Rituximab-induced Serum Sickness Research Articles

#1315 Management and long-term outcome of recurrent idiopathic FSGS in pediatric renal transplant recipients

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a leading cause of pediatric end-stage renal disease (ESRD). While approximately 30% of pediatric FSGS is attributed to monogenic disorders, most cases are idiopathic, carrying a high risk of post-transplantation recurrence and graft loss. Commonly used protocols for recurrent FSGS (rFSGS) include plasmapheresis or immunoadsorption, and/or immunomodulatory therapy. We retrospectively evaluated the efficacy and safety of early plasmapheresis followed by rituximab therapy for induction of remission in rFSGS. Method Between 2014-2023, 8/65 pediatric renal transplant recipients at our center were diagnosed with idiopathic FSGS. Five patients underwent preventive plasmapheresis initiated between day 7 pre-transplantation to day 1 post-transplantation, depending on donor source (living/deceased). rFSGS, was diagnosed based on nephrotic range proteinuria of no other cause, and managed with daily plasmapheresis, followed by frequency tapering. Failure to achieve complete remission while on prolonged plasmapheresis was managed with Rituximab therapy. Results 6/8 patients (75%) experienced rFSGS. All achieved partial or complete remission with plasmapheresis therapy. Nevertheless, 5/6 patients exhibited plasmapheresis-dependence, thereby necessitating rituximab therapy. Of these, 3/5 patients achieved sustained remission enabling plasmapheresis cessation, while in 2/5 showed markedly improved proteinuria, enabling reduction of plasmapheresis frequency to once weekly. Adverse effects included rituximab-induced serum sickness in one patient, requiring therapy discontinuation. While one patient suffered from graft loss due to humoral rejection, no graft was lost to rFSGS, and all other grafts remained functional over an average follow-up period of 50 months. Conclusion We suggest that early introduction of plasmapheresis and rituximab therapy effectively induces remission in most post-transplantation rFSGS, is well tolerated, and prevents graft loss. Additional, large scale studies are needed to establish our observation.

Two cases of rituximab induced serum sickness in children with nephrotic syndrome

Two cases of rituximab induced serum sickness in children with nephrotic syndrome

Severe Reaction to Rituximab in Children

Background: Rituximab is a chimeric monoclonal antibody used in various pathologies involving CD20-positive cells. While it is usually well tolerated, infusion-related reactions are frequent but usually mild. Severe reactions such as anaphylaxis and serum sickness nevertheless can occur. Rituximab-induced serum sickness (RISS) is a rare delayed hypersensitivity reaction that may be unrecognized, as it can be confused with severe infection or in some circumstances with primary disease flare-up. We aim to extend our knowledge about severe infusion related reactions to rituximab in children, focusing on RISS and anaphylaxis. Objectives: Our study objective was to study severe reactions to rituximab by evaluating all children and adolescents who received rituximab in our center. Methods: Children and adolescents who received rituximab between 2014 and 2021 at CHU Sainte-Justine, a tertiary and leading pediatric center in Quebec, Canada, were included in the study. Data was collected retrospectively from our electronic medical records in CHU Ste-Justine. The diagnostic criteria proposed by the World Allergy Organization in 2020 were used to classify patients in the anaphylaxis subgroup. Patients with RISS were included if they developed fever and at least rash and/or arthralgia, starting 1 to 30 days following rituximab infusion, and if no other confirmed diagnosis explained symptoms. The study was approved by local Institutional Review Board. Results and discussion: 1534 rituximab infusions in 391 patients were analyzed. A severe infusion reaction to rituximab occurred in 14 patients (3.6%); none resulted in death. Rituximab was prescribed for an auto-immune disease in 61% of cases. Seven patients presented with RISS (1.8%); all were treated for an auto-immune disease including 4 for immune thrombocytopenia (ITP). Mean time from rituximab to RISS was 9 days (ranging from 6 to 12 days). All RISS patients but one presented with the classical triad of fever, rash and arthralgia. Increased C-reactive protein or sedimentation rate was documented in all patients, and decreased complement in 83%. Three patients required admission to intensive care unit due to hemodynamic instability. Patients received corticosteroids and/or intravenous immunoglobulins; mean duration of RISS was 4 days (ranging from 3 to 6 days). Rituximab was reinfused after RISS in one patient; she presented an immediate anaphylactoid reaction after which rituximab was permanently discontinued. Patients who received lower doses of rituximab were less likely to present RISS compared to patients who received higher doses (risk ratio 0.14, CI 0.03-0.74, p=0.016). Although few ITP patients developed RISS, RISS was associated with a greater chance of achieving partial or complete ITP remission (risk ratio 3, CI 1.47-6.14, p=0.033). Such possible association was not observed in other diseases. Seven patients developed severe anaphylaxis (1.8%), 3 of them reacted after the first dose (42.8%). Five of them were able to receive further rituximab infusion, using desensitization protocols. Conclusion: RISS is a rare hypersensitivity reaction in children. To this day, our study is the first to report more than 3 patients in a pediatric setting. RISS in children seems to be more frequent when rituximab is administered for an autoimmune condition, especially ITP. Although the classic triad of fever, rash and arthralgia appears more frequent in children than in adults, RISS should be considered in the differential diagnosis of any suggestive symptom developing within 30 days of infusion. Presence of biological inflammation and/or low serum complement can further support the diagnosis. In all patients, evolution was favorable within a few days with steroids. However, in contrast with anaphylaxis, RISS should be considered as a contraindication for further rituximab therapy.

The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura.

Rituximab, an anti-CD20 monoclonal antibody, can be used to treat immune thrombotic thrombocytopenic purpura (iTTP) during acute presentation or disease relapse. Undesirable side-effects include severe hypersensitivity reactions, particularly anaphylaxis and rituximab-induced serum sickness, with a minority not maintaining a response to treatment. Alternative humanised anti-CD20 treatments, obinutuzumab and ofatumumab, have been used. A review of the UK TTP Registry showed 15 patients received these drugs over 26 treatment episodes (eight obinutuzumab and 18 ofatumumab). Indications for alternative anti-CD20 treatment were severe infusion-related reactions, acute rituximab-induced serum sickness and a short duration of disease remission. All patients achieved disease remission (ADAMTS13 [A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13] activity ≥30 iu/dl) after a median 15 days and 92% of episodes achieved complete remission (≥60 iu/dl). Seven patients required further treatment for disease relapse with a median relapse-free survival of 17.4 months. All patients continued to respond to re-treatment with the preceding drug when relapse occurred. There were four adverse events in 26 treatment episodes (15%) - two infections and two infusion reactions. These results suggest that obinutuzumab and ofatumumab may be considered as an alternative option to rituximab in the treatment of iTTP with a comparable safety profile, absence of significant hypersensitivity reactions and sustained normalisation of ADAMTS13.

Rituximab-induced serum sickness with idiopathic nephrotic syndrome in a child.

Rituximab-induced serum sickness with idiopathic nephrotic syndrome in a child.

M030 RITUXIMAB-INDUCED SERUM SICKNESS IN A PEDIATRIC PATIENT WITH MULTIPLE AUTOIMMUNE DISEASES AND HISTORY OF COVID-19

Serum sickness, an immune-complex-mediated hypersensitivity reaction, is more common in adults than children. Rituximab has been reported as an agent that can cause serum sickness. This case discusses a pediatric patient who developed rituximab-induced serum sickness in the setting of a positive history of COVID-19 and recently diagnosed neuromyelitis optica, celiac disease, immune thrombocytopenia, and Sjogren’s syndrome.

Rituximab Hypersensitivity: From Clinical Presentation to Management

Rituximab is a chimeric monoclonal antibody (mAb) against CD20 molecule which is expressed on human B cells. It has been used for the treatment of various lymphoid malignancies, lymphoproliferative diseases, and rheumatologic disorders. Rituximab is generally well tolerated. However, increased use of rituximab has been associated with hypersensitivity reactions (HSRs), which can be classified as infusion-related, cytokine-release, type I (IgE/non-IgE), mixed, type III, and type IV reactions. Immediate infusion-related reactions to rituximab are quite common and decrease in frequency with subsequent infusions. However, in about 10% of patients, severe infusion-related reactions develop, which prevent its use. Some of the immediate infusion reactions are due to a cytokine-release but some reactions raise concerns for type I (IgE/non-IgE) hypersensitivity. Recent studies have shown the presence of serum anti-rituximab antibodies, either represented by the IgG or IgE isotype. In some cases, clinical manifestations of IgE-mediated reactions and cytokine-release reactions partially overlap, which is called a mixed reaction. Classified as Type III reaction, rituximab-induced serum sickness reactions have been reported in patients with autoimmune diseases and hematological malignancies. The classic serum sickness triad (fever, rash, and arthralgia) has been observed in patients mainly with an underlying rheumatologic condition. Severe delayed type IV hypersensitivity reactions including non-severe maculopapular rash to severe reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis have been rarely reported following rituximab injection. Comprehensive reviews focused on rituximab-induced HSRs are scarce. We aimed to review clinical presentations, underlying mechanisms of rituximab hypersensitivity, as well as management including rapid drug desensitization.

Rituximab-induced serum sickness: report of one case and review of literature

目的 提高对利妥昔单抗诱导的血清病的认识。 方法 回顾性分析2018年7月川北医学院附属医院1例利妥昔单抗诱导的血清病患者的临床资料，并复习相关文献。 结果 该患者明确诊断为弥漫大B细胞淋巴瘤，给予4个疗程含利妥昔单抗的方案化疗后，出现关节炎、皮疹等表现，再次使用利妥昔单抗后，关节炎进一步加重，最终诊断为利妥昔单抗诱导的血清病。给予激素治疗，并停用利妥昔单抗，未再出现关节症状。 结论 对于有利妥昔单抗输注史，出现关节炎、皮疹、发热等临床表现的患者，需警惕利妥昔单抗诱导的血清病，该病对激素反应佳，但再次使用利妥昔单抗时应谨慎。

Rituximab-induced serum sickness with mucous membrane involvement

Rituximab-induced serum sickness with mucous membrane involvement

Rituximab-induced serum sickness is more frequent in autoimmune diseases as compared to hematological malignancies: A French nationwide study

IntroductionRituximab induced serum sickness (RISS) is a rare delayed hypersensitivity reaction. The aim of this study was to describe the epidemiological and clinical characteristics of the RISS cases reported in France. MethodSerum sickness cases involving rituximab were identified from the French PharmacoVigilance Database from 1998 to 2016. ResultsWe analyzed 37 cases of RISS. Rituximab was prescribed for an autoimmune disease in 78% of cases. Serum sickness occurred mainly after the first injection (54%) with a median time to onset of 12 days. The most frequent manifestations were rheumatologic symptoms (92%), fever (87%), and skin lesions (78%). The incidence was significantly higher when rituximab was used for autoimmune diseases than for a hematological malignancies. Taking into account the existence of a Systemic Lupus Erythematosus (SLE) as the indication of rituximab or as a comorbidity, the incidence of RISS in patients with SLE was even higher. DiscussionWe report on the largest series of RISS studied to date and confirm that this reaction preferentially occurs in patients with autoimmune disease, especially SLE. This may be due to B-cell lysis, leading to the release of intracellular antigens into the serum and subsequent antigen-antibody complex formation, especially in patients with elevated autoantibody production. This could also explain why RISS often occurred after a single injection. ConclusionPatients generally recovered from RISS rapidly without obvious benefit from corticosteroid therapy. The risk of recurrence should prompt clinicians to question the use of rituximab after an episode of RISS.

Avoiding a Rash Diagnosis: Rituximab-Induced Serum Sickness.

Avoiding a Rash Diagnosis: Rituximab-Induced Serum Sickness Bryanna Mantilla;Jean Liew; JCR: Journal of Clinical Rheumatology

Rituximab-induced serum sickness: Not so uncommon

Rituximab-induced serum sickness: Not so uncommon

Rituximab-induced serum sickness in the treatment of idiopathic membranous nephropathy.

We report a case of rituximab-induced serum sickness in a 50-year-old female with idiopathic membranous nephropathy. Presentation was characterized by a widespread rash 1 week after rituximab administration followed by fever and profound haemodynamic instability, mimicking sepsis. Symptoms resolved over 48 h, although adjunct antibiotics, steroids and inotropes were used. This case is notable for being the first reaction with rituximab for a renal indication as well as the severity of presentation.

Plasmapheresis Reverses ARDS in Rituximab Induced Serum Sickness

Plasmapheresis Reverses ARDS in Rituximab Induced Serum Sickness

Rituximab-Induced Serum Sickness in Overlapping Syndrome Between Sjögren Syndrome and Systemic Lupus Erythematosus

Ungprasert, Patompong MD; Srivali, Narat MD; Kittanamongkolchai, Wonngarm MD; Leeaphorn, Napat MD; Griger, David T. DO Author Information

Serum sickness and severe angioedema following rituximab therapy in RA

Dear Editor, Rituximab is being used frequently in rheumatology, particularly in patients with rheumatoid arthritis (RA), systemic vasculitis and systemic lupus erythematosus (SLE). It is a chimeric monoclonal antibody to CD20 antigen expressed on B-cell precursors and mature B-cells. Infusion-related reactions such as fever, rigors and chills are seen in up to 85% of treated patients.1 Reactions tend to be more severe during the first infusion with onset usually within 30–120 min.2 Fortunately, the risk of such a reaction falls significantly after the first episode.3 Serum sickness with the use of rituximab in 22 patients has been reported in the English literature so far.4-9 These patients had either a hematological malignancy or an autoimmune condition. Surprisingly, serum sickness has not been reported in RA. We describe the first reported case of serum sickness following rituximab infusion in a patient with RA. A 60-year-old woman with seropositive RA for 14 years, presented with a history of increased pain and swelling in the left ankle and right knee for one and a half months. She was unable to bear weight on the left ankle and used to limp. For the past 2 years, she had been taking a combination of intramuscular methotrexate 12.5 mg weekly, hydroxychloroquine 200 mg once daily, leflunomide 20 mg once daily and sulphasalazine 1000 mg twice daily. She had also received intra-articular injection of methylprednisolone into the left ankle and right knee in the previous month without much relief. One and a half years ago, the patient had received two doses of rituximab 500 mg each in another hospital without significant benefit. Examination revealed that the left ankle and right knee were swollen and tender. There was no deformity in any joint. The Disease Activity Score (DAS28) was 6.04. Investigations showed an Hb 10.6 g/dL, white blood cell count 6400/mm3, erythrocyte sedimentation rate of 81 mm/h, creatinine 0.9 mg/dL, rheumatoid factor 44.2 units/mL and anti-cyclic citrullinated protein 114 units/mL. Antinuclear antibody was negative. Since the patient was unable to tolerate higher doses of methotrexate because of severe nausea, and the disease was refractory, it was decided to explore biological therapy. As she had received a subtherapeutic dose of rituximab previously, we wondered if a full dose would have achieved the goal. Therefore, she was administered 1000 mg of rituximab intravenously over 4 h. She was premedicated with methylprednisolone 100 mg and pheniramine 25 mg. Six days later, she developed an erythematous, urticarial rash over the feet, hands and face. In addition, she developed pain and swelling in the shoulders (previously never involved) and high-grade fever up to 39°C. The right knee became acutely swollen. There was no hematuria. A diagnosis of serum sickness syndrome was made in view of the triad of fever, arthritis and erythematous rash following a drug exposure. The patient was treated with one intramuscular dose of methylprednisolone 80 mg and oral levocetirizine. There was resolution of symptoms within 3 days. Since the serum sickness subsided promptly, it was considered appropriate to go ahead with the second infusion of rituximab on day 15. After informed consent, the second dose of rituximab was carefully started, observing the standard protocol of premedication and slow rate of infusion. Within minutes, the patient developed swelling of lips and periorbital regions as well as choking sensation. Although blood pressure was normal, she developed tachycardia (100 beats/min). There was no wheezing in the chest. Rituximab infusion was abandoned and adrenaline 0.5 mL (1 : 1000) was injected intravenously. In the next hour the reaction subsided almost completely but heart rate increased to 125 beats/min before returning to normal. Electrocardiogram showed only sinus tachycardia. It is possible this was in keeping with a type 1 immunoglobulin E (IgE) mediated hypersensitivity reaction which should preclude any further use of the drug in this patient. Six months later, the patient was started on etanercept 50 mg subcutaneously per week in combination with weekly methotrexate. There was an excellent response with a DAS28 of 2.5 after 4 weeks. Serum sickness is a type 3 hypersensitivity reaction, which comprises a triad of fever, rash and arthralgias occurring in the appropriate timeframe, usually 10–14 days following primary antigen exposure or within a few days of secondary antigen exposure. Overt arthritis can develop with increased inflammatory markers and decreased C3 level.10 Rituximab causes this syndrome more in patients with autoimmune conditions than in hematological malignancies.9 Typically, it is a self-limiting illness and steroids provide rapid and complete relief of symptoms.11 Altered immune response to foreign antigens is involved in the pathogenesis. In RA, it may be under-recognized because of the clinical similarities between serum sickness and an exacerbation of RA. The lesson learnt from the present case is that rituximab should not be re-administered to those who develop an episode of rituximab-induced serum sickness.

Rituximab-induced serum sickness in a patient with refractory chronic immune thrombocytopenic purpura: a case report and review of the literature

Ates, titreme ve kasilma gibi yan etkiler ilk kez yapilan rituksimab infuzyonu sirasinda sikca gorulmesine karsilik, serum hastaligi ve Steven-Johnson sendromu gibi gecikmis yan etkiler nadir olarak bildirilmistir. Steroide direncli ve splenektomize kronik immun trombositopenili bir hasta, ucuncu rituksimab infuzyonundan iki gun sonra ates, artralji, astim benzeri solunum sistemi semptomlari, makulopapuler ras ve palpabl purpurik lezyonlar ile basvurdu. Rituksimabin kesilmesi, sonrasinda intravenoz steroid ve antihistaminik tedavi uygulanmasi ile hastanin klinigi ve fiziki bulgulari duzeldi. Bu gibi vakalarda rituksimabin kesilmesi ve sistemik steroid tedavi uygulanmasi ile tam ve hizli bir duzelme saglanabilecegini dusunmekteyiz

Rituximab‐induced serum sickness in refractory immune thrombocytopenic purpura

Serum sickness may occur in patients treated with chimeric monoclonal antibody. Rituximab, an anti-CD20 chimeric monoclonal antibody, is used with increasing frequency in chronic immune thrombocytopenic purpura (ITP). Rituximab is relatively safe; however, serum sickness is reported in 1-20% of patients, more commonly among those with autoimmune conditions. We describe a case of serum sickness in a patient with ITP and review the literature of rituximab-induced serum sickness.

Rituximab Induced Serum Sickness Masquerading as Septic Shock

Purpose We describe a case of serum sickness following rituximab infusion in Waldenström macroglobulinemia. Introduction Rituximab is a chimeric monoclonal anti-CD20 antibody used to treat hematologic malignancies and autoimmune diseases. Infusion reactions are very common with rituximab (77%), occurring within 30-120 min of the beginning of the infusion (rituximab package insert; Genentech, Inc); however, rituximab may cause a delayed serum sickness–like reaction as well. Description Our patient is a 51-year-old Caucasian woman diagnosed with Waldenström macroglobulinemia in 2004. At that time, she was treated with 3 cycles of rituximab therapy followed by plasmapheresis for a hyperviscosity reaction. Over the next 3 years she had an uneventful course. However, beginning in 2007 she started having unexplained severe headaches, painful peripheral sensory neuropathy, and night sweats. After a thorough work-up to rule out other etiological causes, we decided to re-challenge her with rituximab in November 2009. She was to undergo 3 cycles of plasmapheresis followed by rituximab infusions (375 mg/m2/week for 4 weeks). Prior to initiation of rituximab, her IgM level was 2447 mg/dL, and her serum viscosity was 2.0. She underwent 3 uneventful cycles of plasmapheresis, after which she received her first rituximab infusion. During the infusion, she did experience some nausea, abdominal pain, tactile hallucinations, and perioral numbness; however, these resolved with extra doses of steroids and antihistaminics. One week after the administration of the first rituximab infusion, she was found to be hypotensive with her systolic BP in the 60s mmHg and was febrile to 1015. She needed admission to the intensive care unit and was presumptively treated as having a catheter-related sepsis needing Norepinephrine pressor support and broad spectrum antibiotic coverage. Her IgM level at the time of admission was 1049 mg/dL, and her serum viscosity was 1.5. She did not have any skin rashes, thrombocytopenia, or proteinuria. During her hospital stay, all of her chemistries were within normal limits, and her microbiologic cultures were repeatedly negative. She did have elevated inflammatory biomarkers such as ESR (66 mm/hr) and CRP (17.5 mg/dL). On her third day in the intensive care unit, she complained of excruciating joint pains with swelling, particularly of her wrists and knees. At this point, her antibiotics were discontinued, and she was treated with systemic steroids leading to a significant improvement in her symptoms and discharge from the hospital. Conclusion Rituximab may present with a severe serum sickness like reaction masquerading as septic shock when used to treat hematologic malignancies. Almost all of the case reports that we reviewed on rituximab-induced serum sickness documented reactions such as fever, arthralgias, and rashes (Jacobs; Clin Nucl Med; 2007; 32:12, and Helfgott; J Rheumatol; 2007; 34:430-3); however, to our knowledge this is the first documented case of rituximab-induced serum sickness presenting with hypotension necessitating pressor support.

Serum sickness with an elevated level of human anti-chimeric antibody following treatment with rituximab in a child with chronic immune thrombocytopenic purpura

Rituximab, a chimeric murine/human monoclonal anti-CD20 antibody, was licensed for the treatment of B-cell lymphoma and has also shown efficacy against autoimmune diseases such as immune thrombocytopenic purpura (ITP). It is relatively safe; however, about 1-20% of patients were reported to have developed rituximab-induced serum sickness, which is more common among patients with autoimmune conditions than among those with hematologic malignancies. Here we describe a pediatric patient with steroid-dependent chronic ITP who presented with arthralgia and fever ten days after the second infusion of rituximab (on day 10), and presented with malaise and maculopapular rash on day 21. Oral prednisolone was started and his symptoms resolved. He had an elevated level of human anti-chimeric antibody (HACA) on day 27; thereafter, the HACA level slowly decreased. To our knowledge, among pediatric patients who received rituximab for chronic ITP, this is the sixth documented case of serum sickness and the only one who manifested an elevated level of HACA. Rituximab is a beneficial treatment option against chronic ITP; however, the risk of serum sickness should be considered. Steroid, usually used for the treatment of serum sickness, may prevent the development of severe serum sickness when administered during and after rituximab treatment.