Visual Abstract
Keywords: refractory, efficacy, Hematopoietic Stem Cell Mobilization, lupus nephritis, Antilymphocyte Serum, Peripheral Blood Stem Cells, Disease-Free Survival, Blood Platelets, Cyclophosphamide, Granulocyte Colony-Stimulating Factor, Hematopoietic Stem Cell Transplantation, Transplantation, Autologous, Recurrence, Immunologic Tests, Granulocytes, proteinuria, Gastrointestinal Tract, peritoneal dialysis
Abstract
Background and objectives
Our study evaluated the efficiency and safety of autologous hematopoietic stem cell transplantation treatment for patients with refractory lupus nephritis.
Design, setting, participants, & measurements
From July 2011 to January 2015, a total of 22 patients with refractory lupus nephritis were enrolled in this study. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony stimulating factor and reinfused after treatment with cyclophosphamide and antithymocyte globulin. The primary end point was the rate of remission, and secondary end points included the survival and relapse rates, changes in proteinuria, kidney function, and serology immunologic test. All complications were recorded for safety assessment.
Results
Twenty-two patients were enrolled and underwent stem cell mobilization. There were nine men and 13 women, with a median lupus nephritis duration of 46 (33–71) months. The mean number of CD34+ cells was (7.3±3.8)×106/kg. All patients had successful engraftment, and the median times of granulocyte and platelet engraftment were 8 (7–9) and 9 (6–10) days, respectively. The major complications of stem cell transplantation were fever and gastrointestinal tract symptoms. The treatment-related mortality was 5% (one of 22). After a median follow-up of 72 (60–80) months, 18 (82%) patients achieved completed remission, one (5%) patient achieved partial remission, and one patient had no response and received peritoneal dialysis at 12 months after transplantation. The 5-year overall survival and disease-free survival rates were 91% and 53%, respectively. Six patients experienced relapse during the follow-up, and the relapse rate was 27%.
Conclusions
Autologous hematopoietic stem cell transplant could be used as a treatment option for refractory lupus nephritis, because it was relatively safe and associated with good outcomes.
Introduction
SLE is an autoimmune disease that can affect essentially any organ or tissue (1). SLE is characterized by loss of tolerance of nuclear autoantigens, lymphoproliferation, polyclonal autoantibody production, immune complex disease, and multiorgan tissue inflammation (2,3). Over recent decades, survival rates have substantially improved, with an estimated 5-year survival of >90% and 15- to 20-year survival rates of approximately 80% (4). One of the most severe manifestations of SLE is lupus nephritis, which remains a cause of substantial morbidity and mortality. The 20-year kidney survival rate in a cohort of 1814 Chinese patients with biopsy-proven lupus nephritis was only 68% (5). Although the introduction of glucocorticoid, cyclophosphamide, and other immunosuppressors has greatly improved the survival of patients with lupus nephritis, it is estimated that 35% of patients with lupus nephritis suffer at least one episode of kidney-related relapse and that 5%–20% develop ESKD (6). Supported by preclinical models (7), autologous hematopoietic stem cell transplantation (autologous stem cell transplantation for short) has been used in severely affected patients with several autoimmune diseases, including SLE (8).
Autologous stem cell transplantation has been proposed as an alternative therapeutic option for patients with SLE who are refractory to standard therapy, which may arrest the autoimmune disease process and achieve sustained remission for refractory disease (9). The mechanism of efficacy of autologous stem cell transplantation on severe lupus may be associated with the autoreactive immunologic memory depletion and resetting of the adaptive immune system (10). Since its first application in 1997 (11), >300 autologous stem cell transplantations have been reported worldwide for SLE (12). The two largest studies to date come from the European Group for Blood and Marrow Transplantation (EBMT) data registry (13) and the single-center study by Northwestern University (14). The probability of 5-year disease-free survival was 50% in both studies, similar to results from smaller pilot studies.
Although many studies have reported the results of autologous stem cell transplantation in patients with SLE, there is limited research focus on lupus nephritis. In this study, we aimed to evaluate the long-term efficacy, remission, survival, and safety of autologous stem cell transplantation in patients with refractory lupus nephritis.
Materials and Methods
Patient Eligibility
The study was approved by the Institutional Review Board (IRB) of Jinling Hospital. The patients or their legal guardians (if <18 years old) signed the informed consent form approved by the IRB of Jinling Hospital, and this study followed the principles of the Declaration of Helsinki or the principles outlined in the “Guideline for Good Clinical Practice” International Committee on Harmonization Tripartite Guideline, whichever afforded greater protection to the individual. All patients were diagnosed with relapsed and refractory lupus nephritis. Refractory lupus nephritis is defined as no response to at least one type of immunosuppressant therapy (including corticosteroids, cyclophosphamide, tacrolimus, mycophenolate mofetil, and cyclosporin) for >6 months or relapse during the period maintenance therapy with kidney pathologic transformation or persistently positive antibodies. Other criteria included age from 14 to 45 years old, serum creatinine <2 mg/dl, alanine aminotransferase less than two times the normal upper limit, left ventricular ejection fraction >50%, and no evidence of active infection. Kidney biopsy was performed in every patient before stem cell collection.
This study was approved by the institutional ethical review board of Jinling Hospital in 2010 and registered at the local clinical trial center of Jinling Hospital. However, at that time, we did not know that registration was a requirement for publication, and we did not register the study. The study has since been registered, and the ClinicalTrials.gov Identifier is NCT03828071.
Stem Cell Mobilization and Collection
Peripheral blood stem cells were mobilized with cyclophosphamide (2.0 g/m2) for 2 days, and granulocyte colony stimulating factor (G-CSF) at 5–10 μg/kg per day was administered when the level of peripheral leukocytes was <1×109/L. Peripheral leukocyte counts were monitored, and harvesting was performed when the peripheral white blood cell level rebounded (usually 11 days after cyclophosphamide). The target acquisition was CD34+ cells >2×106/kg and mononuclear cells >2×108/kg. The graft was preserved at a temperature of −196°C for further use. Transplantation was conducted within 2 months after collection.
Conditioning and Reinfusion of Stem Cells
The conditioning regimen consisted of intravenous cyclophosphamide (40 mg/kg per day ×4 days) 5 days before transplantation (a total dose of 160 mg/kg) and rabbit antithymocyte globulin (ATG; 2.5 mg/kg per day ×3 days) 4 days before transplantation. The doses of cyclophosphamide and ATG could be reduced according to the patients’ condition. Methylprednisolone (80–500 mg/d) was administered through intravenous drip at the same time with ATG to reduce anaphylaxis. The incidence of drug-related complications was decreased by hyperhydration (the volume of infusion liquid was 50 ml/kg per day), urine alkalization (infusion of sodium bicarbonate 250 ml/d), and antiemetic medication. G-CSF (0.5 μg/kg per day) was administered to each patient beginning the day after stem cells reinfusion until the level of absolute peripheral neutrophil count was consecutively >1.0×109/L.
Antibiotic Administration and Blood Transfusion
All of these procedures were carried out in a 100-grade laminar flow ward. Before conditioning, the patients received drugs as follows: oral levofloxacin 0.2 g (three times a day for 3 days), oral fluconazole 0.2 g (once a day for 3 days), oral sulphamethoxazole 0.96 g (once a day for 3 days), oral albendazole 0.2 g (once a day for 3 days), and intravenous ganciclovir 0.25 g (once a day for 7 days). Antibiotics (usually cefoperazone) were used to prevent infection during the granulocyte deficiency phase. Platelet transfusions were given to maintain platelet counts >20,000/μl in patients without hemorrhage. Concentrated red blood cell suspension was transfused for hemoglobin levels <8.0 g/dl. Platelets and concentrated red blood cell suspensions were irradiated, and leukocytes were depleted.
Follow-Up and Outcomes
Close observation was carried out at stem cell harvest; at transplantation; at 3, 6, 12, 18, and 24 months; and then, once a year after autologous stem cell transplantation. The main observations before and after autologous stem cell transplantation were urine sediment red blood cell count, proteinuria, complement 3 (C3), complement 4 (C4), antinuclear antibody (ANA), anti–double-stranded DNA, blood routine, blood biochemistry, Ig, and SLE disease activity index. Low doses of steroid and immune inhibitors were administered to maintain remission. Other immunosuppressants were added in the case of relapse.
The curative effect on the kidney was defined as follows: complete remission: proteinuria <0.4 g/24 h, red blood cells <3/high power field in urine sediment, serum albumin >3.5 g/dl, and serum creatinine <1.24 mg/dl; partial remission: a ≥50% reduction in proteinuria and urinary protein excretion <3.5 g/24 h, serum albumin >30 g/L, and serum creatinine <1.24 mg/dl; and no remission: failed to achieve partial remission. Relapse was defined by any one of the following: (1) proteinuric relapse defined as persistent proteinuria ≥1.0 g/24 h after complete remission or an increase of ≥2.0 g/24 h after partial remission with or without hematuria or (2) an increase in the serum creatinine level defined as a ≥50% increase of serum creatinine in normal baseline-level patients or a 30% increase for those with abnormal serum creatinine level at baseline with increased hematuria (15,16). Adverse reaction classification is according to the Common Terminology Criteria for Adverse Events version 4.0.
Statistical Analyses
Categorical data were presented as numbers (n) or proportions (percentages) and analyzed using a chi-squared test or a Fisher exact test. Continuous data were presented as means (SDs) or medians (quantiles) and analyzed using an F test or a nonparametric test. Overall survival, kidney survival, time to relapse, and complete remission were analyzed using the Kaplan–Meier method. All statistical analyses were conducted using SPSS statistical package 17.0 (Chicago, IL). Statistical significance was set at P<0.05.
Results
Demographics and Clinical Features of Patients with Preautologous Stem Cell Transplantation
From June 2011 to January 2015, a total of 22 patients with refractory lupus nephritis were enrolled in this study. The process of patient enrollment and follow-up is summarized in Figure 1. All 22 patients had sufficient collected CD34+ cells and underwent autologous stem cell transplantation. The median age of these patients was 24 (19–29) years old (range, 14–45 years old), and 59% were women (n=13). Eighteen patients had relapsed, and four patients had no response to therapy. Of the 18 patients who relapsed, five patients relapsed one time, eight patients relapsed two times, four patients relapsed three times, and one patient relapsed seven times. Eight patients had shown pathologic improvement on follow-up kidney biopsy. The preautologous stem cell transplantation median duration was 46 (33–71) months (range, 6–192 months). All patients had received immunosuppressant drug therapy before autologous stem cell transplantation, and the majority of patients (18 patients) accepted multitarget therapy. The demographics and medication history are summarized in Table 1.
Figure 1.
Flow chart for selection of 22 patients and the follow-up outcomes of all the patients. After a median follow-up of 72 months, 20 patients were still alive and two patients died.
Table 1.
Patient demographics and preautologous hematopoietic stem cell transplantation history (n=22)
| Variable | No. of Patients |
|---|---|
| Age, median, yr | 24 (19, 29) |
| Duration of SLE, median, yr | 46 (33, 71) |
| Sex, n (%) | |
| Women | 13 (59) |
| Men | 9 (41) |
| Medication history, n (%) | |
| Corticosteroids, oral | 22 (100) |
| Corticosteroid impulse therapy | 20 (91) |
| RAS inhibitors | 7 (32) |
| Immunosuppressants | |
| Cyclophosphamide, intravenous | 8 (36) |
| Leflunomide | 2 (9) |
| Azathioprine | 3 (14) |
| Hydroxychloroquine | 3 (14) |
| Mycophenolate mofetil | 17 (77) |
| Cyclosporin | 4 (18) |
| Tacrolimus | 16 (73) |
| Sirolimus | 1 (5) |
| Intravenous Ig | 2 (9) |
| Tripterygium glycosides | 9 (41) |
| Methotrexate | 1 (5) |
| Immune adsorption/DFPP | 1 (5)/2 (9) |
| CRRT | 2 (9) |
Data are expressed as the number (%) or median (25th, 75th percentiles). RAS, renin-angiotensin system; DFPP, double-filtration plasmapheresis; CRRT, continuous RRT.
All patients were diagnosed with lupus nephritis by kidney biopsy. At the time of biopsy, ten (46%) patients presented with class 4 + 5 lupus nephritis, six (27%) patients presented with class 3 + 5 lupus nephritis, five (23%) patients presented with class 4 lupus nephritis, and one patient presented with class 3 lupus nephritis. Table 2 lists the clinical features preautologous stem cell transplantation. Hematologic involvement referred to thrombocytopenia in ten patients and anemia in eight patients. The median SLE disease activity index score was 14 before autologous stem cell transplantation.
Table 2.
Pretransplantation clinical features of patients
| Variable | Value |
|---|---|
| ANA | 1:80 (1:128, 1:256) |
| Anti-dsDNA antibody | 1:10 (0, 1:16) |
| Complement 3, g/L | 0.55 (0.44, 0.70) |
| Complement 4, g/L | 0.10 (0.09, 0.11) |
| Proteinuria, g/24 h | 1.7 (1.2, 4.0) |
| Serum albumin, g/dl | 3.2 (2.76, 3.45) |
| Serum creatinine, mg/dl | 0.74 (0.63, 0.96) |
| SLE disease activity index, scores | 14 (12, 16) |
| Involved organ, n (%) | |
| Hematologic system | 17 (77) |
| Rash | 11 (50) |
| Arthralgia | 9 (41) |
| Lupus encephalopathy | 2 (9) |
| Type of kidney pathology pretransplantation, n (%) | |
| Type 4 + 5 | 10 (46) |
| Type 3 + 5 | 6 (27) |
| Type 4 | 5 (23) |
| Type 3 | 1 (5) |
| Activity index, scores | 8 (7, 11) |
| Chronicity index, scores | 2 (1, 3) |
Data are expressed as the number (%), median (25th, 75th percentiles), or mean (SD). ANA, antinuclear antibody; dsDNA, double-stranded DNA.
Stem Cell Mobilization
Stem cell collection occurred at a median time of 11 (10–13) days after cyclophosphamide administration. The mean number of CD34+ cells was (7.3±3.8)×106/kg. Eighteen patients required component blood transfusion; the mean (SD) amounts of erythrocyte suspension apheresis and single-donor platelet were 3.6 (±3.0) and 1.6 (±0.9) U, respectively. Eighteen patients experienced agranulocytosis; the median time to recovery of absolute neutrophil count >500/μl was 7 (6–8) days, and the median duration of agranulocytosis was 3 (3–5) days. The most common complication during collection was fever (50%); others were gastrointestinal reaction (23%), hypokalemia (45%), hypocalcemia (18%), osteodynia (18%), and rash (14%).
Autologous Stem Cell Transplantation
All of the patients successfully transplanted. The median doses of cyclophosphamide and ATG were 8.8 (7.7–9.6) g and 450 (369–450) mg, respectively. The median times to enter agranulocytosis and granulocyte implantation were +2 days (+1, +3 days) and +8 days (+7, +9 days), and the median duration of agranulocytosis was 6 days (5, 7 days). In 21 patients, platelets were <30,000/μl. The median time of platelet implantation was +9 days (+6, +10 days). Nineteen (86%) patients required component blood transfusion; the mean amounts of erythrocyte suspension apheresis and single-donor platelets were 2.0 (±2.0) and 1.8 (±2.2) U, respectively.
The common complications during autologous stem cell transplantation are summarized in Table 3. Most complications were grade 1/2, and no grade 4/5 complications occurred. Fever occurred in every patient after the pretreatment of ATG, and they all recovered after steroid and antiallergic agent administration. Although all patients received prophylactic anti-infection treatment during the agranulocytosis phase, 13 (59%) patients still had fever during agranulocytosis. The other common complications included gastrointestinal reaction, mucositis, and osteodynia.
Table 3.
Transplantation-related toxic effects
| Variable | Total, n (%) | Grade, n (%) | ||
|---|---|---|---|---|
| 1 | 2 | 3 | ||
| Nausea, vomiting | 16 (73) | 8 (36) | 8 (36) | 0 |
| Mucositis | 14 (64) | 9 (41) | 4 (18) | 1 (5) |
| ATG-related fever | 22 (100) | 0 | 0 | 22 (100) |
| Agranulocytosis with fever | 13 (59) | 0 | 0 | 13 (59) |
| Diarrhea | 11 (50) | 4 (18) | 6 (27) | 1 (5) |
| Osteodynia | 13 (59) | 10 (46) | 2 (9) | 1 (5) |
| Arrhythmia | 2 (9) | 1 (5) | 1 (5) | 0 |
| Rash | 10 (46) | 7 (32) | 3 (14) | 0 |
| Elevated liver enzymes | 3 (14) | 2 (9) | 1 (5) | 0 |
| AKI | 2 (9) | 1 (5) | 1 (5) | 0 |
| Herpes simplex infection | 1 (5) | 0 | 1 (5) | 0 |
| Aseptic lymphadenitis | 1 (5) | 1 (5) | 0 | 0 |
ATG, antithymocyte globulin.
Disease Activity and Kidney Outcome
Figure 2 shows the changes of C3, C4, ANAs, and SLE disease activity index during follow-up. The C3 significantly increased (P<0.05) after autologous stem cell transplantation, and the median value of C3 increased from 0.55 (0.44–0.70) to 0.98 (0.84–1.12) g/L at the third month after autologous stem cell transplantation. The value of C4 also improved during follow-up, but there was no statistically significant difference. The median value of ANA also decreased in the short term after autologous stem cell transplantation. The SLE disease activity index score was decreased greatly in the first month after autologous stem cell transplantation and maintained at a low level during follow-up (P<0.05).
Figure 2.
All the complement 3 (C3), complement 4 (C4) antinuclear antibodies (ANAs), and SLE disease activity index score (SLEDAI) improved after autologous stem cell transplantation.
Figure 3 shows the changes in proteinuria and serum albumin during follow-up. The mean proteinuria was <0.5 g/24 h, and the mean serum albumin was >4.5 g/dl during the whole follow-up time. Eighteen patients achieved complete remission, and the median time to complete remission was 3 (1, 8.5) months (Figure 4A). One patient received peritoneal dialysis at 12 months. The overall 5-year kidney survival was 86% (Figure 4B). Kidney-related flares occurred in five patients: two patients were retreated with prednisone (20 mg/d), two patients were treated with tacrolimus (2–3 mg/d), and one patients was treated with cyclosporin (150 mg/d). All five patients achieved complete remission again within 3 months. One patient had a second flare after 2 years of drug withdrawal.
Figure 3.
Proteinuria (UPro) and serum albumin (Alb) improved after autologous stem cell transplantation.
Figure 4.
Probabilities of complete remission, kidney survival, time to relapse and overall survival among patients in the cohort. (A) Kaplan–Meier curves of the probability of complete remission. Eighteen patients achieved complete remission and the median time to complete remission was 3 months. (B) Kaplan–Meier curves of kidney survival. The overall 5-year kidney survival was 86%. (C) Kaplan–Meier curves of the probability of relapse. The 5-year relapse-free survival rate was 53%. (D) The overall survival of all patients. The 5-year overall survival rate was 91%.
For the nonkidney SLE manifestations, the peripheral blood cell count returned to normal 3 months after stem cell transplantation, except for in two patients. Rash and arthritis also recovered in all patients, but arthralgia recurred in one patient at 1 year after transplantation, which was controlled by low-dose prednisone.
Overall Survival and Follow-Up
With a median follow-up of 72 (60, 80) months, the 5-year overall survival rate was 91% (Figure 4D). Two patients died during follow-up. One patient died of severe infection (oral candidiasis and pulmonary and urinary tract infections of Enterococcus faecium) at 1 month, and one patient died of pulmonary infection at 5 months after autologous stem cell transplantation. The transplant-related mortality (TRM) of this study was 5%. The median time to recurrence was 31 (13.5, 55) months, and the 5-year relapse-free survival rate was 53% (Figure 4C). The most common complication during follow-up was infection, mainly occurring within 6 months (Table 4). The other complications include pure erythrocyte aplastic anemia, B-type insulin resistance syndrome, leukopenia, and thrombocytopenia.
Table 4.
Complications during follow-up
| Patient no. | Time, mo | Complications | Treatment | Efficacy |
|---|---|---|---|---|
| 1 | 1 | Infection | Combined anti-infection treatment | Death at 1.5 mo |
| 2 | 1 | Pure erythrocyte aplastic anemia | Androgen | Recovery at 2 mo |
| 3 | 1 | Leukopenia | Prednisone | Recovery at 18 mo |
| 4 | 3 | Pulmonary infection thrombocytopenia | Combined anti-infection treatment | Death at 5 mo |
| 5 | 1 | Herpes zoster infection | Acyclovir | Recovery at 2 wk |
| 6 | 4 | Herpes zoster infection | Acyclovir | Recovery at 2 wk |
| 7 | 18 | B-type insulin resistance syndrome | Prednisone 20 mg/d + cyclophosphamide 0.6 g/m | Recovery at 1 mo |
Discussion
Autologous stem cell transplantation has been proposed as a treatment modality that may arrest the autoimmune disease process and lead to sustained remissions (17). Marmont (18) first selected autologous stem cell transplantation for SLE and proved that it was effective in 1998. Subsequent studies in the literature also showed that autologous stem cell transplantation was effective in the treatment of SLE. Mechanistic studies have shown that autologous stem cell transplantation does not solely act via prolonged immunosuppression but rather, that it rewires an autoreactive immune system into a self-tolerant state (19). Burt et al. (14) reported outcomes of 50 patients with refractory SLE who received autologous stem cell transplantation. With a mean follow-up of 29 months, 5-year overall survival was 84%, and probability of disease-free survival at 5 years after autologous stem cell transplantation was 50%. Another study from the EBMT showed that the disease-free survival at 5 years after autologous stem cell transplantation was 44% (20), consistent with similar results from smaller pilot studies (10,21).
In our study, the majority of patients (82%) achieved completed remission, and the median time of kidney response was only 3 months. After a median follow-up of 72 months, the 5-year overall survival and disease-free survival rates were 91% and 53%, respectively. The outcomes of our study were similar to those of other studies. Considering that all patients had refractory lupus nephritis, this result is encouraging. More recently, two studies on autologous stem cell transplantation for refractory SLE were presented from two Chinese centers. Leng et al. (22) reported outcomes of 24 patients with SLE after receiving autologous stem cell transplantation, with a median follow-up of 120 months; both overall survival and progression-free survival rates were 86% at 10 years, whereas TRM was 4% (one of 24 patients). Most of these patients (88%) had lupus nephritis, and proteinuria significantly decreased in 15 patients from a median of 4 to 0 g/d at 10 years post-transplantation (22). In another study, Cao et al. (23) also reported data on 22 patients with lupus after autologous stem cell transplantation. All patients had lupus nephritis and other visceral manifestations. With a median follow-up of 113 months, overall survival and progression-free survival rates at 5 years post-transplantation were 95% and 68%, respectively. Most importantly, lupus nephritis was controlled in the majority of patients (23). The outcomes of lupus nephritis in both studies seem better than the outcome in our study. The reasons for these different results are unclear, but patient selection may contribute. First, the type of kidney pathology before autologous stem cell transplantation was more severe in our study. Of our patients, 96% had type 4 + 5, 3 + 5, or 4 lupus nephritis. In the study of Cao et al. (23), only 23% of patients had type 4 lupus nephritis, and no patients had type 4 + 5 or 3 + 5 lupus nephritis. Second, all patients received more aggressive immunosuppressant agents before autologous stem cell transplantation in our study, and 82% of the patients were treated with multitarget therapy.
These encouraging results of autologous stem cell transplantation for SLE have to be weighed against the higher risk of short-term mortality associated with autologous stem cell transplantation. Data on TRM are much more variable, ranging from 0% to 25%. The TRM of our study was 5%, comparable with the previous single-center data from the Northwestern University study (TRM of 4%) and the data from the multicenter EBMT analysis (TRM of 12%). The TRM-related factors might include patient selection, center effect, and improved preemptive anti-infectious and other supportive therapies. Patient selection maybe one of the most important factors, but there is still no consensus on appropriate candidates for autologous stem cell transplantation (24). Autologous stem cell transplantation is usually applied at the very end of the line of immunosuppressive therapy. In our study, two patients who died within 6 months both had a course of lupus nephritis >10 years. Compared with continued insufficient or failed chronic immunosuppression, early use of autologous stem cell transplantation has the potential to protect against organ failure and toxicity-related morbidity.
Recurrence after transplantation is still a challenge. The transplantation cannot eliminate aberrant hematopoietic stem cells to the full extent. Relapse may result from the persistence of plasma cells, despite conditioning with insufficient ablation of immunologic memory and sustained autoreactive antibodies (10,25,26). We routinely used low-dose steroids for 6 months after autologous stem cell transplantation, and nine patients stopped using immunosuppressant drugs at 1 year after autologous stem cell transplantation; however, almost every patient needed retreatment after long-term follow-up. Thus, we think that maintenance therapy is still necessary after autologous stem cell transplantation.
There are still some limitations of our study. First, our study is not a prospective clinical trial, and the results may be affected by factors, such as patient selection bias. Second, we have not designed a treatment plan for patients with relapse, and therefore, this study is unable to determine which treatment option is best for these patients. Third, because of the small sample size of the study, we were unable to determine the risk factors associated with efficacy and prognosis. In the future, we will conduct a prospective clinical study to solve the above problems. Our preliminary data show that autologous hematopoietic stem cell transplant could be used as a treatment option for refractory lupus nephritis, because it was relatively safe and associated with good outcomes. Severe infection is still an important cause of treatment failure, and the long-term efficacy of autologous hematopoietic stem cell transplant still needs additional observation.
Editor’s Note
As per International Committee of Medical Journal Editors guidelines, all studies that test an experimental intervention should be registered in a public trials registry, such as ClinicalTrials.gov, before enrollment of study participants. This study violates that guideline, because the research protocol was registered only after the completion of the study. Notwithstanding this violation, the editors concluded that publication of this manuscript was in the interest of both the scientific community and study participants, who agreed to take on the risk of an experimental intervention with informed consent (citation: http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html).
Disclosures
None.
Acknowledgments
This work was supported by Key Research and Development Plan Project of Jiangsu Province Social Development Projects grant BE2017721 and Jiangsu Provincial Medical Youth Talent grant QNRC2016895.
A preliminary report of this study was presented as an oral presentation at the Annual Meeting of the American Society of Nephrology, New Orleans, LA, October 31–November 5, 2017.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
See related editorial, “Treatment Options for Refractory Lupus Nephritis,” on pages 653–655.
References
- 1.Borchers AT, Leibushor N, Naguwa SM, Cheema GS, Shoenfeld Y, Gershwin ME: Lupus nephritis: A critical review. Autoimmun Rev 12: 174–194, 2012 [DOI] [PubMed] [Google Scholar]
- 2.Liu Z, Davidson A: Taming lupus-a new understanding of pathogenesis is leading to clinical advances. Nat Med 18: 871–882, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Tsokos GC: Systemic lupus erythematosus. N Engl J Med 365: 2110–2121, 2011 [DOI] [PubMed] [Google Scholar]
- 4.Pons-Estel GJ, Alarcón GS, Scofield L, Reinlib L, Cooper GS: Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum 39: 257–268, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Yang J, Liang D, Zhang H, Liu Z, Le W, Zhou M, Hu W, Zeng C, Liu Z: Long-term renal outcomes in a cohort of 1814 Chinese patients with biopsy-proven lupus nephritis. Lupus 24: 1468–1478, 2015 [DOI] [PubMed] [Google Scholar]
- 6.Borchers AT, Naguwa SM, Shoenfeld Y, Gershwin ME: The geoepidemiology of systemic lupus erythematosus. Autoimmun Rev 9: A277–A287, 2010 [DOI] [PubMed] [Google Scholar]
- 7.Ikehara S, Good RA, Nakamura T, Sekita K, Inoue S, Oo MM, Muso E, Ogawa K, Hamashima Y: Rationale for bone marrow transplantation in the treatment of autoimmune diseases. Proc Natl Acad Sci U S A 82: 2483–2487, 1985 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Alexander T, Hiepe F: Autologous haematopoietic stem cell transplantation for systemic lupus erythematosus: Time ready for a paradigm shift? Clin Exp Rheumatol 35: 359–361, 2017 [PubMed] [Google Scholar]
- 9.Leone A, Radin M, Almarzooqi AM, Al-Saleh J, Roccatello D, Sciascia S, Khamashta M: Autologous hematopoietic stem cell transplantation in Systemic Lupus Erythematosus and antiphospholipid syndrome: A systematic review. Autoimmun Rev 16: 469–477, 2017 [DOI] [PubMed] [Google Scholar]
- 10.Alexander T, Thiel A, Rosen O, Massenkeil G, Sattler A, Kohler S, Mei H, Radtke H, Gromnica-Ihle E, Burmester GR, Arnold R, Radbruch A, Hiepe F: Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood 113: 214–223, 2009 [DOI] [PubMed] [Google Scholar]
- 11.Marmont AM, van Lint MT, Gualandi F, Bacigalupo A: Autologous marrow stem cell transplantation for severe systemic lupus erythematosus of long duration. Lupus 6: 545–548, 1997 [DOI] [PubMed] [Google Scholar]
- 12.Alexander T, Arnold R, Hiepe F: [Autologous hematopoietic stem cell transplantation in systemic lupus erythematosus]. Z Rheumatol 75: 770–779, 2016 [DOI] [PubMed] [Google Scholar]
- 13.Jayne D, Passweg J, Marmont A, Farge D, Zhao X, Arnold R, Hiepe F, Lisukov I, Musso M, Ou-Yang J, Marsh J, Wulffraat N, Besalduch J, Bingham SJ, Emery P, Brune M, Fassas A, Faulkner L, Ferster A, Fiehn C, Fouillard L, Geromin A, Greinix H, Rabusin M, Saccardi R, Schneider P, Zintl F, Gratwohl A, Tyndall A; European Group for Blood and Marrow Transplantation; European League Against Rheumatism Registry : Autologous stem cell transplantation for systemic lupus erythematosus. Lupus 13: 168–176, 2004 [DOI] [PubMed] [Google Scholar]
- 14.Burt RK, Traynor A, Statkute L, Barr WG, Rosa R, Schroeder J, Verda L, Krosnjar N, Quigley K, Yaung K, Villa Bs M, Takahashi M, Jovanovic B, Oyama Y: Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA 295: 527–535, 2006 [DOI] [PubMed] [Google Scholar]
- 15.Liu Z, Zhang H, Liu Z, Xing C, Fu P, Ni Z, Chen J, Lin H, Liu F, He Y, He Y, Miao L, Chen N, Li Y, Gu Y, Shi W, Hu W, Liu Z, Bao H, Zeng C, Zhou M: Multitarget therapy for induction treatment of lupus nephritis: A randomized trial. Ann Intern Med 162: 18–26, 2015 [DOI] [PubMed] [Google Scholar]
- 16.Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, Boletis J, Cervera R, Dörner T, Doria A, Ferrario F, Floege J, Houssiau FA, Ioannidis JP, Isenberg DA, Kallenberg CG, Lightstone L, Marks SD, Martini A, Moroni G, Neumann I, Praga M, Schneider M, Starra A, Tesar V, Vasconcelos C, van Vollenhoven RF, Zakharova H, Haubitz M, Gordon C, Jayne D, Boumpas DT; European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association : Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 71: 1771–1782, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Marmont AM: Immune ablation with stem-cell rescue: A possible cure for systemic lupus erythematosus? Lupus 2: 151–156, 1993 [DOI] [PubMed] [Google Scholar]
- 18.Marmont AM: Stem cell transplantation for severe autoimmune diseases: Progress and problems. Haematologica 83: 733–743, 1998 [PubMed] [Google Scholar]
- 19.Tyndall A: Application of autologous stem cell transplantation in various adult and pediatric rheumatic diseases. Pediatr Res 71: 433–438, 2012 [DOI] [PubMed] [Google Scholar]
- 20.Farge D, Labopin M, Tyndall A, Fassas A, Mancardi GL, Van Laar J, Ouyang J, Kozak T, Moore J, Kötter I, Chesnel V, Marmont A, Gratwohl A, Saccardi R: Autologous hematopoietic stem cell transplantation for autoimmune diseases: An observational study on 12 years’ experience from the European Group for Blood and Marrow Transplantation Working Party on Autoimmune Diseases. Haematologica 95: 284–292, 2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Illei GG, Cervera R, Burt RK, Doria A, Hiepe F, Jayne D, Pavletic S, Martin T, Marmont A, Saccardi R, Voskuyl AE, Farge D: Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus. Ann Rheum Dis 70: 2071–2074, 2011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Leng XM, Jiang Y, Zhou DB, Tian XP, Li TS, Wang SJ, Zhao YQ, Shen T, Zeng XF, Zhang FC, Tang FL, Dong Y, Zhao Y: Good outcome of severe lupus patients with high-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation: A 10-year follow-up study. Clin Exp Rheumatol 35: 494–499, 2017 [PubMed] [Google Scholar]
- 23.Cao C, Wang M, Sun J, Peng X, Liu Q, Huang L, Chai Y, Lai K, Chen P, Liu Q, Li Q, Peng Y, Xiong H, Zhang J, Chen M, Zeng K: Autologous peripheral blood haematopoietic stem cell transplantation for systemic lupus erythematosus: The observation of long-term outcomes in a Chinese centre. Clin Exp Rheumatol 35: 500–507, 2017 [PubMed] [Google Scholar]
- 24.Snowden JA, Saccardi R, Allez M, Ardizzone S, Arnold R, Cervera R, Denton C, Hawkey C, Labopin M, Mancardi G, Martin R, Moore JJ, Passweg J, Peters C, Rabusin M, Rovira M, van Laar JM, Farge D; EBMT Autoimmune Disease Working Party (ADWP); Paediatric Diseases Working Party (PDWP) : Haematopoietic SCT in severe autoimmune diseases: Updated guidelines of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 47: 770–790, 2012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Zhang L, Bertucci AM, Ramsey-Goldman R, Burt RK, Datta SK: Regulatory T cell (Treg) subsets return in patients with refractory lupus following stem cell transplantation, and TGF-beta-producing CD8+ Treg cells are associated with immunological remission of lupus. J Immunol 183: 6346–6358, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Burt RK, Slavin S, Burns WH, Marmont AM: Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: Getting closer to a cure? Blood 99: 768–784, 2002 [DOI] [PubMed] [Google Scholar]