | 21 (65.63) |
| Azathioprine | 14 (43.75) |
| Ciclosporin | 9 (28.13) |
| Tacrolimus | 3 (9.38) |
| Methotrexate | 6 (18.75) |
| Hydroxychloroquine | 23 (71.88) |
| Number of immunosuppressive agents (excluding antimalarial drugs) before RTX biosimilar infusion, mean±SD | 1.72±0.13 |
| Intravenous immunoglobulin | 4 (12.50) |
| Plasma exchange | 4 (12.50) |
dsDNA, double-stranded DNA; HBV, viral hepatitis B; RTX, rituximab; SLICC, Systemic Lupus International Collaborating Clinics.
At baseline, all patients received glucocorticoid and 1.7±0.1 immunosuppressive agents, excluding antimalarial drugs. Mycophenolate mofetil (65.6%), cyclophosphamide (43.8%) and azathioprine (43.8%) are among the most common CT-P10-associated treatment. The most common RTX biosimilar regimen was two infusions of 1000 mg in a 2-week interval (13 patients, 40.6%).
Efficacy of RTX biosimilar
Overall response was achieved in 25.0% of patients. The median modified SLEDAI-2K score reduced from 4 (1.3–8.0) at baseline to 1 (0.0–5.8) at 6 months (p=0.005). Total response according to specific organ was 71.8% (table 2). Complete and partial renal response were achieved in three (23.1%) and five (15.6%) patients, respectively. Serological improvement was also observed, with an increase in C3 levels and a decrease in anti-double-stranded DNA level (table 2). RTX biosimilar treatment facilitated steroid reduction from 20 (12.5–40.0) mg to 10 (7.5–15.0) mg (p<0.001). Disease flare was observed in two patients (6.3%) at 6 months, who had new onset of microscopic haematuria and pyuria, without a decline in renal function. Details of the 32 enrolled patients are summarised in table 3.
Table 2.
Response to rituximab biosimilar at 6 months after treatment of patients with SLE
| Clinical parameter | Patients evaluable for outcome | Baseline | 6 months | P value | Overall response* (%) |
| Modified SLEDAI-2K, median (IQR) | 32 | 4 (1.25–8.00) | 1 (0.00–5.75) | 0.005 | 8/32 (25.00) |
| Anti-dsDNA level, median (IQR), IU/mL | 20 | 10.70 (0.00–109.28) |
0.00 (0.00–89.68) |
0.041 | – |
| C3 mean±SD (range), g/L | 32 | 0.90±0.33 (0.23–1.60) | 1.05±0.28 (0.55–1.55) | 0.015 | – |
| Prednisolone dose, median (IQR), mg | 32 | 20 (12.50–40.00) |
10 (7.50–15.00) |
<0.001 | – |
| Response according to specific organ† | Response (%) | ||||
| NPSLE | 7 | – | – | – | 7/7 (100.00) |
| Seizure | 1 | – | – | – | 1 |
| Myelitis‡ | 1 | – | – | – | 1 |
| Peripheral neuropathy‡ | 2 | – | – | – | 2 |
| Organic brain syndrome | 2 | – | – | – | 2 |
| Lupus headache | 1 | – | – | – | 1 |
| Vasculitis | 2 | – | – | – | 2/2 (100.00) |
| Gastrointestinal‡ | 1 | – | – | – | 1 |
| Cutaneous | 1 | – | – | – | 1 |
| Arthritis | 3 | – | – | – | 3/3 (100.00) |
| Proteinuria, median (IQR), g/day | 13 | 4.10 (1.20–6.65) |
0.85 (0.36–2.45) |
0.012 | 8/13 (61.54) |
| Rash | 1 | – | – | – | 1/1 (100.00) |
| Thrombocytopaenia (<140 x 109/L), median (IQR) |
9 | 74 x 109 (42 x 109–108.5 x 109) |
186.5 x 109 (132 x 109–241.75 x 109) |
0.092 | 5/9 (55.56) |
| Leucopenia (<4 x 109/L), median (IQR) |
3 | 3.16 x 109 (1.20 x 109–3.97 x 109) |
3.68 x 109 (1.88 x 109–3.84 x 109) |
0.285 | 0/3 (0.00) |
| Others | 1 | – | – | – | 1/1 (100.00) |
| Total response | 39 | – | – | – | 28/39 (71.79) |
*Reduction in SLEDAI-2K or modified SLEDAI-2K score of ≥4.
†≥50% improvement according to SLEDAI-2K Responder Index-50 definitions; six patients had more than one specific organ involvement.
‡Significant improvement (≥50%) of initial disease, based on clinical judgement.
dsDNA, double-stranded DNA; NPSLE, neuropsychiatric SLE; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index-2000.
Table 3.
Characteristics, main indication for rituximab biosimilar, regimen and response to treatment of 32 enrolled patients
| Number | Previous therapy (other than steroids and antimalarial) |
Specific organ involvement | Baseline prednisolone (mg/day) | RTX biosimilar regimen (mg) × infusion(s) |
Concomitant therapy (other than steroids and antimalarial) |
Prednisolone at 6 months (mg/day) |
Response by organ involvement |
| 1 | IVCY | Seizure* | 60 | 1000×2 | IVCY | 15 | Y |
| 2 | IVCY | Transverse myelitis* | 60 | 1000×2 | AZA | 7.5 | Y |
| 3 | MTX, TAC, MMF, IVIG | Chronic inflammatory demyelinating polyneuropathy* | 30 | 1000×2 | LEF, TAC, MMF | 30 | Y |
| 4 | MMF, CY | Small fibre neuropathy* | 15 | 500×2 | CY | 10 | Y |
| 5 | IVCY, IVIG, PLEX | Acute confusional state, lupus nephritis* | 60 | 1000×1 | AZA | 17.5 | Y, Y |
| 6 | IVCY | Acute confusional state, lupus nephritis, thrombocytopaenia* | 75 | 1000×1 | AZA | 10 | Y, Y, Y |
| 7 | AZA, IVCY | Lupus headache* | 20 | 1000×2 | AZA, CYA | 10 | Y |
| 8 | IVCY, PLEX | Gastrointestinal vasculitis*, lupus nephritis (class III) | 50 | 1000×1 | MMF, IVCY | 30 | Y, Y |
| 9 | MMF, CY | Cutaneous vasculitis* | 15 | 1000×2 | MMF, AZA | 15 | Y |
| 10 | CYA, IVCY | Arthritis* | 30 | 1000×2 | CYA, MTX | 10 | Y |
| 11 | MTX | Arthritis* | 17.5 | 500×2 | MTX, MMF | 10 | Y |
| 12 | MTX | Arthritis* | 5 | 500×2 | MTX, MMF | 10 | Y |
| 13 | MMF, IVCY | Lupus nephritis* | 25 | 500×2 | MMF, TAC | 10 | Y |
| 14 | IVCY, PLEX | Lupus nephritis* | 40 | 500×2 | MMF | 10 | Y |
| 15 | CYA, MMF, IVCY | Lupus nephritis (class IV)* | 20 | 1000×2 | CYA, MMF | 10 | Y |
| 16 | MTX, MMF | Lupus nephritis* | 1.5 | 1000×2 | MTX, MMF | 0.5 | N |
| 17 | CYA, MMF | Lupus nephritis (class IV+V)* | 10 | 1000×2 | CYA, MMF | 7.5 | N |
| 18 | MTX, MMF | Lupus nephritis* | 5 | 1000×2 | MTX, CYA, MMF | 5 | N |
| 19 | MMF, IVCY | Lupus nephritis (class III)* | 75 | 500×2 | MMF, IVCY | 20 | Y |
| 20 | AZA, MMF | Lupus nephritis*, thrombocytopaenia | 40 | 1000×1 | AZA, MMF | 7.5 | Y, Y |
| 21 | IVCY | Lupus nephritis*, thrombocytopaenia | 60 | 500×3 | None (expired from infection) | – | N, N |
| 22 | MMF, IVIG | Lupus nephritis (class III+V)*, thrombocytopaenia | 30 | 1000×1 | MMF | 20 | N, Y |
| 23 | MMF | Photosensitive lupus rash* | 15 | 500×2 | MMF | 10 | Y |
| 24 | AZA, CYA, MMF | Thrombocytopaenia* | 12.5 | 500×2 | AZA, CYA, MMF | 7.5 | N |
| 25 | MMF | Thrombocytopaenia* | 20 | 500×2, 1000×1 |
MMF, IVIG | 10 | N |
| 26 | AZA, CYA | Thrombocytopaenia* | 15 | 1000×2 | AZA, CYA | 5 | Y |
| 27 | AZA, CYA | Thrombocytopaenia* | 15 | 1000×2 | AZA, CYA | 2.5 | Y |
| 28 | AZA, CYA, MMF | Thrombocytopaenia* | 12.5 | 500×2 | AZA, CYA, MMF | 10 | N |
| 29 | AZA, TAC | Leucopenia* | 12.5 | 500×2 | AZA, TAC | 7.5 | N |
| 30 | AZA | Leucopenia* | 40 | 1000×2 | AZA | 25 | N |
| 31 | AZA, MMF | Leucopenia* | 5 | 500×1 | AZA, MMF | 5 | N |
| 32 | AZA | Coagulation factor inhibitor* | 75 | 500×4 | MMF | 30 | Y |
*Main indication for rituximab biosimilar infusion.
AZA, azathioprine; CY, oral cyclophosphamide; CYA, ciclosporin A; IVCY, intravenous cyclophosphamide; IVIG, intravenous immunoglobulin; LEF, leflunomide; MMF, mycophenolate mofetil; MTX, methotrexate; N, no; PLEX, plasma exchange; RTX, rituximab; TAC, tacrolimus; Y, yes.
Safety of RTX biosimilar
Immediate infusion reaction was observed in three patients (9.4%) (flushing and skin pruritus). No severe infusion reactions were observed.
Infections were noted in six patients (18.8%) and were severe in four patients (12.5%). Acute pyelonephritis (3 patients, 9.4%) and cytomegalovirus (CMV) infection (3 patients, 9.4%) were the most common infections. Two patients had multiple infections, resulting in one death. The median time of occurrence of infections in all infected patients was 35.5 (17.0–72.5) days after CT-P10 infusion.
Discussion
Our study is based on retrospective data of patients with refractory SLE using CT-P10 in actual clinical practice. Overall response was achieved in only 25.0% of patients. This number is much lower than the previous meta-analysis of RTX originator in refractory SLE that reported the overall response to be 72.0%.9 First, this discrepancy might be explained by a different definition of overall response. Second, the modified SLEDAI-2K cannot distinguish features of clinical activities that are only partly improved. Third, this index also misses out some clinical features of patients in this study. The reason for relatively low disease activity in our study may be explained by the main indication for RTX biosimilar use in 16 patients (50.0%) being non-severe manifestations or organ that is not included in the modified SLEDAI-2K score. Response according to specific organ using more sensitive criteria able to capture partial improvement was 71.8%, much higher than the overall response number.
RTX biosimilar displayed promising effects in neuropsychiatric SLE with 100% clinical response. Renal response (complete and partial) was 61.5%, comparable with previous studies (56.9%–67.0%).3 6 Patients with immune thrombocytopaenia demonstrated 55.6% response. Moreover, RTX biosimilar might be used as a steroid-sparing drug, demonstrated by reducing the median dose of prednisolone from 20 (12.5–40) to 10 (7.5–15) mg/day.
Severe infections were noted in 12.5% of patients, slightly higher than a previous study of RTX originator (4.7%–11.0%).5 7 8 11 The high incidence of CMV infection in the current study (9.4%) might be explained by the use of high-dose corticosteroids and strong immunosuppressive drug, such as intravenous cyclophosphamide.15
The majority of infections occurred in the first 2 months post RTX biosimilar infusion, when most of the patients were still in high disease activity, on high-dose steroid and a maximum period of B cell depletion. Immediate infusion reaction was 9.4%, comparable with previous studies of RTX originator (3.7%–21.2%).5 7 8
Our study possesses some limitations. First of all, the study design is retrospective. The sample size in this study is relatively small. Moreover, this study only reported short-term outcomes up to 6 months.
The unmet need in the therapeutics of SLE is to develop affordable treatment regimens that are more efficacious but associated with fewer side effects. Our findings demonstrate that RTX biosimilar achieved significant efficacy and an acceptable safety profile in refractory SLE. The results are comparable with RTX originator studies.
Footnotes
Contributors: All authors were involved in drafting the article or revising it critically. All authors approved the final version to be published.
Funding: This work was supported by the Faculty of Medicine Ramathibodi Hospital (grant number CF_63001).
Competing interests: None declared.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication: Not required.
Ethics approval: The study was approved by the Committee on Human Rights Related to Research Involving Human Subjects (MURA2020/8), following the Declaration of Helsinki.
Provenance and peer review: Not commissioned; externally peer reviewed.
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