Abstract
Objective. Rituximab (RTX) has been used to treat many pediatric autoimmune conditions. We investigated the safety and efficacy of RTX in a variety of pediatric autoimmune diseases, especially systemic lupus erythematosus (SLE).
Methods. Retrospective study of children treated with RTX. Effectiveness data was recorded for patients with at least 12 months of followup; safety data was recorded for all subjects.
Results. The study included 104 children; 50 had SLE. Improvements in corticosteroid dosage, physician’s global assessment of disease activity, and SLE-associated markers of disease activity were seen. The incidence of hospitalized infections was similar to previous studies of patients with childhood-onset SLE.
Conclusion. RTX can be safely administered to children and appears to contribute to decreased disease activity and steroid burden.
Rituximab (RTX) is a chimeric monoclonal antibody that specifically targets CD20-positive B cells. Although it lacks any pediatric indications, RTX has been widely studied for various pediatric rheumatologic conditions, including autoimmune hemolytic anemia, immune thrombocytopenic purpura, systemic lupus erythematosus (SLE), vasculitis, and juvenile dermatomyositis1,2,3,4. The use of RTX to treat pediatric autoimmune disease has particularly focused on SLE5,6. Although only 15–20% of cases are diagnosed in childhood, SLE has a more severe phenotype in children compared to adults, particularly in those with nonwhite ethnicity7,8,9. Several open-label studies of RTX in pediatric subjects have demonstrated benefit in life-threatening or organ-threatening SLE5,10,11,12,13,14,15. However, limitations of these studies include low patient numbers and demographic cohorts not representative of many patients with SLE in the United States. Herein, we report on the safety and effectiveness of RTX in 104 subjects with a variety of pediatric autoimmune diseases, with a focus on SLE.
MATERIALS AND METHODS
Patients
This was a retrospective study of children treated by 1 or more pediatric rheumatologists at Children’s Hospital of Alabama (CoA) with at least 1 course of RTX between August 1, 2007, and April 1, 2014. Patients were identified in the electronic medical record using medication codes for RTX, limited to those evaluated by a rheumatologist16. Institutional Review Board approval at the University of Alabama at Birmingham was obtained.
RTX administration
RTX was typically administered at a dose of 750 mg/m2 × 2 doses (max 1 g/dose) 2 weeks apart17. Subjects were premedicated with methylprednisolone at doses ranging from 2 mg/kg to 30 mg/kg, depending on the underlying diagnosis and disease severity, maximum of 1 g; additional premedications included standard doses of acetaminophen and diphenhydramine. The RTX was diluted in normal saline at a concentration of 4 mg/ml and administered at a starting rate of 0.25 ml/kg/h (max 25 ml/h) for the first hour, then increased by increments of 0.25 mg/kg/h every 20 min up to a maximal rate of 100 ml/h. Vital signs were obtained every 15 min for the first hour, then hourly. RTX was administered in our outpatient infusion department or on an inpatient basis.
Data collection
Effectiveness data were collected for all patient visits 12 months following the first RTX infusion and entered into a Microsoft Excel database, while safety data were recorded from the time of the first infusion until the final visit that occurred at or before April 1, 2014. Safety events were identified through review of all visit notes, emergency department visits, hospitalization records, and phone notes.
Outcomes
For effectiveness, the physician’s global assessment (PGA) of disease activity18 and oral corticosteroid (CS) dosage at baseline (just prior to RTX) and at 12 months of followup were documented on all patients. Additional documentation on patients with SLE included complement levels, erythrocyte sedimentation rate, complete blood count, creatinine, albumin, urine protein, and anti-DNA levels6. SLE Disease Activity Index scores are not routinely obtained at this center, so they were not available for this retrospective study. Safety was evaluated in all patients. The primary safety outcomes evaluated included (1) all serious adverse events (SAE) according to the US Food and Drug Administration definition (any events resulting in death, hospitalization, or prolongation of existing hospitalization, significant loss of function, or congenital anomaly); (2) all medically important infections defined as those requiring intravenous antimicrobial therapy or hospitalization; and (3) all infusion reactions.
Statistical analysis
Continuous data were reported as medians and ranges, and categorical data were reported as percentages. Comparisons of effectiveness data at baseline and 12 months were performed with the paired Student t test. Analyses were performed using SPSS software, version 22.
RESULTS
Patient population
The study included 104 children, 50 of whom had SLE. Their demographic information and diagnoses are shown in Table 1. Sixty-four percent of the entire cohort and 76% of the patients with SLE were African American, and most of the remainder were white. Twenty of the 50 patients with SLE and 11 of the 54 additional subjects were treated with RTX as part of their initial therapy, while the remainder had previously failed 1 or more additional agents. A summary of previous as well as concurrent therapies is shown in Table 2. Among those who had previously failed conventional therapy, the mean (± SD) disease duration was 1.6 ± 1.3 years for the patients with SLE and 1.8 ± 1.8 years for the others. All of the subjects received at least 1 course of RTX, with a course consisting of 2 doses at 750 mg/ m2 (max 1 g), administered 2 weeks apart. Median number of courses received was 2 (range 1–11). In total, 466 infusions were administered. Ninety-nine patients had at least 12 months of followup (range 1 month–6.4 yrs). A total of 253.3 person-years of followup was available.
Subjects included in this study. Data are n (%) unless otherwise indicated.
Prior and concurrent medications of subjects included in the current study.
Effectiveness of depletion
Post-RTX CD19 counts were available on 100 of 104 subjects, of whom 78 also had pre-RTX CD19 counts available. At least partial depletion was observed in all cases (mean CD19 counts decreased from 422 to 2.9 cells/µl, p < 0.0001), with B cell counts dropping to fewer than 5 cells/µl in 82 subjects, with the highest post-RTX B cell count of 37 cells/µl.
Clinical effectiveness
Of the 99 subjects with at least 12 months of followup, 12-month data are available on 98. Mean daily oral CS (prednisone) dose decreased from 29.8 ± 25.7 mg to 8.7 ± 13.1 mg (p < 0.001), and among the 88 subjects on whom data were available, mean PGA of disease activity decreased from 34.4 ± 19.2 to 15.7 ± 12.3 (p < 0.001). Data for the 48 patients with SLE who had at least 12 months of followup is shown in Table 3. Consistent with the cohort as a whole, significant improvement was observed in CS dosage and PGA of disease activity, as well as in multiple SLE-associated markers of disease activity. Similar improvements were observed among the 22 patients with SLE who had nephritis and at least 12 months of followup (Figure 1).
Changes in C3 before and after rituximab (RTX) therapy among subjects with lupus nephritis. The wider grey line represents the regression line. This improvement was significant at p < 0.001, paired Mann-Whitney U test.
Effectiveness data among patients with SLE who had at least 12 months of followup. Data are median ± SD.
Safety
Overall, RTX was well tolerated. Twenty-six infusion reactions (5.6% of infusions, none of which required intervention with epinephrine or urgent admission), were reported in 18 patients. All of those patients were able to successfully complete the infusion or tolerated subsequent infusions. Most of the time, slowing the rate of the infusion appeared to be of benefit.
Excluding admissions for disease flares, 26 patients underwent 29 admissions over 253.3 person-years of followup (114/1000 person-yrs). Of those, 20 subjects underwent 22 admissions for possible or definite infections (86.9/1000 person-yrs; Table 4), with the remainder consisting of 1 DVT, 2 admissions in 1 subject for poor weight gain thought to be attributed to depression, 2 admissions for psychiatric issues, 1 for appendicitis, and 1 for vomiting attributed to mycophenolate mofetil (MMF). Additionally, an 18-year-old female with Ro-positive Sjögren syndrome gave birth to a child with fetal heart block. There was also a case of herpes zoster that did not result in admission, but was considered an opportunistic infection. Among the 50 patients with SLE, there were 12 infections requiring hospitalization out of a total of 132.2 person-years (90.8/1000). One subject with progressive interstitial lung disease died after transition to adult rheumatology care. There was no obvious association between race and incidence of infection. Intravenous immunoglobulin (IVIG) was administered to 26 patients, 13 of whom received IVIG therapy as treatment for their underlying disorder (e.g., dermatomyositis, idiopathic thrombocytopenic purpura). Of the 13 subjects who received IVIG for replacement secondary to hypogammaglobulinemia, the median IgG level was 386 mg/dl, with a range of 160–798 mg/dl. Baseline IgG levels were available on 7 of those patients, 3 of whom had low levels (250–706 mg/dl) prior to RTX. Two of those 13 subjects were found to have hypogammaglobulinemia within weeks of the initial infusion, while most others did not develop hypogammaglobulinemia for months to years after the initial infusion (mean 8 mos).
Infectious SAE and opportunistic infections among patients taking RTX.
DISCUSSION
To our knowledge, this work represents the largest single-center collection of pediatric patients treated with RTX for autoimmune/rheumatic indications. In this ethnically diverse population with a variety of rheumatologic conditions, we demonstrated that treatment regimens that included RTX are safe and generally appear to be effective. Although there was a rate of hospitalized infections of 86.9/1000 person-years among the cohort as a whole, and 90.8/1000 among the patients with SLE, the safety profile compares favorably with several previous studies. For example, Costa-Reis, et al reported a rate of 169 “serious infections”/1000 person-years; however, their definition included those requiring oral antibiotics for 7 or more days and is thus not directly comparable to ours19. Opastirakul and Chartapisak reported a rate of infections requiring hospitalization for IV antibiotics of 176/1000 among subjects receiving IV cyclophosphamide (CYC; calculated from text)20. Vachvanichsanong, et al reported 23 deaths out of 108 childhood-onset subjects with SLE followed for 3 years21, although this study as well as the one by Opastirakul and Chartapisak were both published from Thailand, where there may be higher risk of infections and less-advanced medical care. Two smaller studies did show more favorable safety profiles of CYC usage in childhood-onset SLE: Lehman and Onel reported no serious infections among 16 CYC-treated patients followed 3 years each22, nor did Barbano, et al among 14 subjects followed for a mean of 9.2 years each23.
The nature of our study did not permit direct effectiveness comparisons with regimens containing CYC or MMF, accompanied by CS, although a recent open-label study showed RTX to be comparable to both agents over a 12-month period in the management of lupus nephritis24. The reduction of the CS dose from 31 mg at baseline to 8.8 mg at 12 months among the 50 patients with SLE appears to compare favorably with the reduction reported by Lehman and Onel in the pre-RTX era22, and is similar to that reported by Lehman, et al following use of RTX5. Because major risk factors for SAE, including mortality, in patients with SLE are active disease and high doses of CS25, any medicine that can help minimize CS use and help attain disease control is likely to be of substantial benefit.
Limitations of our study include its retrospective design, the absence of a standardized approach to treatment and monitoring, and lack of a comparator group that was not treated with RTX. In addition, this was a heterogeneous population; even among the patients with SLE, only 22 of them had nephritis. Further, while all the infusions were administered at CoA, it is possible that not all safety events were identified, because many of our patients live a considerable distance from our center. However, in this critically ill population, it is unlikely that any significant illness, including hospitalizations, would not have been reported to us or noted in a subsequent visit.
In a diverse population of pediatric patients with autoimmune diseases, RTX therapy when combined with standard immunosuppressive therapy appears to be safe and to permit reductions in CS dosage, among other beneficial effects. Clearly, future prospective studies are warranted in the pediatric population.
- Accepted for publication November 24, 2014.
REFERENCES
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