Rituximab-induced serum sickness in a girl with nephrotic syndrome

Abstract

Rituximab (RTX) has been used to treat B cell lineage lymphoma/leukemia or autoimmune or autoinflammatory disorders. RTX therapy has been extensively applied to cases of frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome. Rituximab-induced serum sickness (RISS) has been recognized as a rare severe type-3 hypersensitivity reaction in patients treated with RTX. We herein report a 10-year-old girl with RISS in FRNS. She was diagnosed with RISS based on characteristic symptoms, such as a fever, rash, arthritis, or proteinuria, during RTX therapy associated with a high level of human anti-chimeric antibody. Even after recovering from acute symptoms by RISS, she suffered from worsening relapses of nephrotic syndrome. The symptoms of RISS are non-specific, resembling viral infections, autoinflammatory diseases and Kawasaki disease, especially in children. While RISS is a rare complication among patients with nephrotic syndrome, it should be carefully considered as a severe complication in patients being treated with RTX.

Introduction

Rituximab (RTX) is a chimeric murine/human monoclonal antibody binding to CD20, an antigen-specific to mature B cells. RTX has been clinically used to treat malignant lymphoma, chronic immune thrombocytopenic purpura, and various autoimmune diseases. RTX is also used in cases of frequently relapsing nephrotic syndrome in which the steroid dose cannot be reduced, even being treated by immunosuppressive agents [1, 2]. However, serious side effects are reported to rarely occur during RTX treatment (frequency < 1%), including severe infection, progressive multifocal leukoencephalopathy, fulminant hepatitis due to hepatitis B virus [3], and rituximab-induced serum sickness (RISS) [4].

RTX is generated as a human-mouse chimeric antibody, and the variable region of the globulin is derived from mice; therefore, the formation of an immune complex by RTX and anti-RTX antibody can induce a type III allergic reaction, called serum sickness. RISS was first reported in a patient with refractory autoimmune polyneuropathy after treatment with RTX in 2001 [5]; since then, many patients with blood malignancy and autoimmune diseases have already been described. In contrast, the occurrence of RISS in patients with nephrotic syndrome (NS) has been relatively rare, partly because patients with NS are extensively treated with various immunosuppressants, such as prednisolone, cyclosporine A and cyclophosphamide, for long periods, which may result in the suppression of the development of autoimmune or allergic reactions.

We herein report a 10-year-old girl with FRNS who developed RISS. We also review the literature on reported FRNS cases with RISS.

Case report

We encountered a 10-year-old girl who had developed NS at 2 years of age. She achieved complete NS remission after 8 days of treatment with oral PSL, she suffered from relapses of NS during PSL tapering. Therefore, mizoribine (MZR) in addition to PSL was started from three years old. However, frequent relapses of NS occurred, and six months later, MZR was replaced with cyclosporine A (CyA). The control of NS was not sufficient to decrease the frequency of relapse by CyA.

At 4 years of age, RTX treatment was started at 375 mg/m² every week for 4 weeks per course. RTX was quite effective in maintaining NS remission for 1 year, and PSL was able to be discontinued after 3 months, and CyA discontinued after 6 months. She subsequently received two courses of RTX treatment (two doses per course) at intervals of about 1–2 years. Then the frequency of NS relapse reduced approximately twice a year, and PSL was shortly used at that time for only 2–3 months per year. At eight years of age, however, the frequency of recurrence increased again, and additional treatment with MZR was started, but it was insufficient. MZR was then replaced with MMF without any significant change (Fig. 1a).

Fig. 1.

The treatment course of the present case. a Treatments from 2 to 10 years old. b The 10th RTX treatment and clinical manifestations. c The 11th RTX treatment and clinical manifestations. RTX rituximab, PSL prednisolone, CyA cyclosporine A, MZR mizoribine, MMF mycophenolate mofetil, ABPC/SBT ampicillin/sulbactam

At 9 years of age, the 10th administration of RTX was performed approximately 1 year after the 9th administration of RTX, under treatment with PSL (30 mg, every other day) and MZR (1500 mg/day) (Fig. 1b). The CD19- and CD20-positive B cell counts in peripheral blood were 405/mm³ and 892/mm³ 14 days before the administration of RTX. 7 days after the administration of RTX (day 7), bilateral thigh pain, arthralgia in both shoulders and all fingers, abdominal pain and nausea occurred. She was admitted to our hospital on day 8. At admission, she had a slight fever of 37.8 °C and severe pain in both legs, resulting in her being barely able to walk by herself. Marked erythema on both cheeks and hyperemia in the bilateral conjunctiva also appeared. The blood laboratory findings demonstrated marked leukocytosis (white blood cells: 14,360/μL) with neutrophil predominance (90%) and a high C-reactive protein (CRP) level of 2.18 mg/dL. The serum creatinine kinase level was within the normal range (80 U/mL). The serum antinuclear antibodies and rheumatoid factor were negative. Urinalysis revealed proteinuria (2+).

Contrast-enhanced magnetic resonance imaging (MRI) (Fig. 2) of both thighs was performed, and a small amount of fluid retention was detected in both hips with contrast enhancement of synovium and signal elevation with fat suppression in and around the bilateral square-shaped fascia, suggesting synovitis and myositis. She was tentatively diagnosed with acute myositis.

Fig. 2.

MRI findings of the thigh. a T1WI with contrast-enhanced MRI showed bilateral hip joints with a small amount of fluid retention (arrow) and enhancement of the synovium. b T2WI with fat suppression shows an increased signal in and around the bilateral square-shaped fascia

Anti-inflammatory and antibiotics treatment was started (ampicillin-sulbactam, 150 mg/kg/day). The next day (day 9), her symptoms, especially pains, gradually disappeared on day 10. However, proteinuria continued with increased protein amount (4+), suggesting a relapse of NS. On day 12, oral PSL treatment was strengthened up to a daily dose of 60 mg/m², and the proteinuria disappeared on day 18. At that time, the CD19- and CD20-positive B cell counts in the peripheral blood decreased to 7/mm³ and 49/mm³, respectively. The frequency of NS relapse increased to approximately six times per year thereafter, and management with PSL, MMF, and MZR was reintroduced.

One year later, the 11th administration of RTX treatment was carried out (Fig. 1c). At the time of administration, NS was kept in remission with PSL 30 mg every other day and MMF 2000 mg/day, and MZR 150 mg/day. 7 days after the 11th administration of RTX, a fever, arthralgia of the lower limbs and erythema of the extremities appeared again. At that time, we suspected she had RISS, and an extremely high level of human anti-chimeric antibody (HACA) (> 5000 ng/mL) was detected, confirming the diagnosis as such. The CD19 and CD 20 positive B cells counts at 14 days after the 11th administration of RTX were decreased to 4/mm³ and 86/mm³, respectively. Approximately 3 months after the 11th administration of RTX, the CD19 and CD20 positive B cells counts were still low (11/mm³ and 36/mm³), but recovered to almost normal levels at 6 months (165/mm³ and 214/mm³, respectively).

Discussion

We encountered a pediatric patient with serum sickness caused by RTX, as revealed by reproducible systemic symptoms, such as a fever, arthralgia, erythema and proteinuria, as well as the presence of serum anti-RTX antibody.

Serum sickness was first described in 1905 by Von Pirquet. Later, similar cases were reported after the injection of monoclonal antibodies prepared from animal serum [6]. Serum sickness is a type III hypersensitivity reaction that results from the injection of heterologous or foreign protein or serum. It presents with nonspecific symptoms, such as a fever, skin rash, arthralgia, lymphadenopathy and fatigue, 7–14 days after the administration of the heterologous serum. Other symptoms are varied and include renal symptoms, such as proteinuria, hematuria and edema; gastrointestinal symptoms, such as nausea, abdominal pain and bloody stool; and other symptoms, such as myalgia, serositis, myocarditis and uveitis. About half of patients with serum sickness show urinalysis abnormalities, such as proteinuria and hematuria [7]. In a rat model of immune complex glomerulonephritis by serum sickness, extremely brief periods of active immunological injury to the peripheral capillary wall were sufficient to produce persistent abnormalities of the glomerular structure and function to cause massive proteinuria [8].

RISS is defined as a serum sickness caused by the RTX treatment [9, 10]. According to a previous report of 37 RISS patients in France, the median time from RTX administration to the onset of RISS was 12 days, and about half of those cases developed after the first RTX therapy session. The most common clinical symptoms were fever, arthritis or arthro-myalgia and skin symptoms (purpura, urticaria and indeterminate erythema), most of which were non-specific symptoms for autoinflammatory diseases. Autoimmune diseases are predominant over hematological malignancies as underlying diseases wherein RISS was induced by RTX [11]. In contrast, the occurrence of RISS in cases of NS has been relatively rare. RISS with NS was first reported in 2018 [12], with a few additional reports having been published since then. Most NS patients are treated with immunosuppressive drugs along with RTX for a long time, which may be a contributing factor to the low incidence of RISS in NS patients. To our knowledge, four cases of RISS in patients with idiopathic NS have been previously reported [12–15]. All patients were concomitantly treated with PSL and an immunosuppressant (CyA in four cases) along with RTX treatment. The age at onset was 6–17 years, the number of RTX administrations before the onset of RISS was 1–5, and the period from the administration of RTX to the onset of RISS was 7–10 days. In comparision to these reported cases, the present case developed RISS after the 9th administration of RTX. This may suggest that RISS may occur, even after RTX has been safely administered many times without apparent complications.

The clinical symptoms of RISS are difficult to distinguish from other inflammatory diseases. Therefore, measurement of HACA may be critical for the diagnosis of RISS when RISS is clinically suspected. However, serum levels of HACA are not always elevated in patients of RISS probably by concomitant medication with immunosuppressive drugs. Proteinuria is one of the most common manifestations of serum sickness, which is an overlapping sign of relapse of NS. Therefore, careful investigation of the clinical symptoms and laboratory studies are important for the early and accurate diagnosis of RISS, especially for patients with NS. It may also be necessary to distinguish between RISS and Kawasaki disease (KD), especially in children. Sato et al. reported a case of nephrotic syndrome triggered by the administration of RTX that led to the development of KD. In this patient, with similar symptoms to RISS, serum HACA elevation was detected [16]. Previous studies have reported that increased levels of immune complexes were detected in the serum or plasma from patients with KD. Consequently, immune complexes play, at least in part, an important role in the similarity of symptoms and etiopathogenesis between KD and RISS [17]. Retrospectively, the symptoms of the present case were partially similar to those of KD (e.g., fever, erythema on the cheeks, and hyperemia in the bilateral conjunctiva). Although we did not consider the diagnosis of KD at that time, we should have considered incomplete-type KD as one of the differential diagnoses. Since KD requires rapid treatment to avoid the formation of coronary artery lesions, it is important to make a differential diagnosis of KD at an early stage of the disease.

Another important finding from this case was that the frequency of relapse of NS apparently increased after the occurrence of RISS, whereas the frequency of relapse had already increased prior to the onset of RISS. It seems the formation of immune complexes between RTX and HACA might attenuate the apoptotic effect of RTX on B cells; thus, nephrotic syndrome began to recur frequently. However, the B cells in the peripheral blood had been effectively decreased by RTX, even after the onset of RISS. We suspect that the effect of rituximab on B cell depletion was insufficient to suppress the overall function of B cell lineage cells, or that it was not sufficient to accelerate the function of B-regulatory (B_REG) cells [18]. Alternatively, the immunocytochemical deposits in renal tissues led to local inflammation or organ damage, complement activation, and the influx of inflammatory, similarly to other renal diseases like membranoproliferative glomerulonephritis and systemic lupus erythematosus (SLE) nephritis. However, this is only a speculation, as we did not perform a histological evaluation of kidney biopsy specimens. Further studies are needed to elucidate the pathogenesis of frequent relapses of NS after RISS.

In conclusion, RISS is a rare but important complication of RTX therapy for FRNS. Proteinuria caused by RISS mimics relapses of NS, so careful observation of clinical manifestations is needed during RTX treatment for NS.

Funding

There was no funding source.

Declarations

Conflict of interest

The authors have declared that no conflict of interest exists.

Ethical approval

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from the parents of the patient included in this case report.