A multicenter recall survey of the side effects of Rituximab in Iranian children with kidney disease
Khadijeh Ghasemi
1*, Mitra Basiratnia
2, Mastaneh Moghtaderi
3, Simin Sadeghi –Bojd
4, Nakysa Hooman
5, Iranspn RIXSE Consortium #
1Assistant Professor of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Persian Gulf Shohada hospital, Bushehr University of Medical Sciences, Bushehr, Iran,
2Preofessor of Pediatric Nephrology, Shiraz nephro-urology research center, Shiraz University of Medical Sciences, Shiraz, Iran,
3Pediatric Chronic Kidney Disease Research Center, Children's Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran,
4School of Medicine, Children & Adolescents Health Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran,
5Professor of Pediatric Nephrology, Ali-Asghar Clinical Research Development Center (AARDC), Ali-Asghar Children Hospital, Iran University of Medical Sciences, Tehran, Iran,
*Corresponding Author: Khadijeh Ghasemi, Bushehr University of Medical Sciences, Bushehr, Iran; Email:
ABSTRACT
Introduction: Rituximab is a monoclonal antibody against CD20 marker of B lymphocytes that is widely used in the treatment of various diseases including malignancies, connective tissue diseases, nephrotic syndrome, and organ transplantation. Side effects of rituximab include early and late-onset complications and range from allergic reactions in mild early onset to severe anaphylactic shock. Late-onset lymphoproliferative disorders (PTLD) have been reported as a long term complication. Since it has been used in patients with nephrotic syndrome, evaluation of early and long term side effects is very important. Materials and Methods: This study was conducted in 18 districts of Iran. 27 university-affiliated hospitals were recruited and 31 pediatric nephrologists completed the questionnaires. A questionnaire containing patient's demographic data, use of rituximab in kidney diseases, times of injections, protocol of receiving medication, and early and late side effects was sent to all collaborators via email. The completed questionnaires were collected via e-mail. Results: The results from recall showed that of the nephrologists who completed the questionnaires, 65.5% prescribed medication in less than 10 eligible patients and 34.5% prescribed rituximab in more than 10 patients in the last year. Side effects during the administration were reported in 77%, the most common being fever, chills, and rigor. Mild and early complications were reported in 54%. Infection, cardiovascular, pulmonary and renal disorders were the most reported side effects. Conclusion:
Despite the numerous and serious side effects of rituximab reported in the literature, it seems to be a safe drug for patients with nephrotic syndrome.
Keywords
Rituximab, Nephrotic Syndrome, side effects
Introduction
Rituximab is a monoclonal antibody for the CD20 marker of B lymphocytes. The antibody was initially used in lymphoproliferative disorders such as B cell lymphoma and connective tissue diseases [1-3]. Before the administration of monoclonal antibodies, any acute or chronic infection and possible immunodeficiency should be diagnosed [1]. Symptoms of administration of rituximab in children with nephrotic syndrome include:
Patients with steroid-dependent nephrotic syndrome
Patients with recurrent attacks who have not responded to various immunosuppressive treatment protocols.
In frequent relapsing patients, improvement of patient outcomes has been reported [4-10].
In steroid-resistant nephrotic syndrome, membranous nephropathy, and relapse of focal segmental glomerulosclerosis in the transplanted kidney, promising results have been described [11-13].
Adding low doses of mycophenolate mofetil to rituximab regimen may prolong the recovery time to 24 months in nephrotic syndrome [14].
The main mechanism of action of this medication is the reduction of B lymphocytes in cases caused by autoantibodies. It eliminates B cells without affecting other leukocytes, mainly by binding to 4 amino acids on the CD20 marker of B cells, and T cells containing CD20 marker. This causes B-Cells to be phagocytized by the reticuloendothelial system or killed by natural killer cells through antibody-dependent cellular toxicity (ADCC) [3]. Complement activation by the rituximab-CD20 complex leads to B cell destruction. B lymphocytes also undergo apoptosis by activation of the MAP kinase and p38 pathway [3].
Remarkable in the use of rituximab is the lack of antibody-producing plasma cells elimination, because they do not express CD20 antigen. In general, the efficacy of the medication is based on limiting the production of B cells[3, 11]. B and T lymphocytes as well as various circulating cytokines cause early injury to the surface of glomerular podocytes and play an important role in the pathogenesis of nephrotic syndrome [11]. Rituximab eliminates B cells, reduces T cell subsets, modulates cytokines, and has direct and non-immunological effects on podocytes. Therefore, the use of this medication in this disease has been suggested. This medication is most effective when the serum albumin is normal, the patient is young, and is prescribed at the remission phase [4].
Infusion-related reactions occur during or 24 hours after injection. Using pre-medications is helpful to prevent or relieve these symptoms. These complications depend on the dose and rate of infusion. In several studies, 80-90% of cases have been reported and are mostly observed at the first injection [1, 2, 15]. Fever, chills and rigor, itching, hives, nausea and vomiting, headache, flushing, dizziness, respiratory problems, tongue and throat swelling, blurred vision, changes in blood pressure, changes in stool consistency and stool color and shortness of breath are most common complications at this phase [2, 15]. Hunger, thirst, tingling sensation and anaphylaxis rarely occur at this time [1, 2, 15]. Skin and oral reactions appear at any time after administration and include painful ulcers, blisters, and skin detachment. Activation of hepatitis B and lethal fulminant hepatitis have also been reported [2].
Other side effects of this medication include rare but fatal progressive multifocal leukoencephalopathy, weakness, and muscle spasm [16]. Risk of viral, bacterial, and fungal infections increases due to the compromised immune system. Renal, hepatic, cardiopulmonary, and gastrointestinal complications such as intestinal obstruction and colitis are unintended side effects [1, 16].
The recommended dose is 375 mg / m2 and the duration of treatment varies from one to four weeks. Antihistamines, antipyretics, and corticosteroids reduce the potential complications of injection [1, 4, 8].
The main purpose of this study was to evaluate the complications of Rituximab in Iranian children with kidney disease.
Methods and Material
This survey was conducted in 18 districts of Iran. 27 university-affiliated hospitals were recruited and 31 pediatric nephrologists completed the questionnaires. As the first step of the questionnaire containing patient's demographic data, use of rituximab in kidney diseases, times of injection, protocol of receiving medication, and early (Fever, chills, nausea, vomiting, changes in blood pressure, etc) and late side effects (neurological, pulmonary, cardiovascular, renal, serum sickness, gastrointestinal problems, and infections) of rituximab has been sent to all collaborators via email. The completed questionnaires were collected via e-mail.
Since this study was survey-based research, no ethical approval was required.
Results:
From 31 questionnaires completed by pediatric nephrologists, the following results were obtained:
Of the nephrologists who completed the questionnaires, 65.5% prescribed medication in less than 10 eligible patients and 34.5% prescribed rituximab in more than 10 patients in the last year (Table 1).
Table 1. The number of patients reported per questionnaire.
Number of patients Percentage(%)
=<10
<5
5-10
65.5
32.3
33.2
>10
10-20
>20
34.5
25
9.5
The dose used in all cases was 375 mg / m2 weekly. In 54.8% of the questionnaires, patients received weekly doses up to 4 weeks, in 16.1% they received weekly doses up to 4 weeks, and 1 booster dose after 6 months, and in 29.1%
they had once or twice and repeat if necessary (Table 2).
Table 2. The number and interval of prescribed doses of rituximab
Dosage Percentage(%)
=<2 doses 29.1%
4 doses in 4 weeks 54.8%
4 doses in 4 weeks and 1 booster after
6 months 16.1%
Complications during injection were reported in 77% of the questionnaires, the most common being fever, chills, rigor, pruritus, and the least common ones were myalgia and dizziness. The rate of other infusion-related complications are shown in Figure 1.
Figure 1. Infusion-related complications of rituximab.
Short term complications were reported in 54% of the questionnaires. Infectious diseases,, as well as cardiovascular, pulmonary and renal complications, were more common (Figure 2).
Figure 2. Short term complications of rituximab.
Other post-injection complications included the following (Table 3):
Reported respiratory complications include pneumonia, bronchiolitis, asthma, chemical pneumonia, restrictive lung disease, pulmonary emboli, and pulmonary hemorrhage .
Complications involving the central nervous system include speech and gait disturbance, confusion, Pseudotumor cerebri, blurred vision, and thrombosis.
Most infectious diseases reported were bacterial including pneumonia, urinary tract infections, tuberculosis, and gram-negative sepsis.
Renal complications included proteinuria, acute kidney injury, and dysuria.
Complications involving the gastrointestinal tract were severe abdominal pain, gallbladder stone and hydrops, and appendicitis.
Progressive leukoencephalopathy and serum sickness were also reported.
There have been no reports of hepatitis B activation.
The rate of each complication is also shown in table 3.
Table 3. Short term complications of rituximab (Number of questionnaires)
Respiratory
Pneumonia: 3 (10%) Bronchiolitis: 2 (6%) Asthma: 2(6%)
Chemical pneumonitis: 2(6%) Pulmonary thromboembli: 1(3%) Pulmonary hemorrhage: 1(3%) Restrictive lung disease: 1(3%)
CNS
Speech and gait disturbance: 4 (13%) Confusion: 2(6%)
Thrombosis: 1(3%)
Pseudotumor cerebri: 1(3%) Blurred vision: 1(3%) PMLE: 1(3%)
Infectious disease
Bacterial: 7 (Pneumonia: 3, UTI: 1, Gram negative sepsis:
1, TB: 1)
Viral: 2 (Influenza: 1, Herpes zoster: 1) (6%) Fungal : 1(Pneumocystis jirovecii:1)
Renal
Protein-uria: 5(16%) Acute kidney injury: 2(6%) Dysuria: 1(3%)
Cardio-
vascular Chest pain: 19(61%)
Ventricular Fibrillation: 1(3%) Myocarditis: 1(3%)
Cardiogenic shock: 1(3%)
Gastro- intestinal
Severe abdominal pain: 1(3%) Gallbladder hydrops and stone: 1(3%) Appendicitis: 1(3%)
Others
Serum sickness: 2 (6%) Severe Leukopenia: 1 (3%)
Discussion
The main purpose of this study was to evaluate the side effects of rituximab in children with idiopathic nephrotic syndrome. It has been used in combination with other drugs for the past two decades. The use of this medication appears to be most effective in steroid-dependent patients with recurrent relapses, especially in the remission phase, normal serum albumin status, and younger age.
Its mechanism of action, due to the importance of B cells, T cells, cytokines, and podocytes in the pathogenesis of nephrotic syndrome expose the use of this medication to the discussion as a door of hope to control and increase the duration of disease remission [3, 4, 11].
The most common side effects occur during infusion and are reported in 80-90% of cases. These reactions are mainly reported as skin manifestations, itching, hives, fever and chills, sweating, headaches, changes in blood pressure, palpitations, nausea and vomiting [1, 2]. In this study, of the 31 questionnaires submitted, 77% reported infusion- related complications including fever, chills, rigor, nausea, vomiting, pruritus, headache, bronchospasm, urticaria or rash, myalgia, dizziness, and blood pressure changes (hypotension and hypertension).
In the gastrointestinal tract, problems such as darkening of the stool color and intestinal obstruction may occur from 1 to 77 days after the first dose of the medication, with an average occurrence of 6 days after the first dose [1]. Appendicitis has also been reported, possibly due to a decrease in B cells in the blood and lymphatic tissues [17]. In our patients, appendicitis was reported in a questionnaire. There was also a report of severe abdominal pain.
Many studies have been performed to evaluate the efficacy of this medication in children with idiopathic nephrotic syndrome or recurrent focal and segmental glomerulosclerosis (FSGS) in the transplanted kidney [11].
Renal complications of rituximab include discoloration of urine, dysuria, and acute renal failure due to tumor lysis syndrome [16]. The relapse of proteinuria has also been reported in several articles from 6 to 32 months after use [10]. In this study, 5 questionnaires reported proteinuria, 2 reported acute kidney injury and 1 questionnaire reported dysuria and frequency.
Acute and delayed arthritis, spasms, and muscle weakness are other complications of this medication [16]. In our study, myalgia was reported in a questionnaire.
Pseudotumor cerebri was reported by colleagues in a questionnaire. There have been no reports of such a complication in the literature review, and even rituximab has been used as a treatment for pseudotumor cerebri in
SLE patients [18]. This problem may be related to the complication of steroid treatment as the patient's main and primary medication [19].
Possible thrombosis of the central nervous system vessels was reported in a questionnaire. There was a case report of this complication in a patient with lymphoma in the literature [20]. Central nervous system thrombosis is probably due to coagulopathy as a complication of nephrotic syndrome and cannot be associated with rituximab [21].
Blood pressure changes have been reported in several articles more in the form of hypotension [21]. In the current study, reported cases of hypotension were higher than those of hypertension. Cardiac involvement in the form of chest pain, arrhythmia, angina, non-ischemic cardiomyopathy with persistent decreased cardiac function and fulminant viral myocarditis have been reported in various articles [22, 23]. In this study, in 19 questionnaires chest pain was reported. Ventricular fibrillation, myocarditis, and cardiogenic shock were also reported, each in one questionnaire.
Pulmonary involvement varies from an asthma attack, bronchiolitis, pneumonia, pneumocystis jirovecii infection, bronchospasm to acute respiratory failure [1, 2]. In this study, pneumonia, asthma, and bronchiolitis were the most commonly reported complications. Tuberculosis was also reported in a questionnaire which according to the literature, is due to neutropenia and compromised immune system resulting in an increased risk of infection [24, 25]. At the time of infusion of rituximab, none of the questionnaires reported anaphylaxis. The most common causes of death in patients receiving the medication are cardiovascular complications, systemic inflammatory response syndrome (SIRS) and gastrointestinal complications [1]. In our study, none of the questionnaires reported mortality due to rituximab injection.
Gallbladder involvement as cholecystitis, stasis, and gallbladder sclerosis using other cytotoxic medications have been reported [26], but not with rituximab. However, in this study, one questionnaire reported gallbladder hydrops and gallstones.
The dose prescribed in various studies was 375mg / m2 at a one-week interval from one dose to four doses and one 6- month reminder dose [4, 8]. In this study, in 29.1% of the questionnaires patients received one or two doses of rituximab and repeat if necessary, in 54.8% they received 4 doses, and in the rest, they received 4 doses at the one- week interval and six-month reminder dose.
Limitations:
Since this was a questionnaire-based survey, recall bias should be considered and a reported number of complications may not be precise.
Another limitation is that some of the late complications may become evident in the long term follow up.
Conclusion
Given the pros and cons of rituximab prescription, it appears to be safe and useful in children with idiopathic steroid- dependent and frequently relapsing nephrotic syndrome.
Acknowledgment:
We would like to thank the Iranian Society of Pediatric Nephrology (iranspn.com) to assist in collecting data and provided facilities.
# Iranspn RIXSE Consortium consists of the authors, as well as:
Ali Derakhshan (Shiraz nephro-urology research center, Shiraz University of Medical Sciences, Shiraz, Iran), Fahimeh Asgarian (Assistant Professor of Pediatric Nephrology, Department of Pediatrics, School of Medicine,Childrens Medical Center,Tehran University of Medical Sciences,Tehran,Iran ), Alaleh Gheissari
(Department of Pediatric Nephrology, Isfahan Kidney Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran), Nasrin Esfandiar (Pediatric nephrology research center, Research institute for children health, Shahid Beheshti University of Medical Sciences, Tehran, Iran), Hadi Sorkhi (Pediatric Nephrologist,Non- Communicable Pediatric Diseases Research Center, Health Research Institute, Babol University, Babol, Iran), Mahmood Reza Khazaei (Islamic Azad University Mashhad Branch: Mashhad, Razavi Khorasan, Iran) , SMT Hosseini-Tabatabaei (Pediatric nephrology research center, Research institute for children health, Shahid Beheshti University of Medical Sciences, Tehran, Iran) , Rahimpour Amiri (Hamadan University of Medical Sciences: Hamadan, Iran), Rama Naghshizadian (Kurdestan University of Medical Sciences, Sanandaj, Iran), Fatemeh Ghane Sharbaf (Mashad University of Medical Sciences, Mashah, Iran) , Maryam Esteghamati ) Hormozgan University of Medical Sciences, Bandar Abbas, Iran(, Afshin Safaeiasl ) Guilan University of Medical Sciences(, Mojgan Mazaheri Semnan university of medical sciences (, Masoumeh Mohkam (Pediatric Nephrology Research Center. Shahid Beheshti University of Medical Sciences. Tehran. Iran), Hossein Emad Momtaz (Hamedan University of Medical Sciences, Hamedan, Iran), Farshid Kompani (Golestan University of Medical Sciences), Mohsen Akhavan Sepahi (Hazrat-e Fateme Massomeh hospital, Qum university of Medical Sciences), Baranak Safaeian (Golestan University of Medical Sciences), Abolhassan Seyedzadeh (Kermanshah University of Medical Sciences. Shahid Beheshti BLVD, Kermansha, Iran), Parisa Honarpisheh (Aliasghar Children Hospital, Iran University of Medical Sciences, Tehran, Iran) , Ehsan Valavi (Ahvaz Jundishapur University of Medical Sciences), Kamran Sabzian (Lorestan University of Medical Sciences: Khoram-Abad, lorestan, Iran), Anita Ranjbar (Faiazbakhsh hospital, Tehran) , Ahmad Ali Nikibakhsh (Nephrology and kidney transplant research center, Urmia university of medical sciences), Hashem Mahmoudzadeh (Nephrology and kidney transplant research center, Urmia university of medical sciences.), Anoush Azarfar (Kidney transplantation complication research center, Mashhad University of Medical Sciences) , Mahmoud Maleknejad (Transplant & Dialysis Research Center, Montaserieh Hospital, Mashhad, Iran).
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