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

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. Key words: membranous nephropathy, nephrotic syndrome, rituximab, rituximab-induced serum sickness, serum sickness Case report urticaria and the patient was commenced on oral doses of pred- A 50-year-old female with relapsing idiopathic membranous nisolone 30 mg, cetirizine 10 mg and promethazine 25 mg. nephropathy (IMN) presented to our hospital in August 2016 Twenty-four hours later she became hypotensive (systolic with a maculopapular rash, having received the monoclonal blood pressure 70 mmHg), febrile (38.1 C) and tachycardic (heart anti-CD20 antibody rituximab 1 week prior. rate 110 bpm). She developed generalized myalgias, arthralgias The only background history is IMN first diagnosed in 2000 and cervical lymphadenopathy. She did not respond to fluid with complete remission attained with cyclophosphamide and resuscitation, prompting admission to the intensive care unit prednisolone. Remission was maintained with methotrexate for inotropic support. Empirical antibiotics were commenced for due to intolerance to cyclosporine. In July 2016, the patient pre- potential sepsis and intravenous hydrocortisone for anaphyl- sented with nephrotic syndrome with intact renal function. actic shock. Renal biopsy confirmed relapse and new nodular changes Investigations demonstrated leucocytosis (white cell count 9 9 consistent with unrecognized, early diabetic nephropathy. 24.9 10 /L) with accompanying lymphocytosis (7.2 10 /L); Serum antiphospholipase-A2 receptor antibody was negative. serum eosinophils and neutrophils were normal (0.0 10 /L and Because of concerns about cumulative cyclophosphamide ex- 6.4 10 /L, respectively). Blood film demonstrated a non-specific posure, treatment with rituximab (two doses of 1000 mg a fort- reactive leucocytosis. C-reactive protein was elevated (3581 nmol/ night apart) was commenced. Trimethoprim-sulfamethoxazole L), C3 was low (0.63 g/L) and C4 was normal (0.20 g/L). Septic was started for Pneumocystis jirovecii pneumonia prophylaxis workup for infective aetiologies was negative. Biochemistry dem- and metformin for diabetes. onstrated lactic acidosis (lactate 15 mmol/L; pH 7.12) and acute On admission to hospital she had a widespread maculopapular kidney injury (serum creatinine 339 mmol/L). Urine microscopy rash involving the face, torso and peripheries but was haemo- showed 36  10 red cells without pyuria. Procalcitonin levels dynamically stable. The presumptive diagnosis was allergic were not tested due to unavailability. Received: December 15, 2016. Editorial decision: June 3, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/51/4080235 by Ed 'DeepDyve' Gillespie user on 16 March 2018 52 | J. Cheong and K. Ooi Table 1. Differential diagnosis of serum sickness Onset Clinical presentation Notable investigations • • Serum sickness Commonly 1–2 weeks, Pruritic urticarial rash from the lower Reduced C3 and C4 in severe episodes rarely 1 month trunk spreading to the back, upper Reduced neutrophils Resolves within a few trunk and extremities Reactive plasmacytoid lymphocytes • • weeks of drug cessation Sparing of mucous membranes Uncommon eosinophilia • • Rapid resolution of rash Elevated CRP, ESR High-grade temperatures Lymphadenopathy Myalgia, arthralgia • • Viral exanthema Variable depending Mucous membranes Reduced C3 and C4 • • on exposure Can cause urticarial rash Positive serology, viral polymerase Low-grade temperatures chain reaction Arthralgia • • Hypersensitivity 7–10 days after Palpable purpuric rash, maculopapular Reduced C3 and C4 vasculitis and exposure rash May have active urinary sediment and urticarial vasculitis Abdominal pain abnormal renal function • • Lymphadenopathy Skin biopsy: neutrophils around vessels Arthralgia High-grade temperatures • • DRESS Delayed reaction 2–6 Morbilliform rash confluent and Eosinophilia weeks after exposure desquamating Elevated transaminases • • Uncommon urticarial rash Atypical lymphocytosis • • Diffuse lymphadenopathy HHV-6 positive (40–60%) No arthralgia • • Reactive arthritis 1–4 weeks after infection Mucosa involved Constitutional symptoms, headache Distinct skin lesions (circinate balanitis) and neck pain common • • Low-grade temperatures Elevated CRP and ESR Joint effusions Arthralgia • • Bacterial endocarditis Variable Typical peripheral stigmata (Oslers’ Positive microbiology nodes, Janeway lesions) Elevated CRP and ESR • • Febrile Echocardiogram diagnostic Cardiac murmur Potential history for initial source (den- tal work, skin cracks) • • Generalized Rapid onset during Typical urticarial rash Eosinophilia • • hypersensitivity course of therapy Angioedema, acute anaphylaxis Elevated serum tryptase and urticarial reactions CRP, C-reactive protein; ESR, erthrocyte sedimentation rate; HHV-6, human herpesvirus 6. Symptoms resolved within 48 h, with inotropic support neutrophil cytoplasmic antibody–associated vasculitis. It is weaned within 24 h. Renal function normalized. Rituximab- not licensed for use in IMN but has been used off label for re- induced serum sickness (RISS) was concluded as the most fractory disease. Dosage regimens have been either four likely diagnosis due to the timeline of medication exposure weekly doses of 375 mg/m or two doses of 1000 mg given a and rapid clinical improvement. Antibiotics were ceased and fortnight apart [1]. hydrocortisone was changed to a 1 week weaning course of Rituximab reactions commonly occur with the first infusion, prednisolone. The patient was rechallenged with trimethoprim- ranging from simple flushing and dyspnoea to anaphylaxis. sulfamethoxazole with no issues. Arrangements were made for Simple reactions are thought to be due to a cytokine release outpatient skin allergen testing. The patient was discharged syndrome [2] potentially triggered by the murine element of the home and follow-up phone calls revealed no recurrence of antibody, with studies looking into reducing reactions with pure symptoms over 3 months. human monoclonal CD20 antibodies (ofatumumab) [3]. RISS was first identified in 2001 and appears to be an im- mune complex–mediated type III hypersensitivity reaction that Discussion results in complement activation and mast cell degranulation. It typically occurs 1 week after exposure but can occur up to a Rituximab is a CD20 mouse monoclonal antibody designed to month after. Incidence ranges between 1 and 20% [4]. eliminate B cells by direct, complement and antibody- The classical syndrome consists of a triad of fever, lymphaden- dependent cellular cytotoxicity. In Australia, it has been opathy and polyarthralgia. Other symptoms can include rash, licenced for use in chronic lymphocytic leukaemia, non- proteinuria and gastrointestinal symptoms. It is often Hodgkin’s lymphoma, rheumatoid arthritis and recently anti- Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/51/4080235 by Ed 'DeepDyve' Gillespie user on 16 March 2018 RISS in IMN treatment | 53 accompanied by elevated inflammatory markers, low comple- Conflict of interest statement ments and lymphocytosis without eosinophilia. K.O. has received travel support and conference sponsorship It can be difficult to differentiate RISS from diagnoses such from Roche. There are no other disclosures. as bacterial infection or anaphylaxis. Table 1 offers a list of dif- ferential diagnoses. To date, there are only a few case reports of this reaction, References confined to haematological and rheumatological populations 1. Bomback AS, Derebail VK, McGregor JG et al. Rituximab ther- [2, 4]. Only one report has documented RISS being associated apy for membranous nephropathy: a systematic review. Clin J with shock requiring inotropic support [5]. A systematic re- Am Soc Nephrol 2009; 4: 734–744 view of 33 haematological and rheumatological patients with 2. Karmacharya P, Poudel DR, Pathak R et al. Rituximab-induced RISS found that the classic triad was only seen in 16 cases serum sickness: a systematic review. Semin Arthritis Rheum (48.5%) and symptoms resolved in 2.156 1.34 days [2]. 2015; 45: 334–340 Corticosteroids were the most commonly used treatment. 3. Haarhaus ML, Svenungsson E, Gunnarsson I. Ofatumumab treat- In total, 4 of the 33 patients were rechallenged with a further ment in lupus nephritis patients. Clin Kidney J 2016; 9: 552–555 infusion. Two patients tolerated it well, one patient had a 4. Le Guenno G, Ruivard M, Charra L et al. Rituximab-induced mild immediate reaction and one patient experienced serum sickness in refractory immune thrombocytopenic pur- RISS again [2]. pura. Intern Med J 2011; 41: 202–205 Currently there are no reports of RISS in a renal 5. Rampurwala M, Kannan S, Gorusu M. Rituximab induced population. Our case demonstrates that serum sickness can serum sickness masquerading as septic shock. Clin Lymphoma occur in this population and it is the second case report of Myeloma Leuk 2010; 10: E41 such severity. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/51/4080235 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

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

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European Renal Association - European Dialysis and Transplant Association
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© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.
ISSN
2048-8505
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2048-8513
D.O.I.
10.1093/ckj/sfx072
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Abstract

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. Key words: membranous nephropathy, nephrotic syndrome, rituximab, rituximab-induced serum sickness, serum sickness Case report urticaria and the patient was commenced on oral doses of pred- A 50-year-old female with relapsing idiopathic membranous nisolone 30 mg, cetirizine 10 mg and promethazine 25 mg. nephropathy (IMN) presented to our hospital in August 2016 Twenty-four hours later she became hypotensive (systolic with a maculopapular rash, having received the monoclonal blood pressure 70 mmHg), febrile (38.1 C) and tachycardic (heart anti-CD20 antibody rituximab 1 week prior. rate 110 bpm). She developed generalized myalgias, arthralgias The only background history is IMN first diagnosed in 2000 and cervical lymphadenopathy. She did not respond to fluid with complete remission attained with cyclophosphamide and resuscitation, prompting admission to the intensive care unit prednisolone. Remission was maintained with methotrexate for inotropic support. Empirical antibiotics were commenced for due to intolerance to cyclosporine. In July 2016, the patient pre- potential sepsis and intravenous hydrocortisone for anaphyl- sented with nephrotic syndrome with intact renal function. actic shock. Renal biopsy confirmed relapse and new nodular changes Investigations demonstrated leucocytosis (white cell count 9 9 consistent with unrecognized, early diabetic nephropathy. 24.9 10 /L) with accompanying lymphocytosis (7.2 10 /L); Serum antiphospholipase-A2 receptor antibody was negative. serum eosinophils and neutrophils were normal (0.0 10 /L and Because of concerns about cumulative cyclophosphamide ex- 6.4 10 /L, respectively). Blood film demonstrated a non-specific posure, treatment with rituximab (two doses of 1000 mg a fort- reactive leucocytosis. C-reactive protein was elevated (3581 nmol/ night apart) was commenced. Trimethoprim-sulfamethoxazole L), C3 was low (0.63 g/L) and C4 was normal (0.20 g/L). Septic was started for Pneumocystis jirovecii pneumonia prophylaxis workup for infective aetiologies was negative. Biochemistry dem- and metformin for diabetes. onstrated lactic acidosis (lactate 15 mmol/L; pH 7.12) and acute On admission to hospital she had a widespread maculopapular kidney injury (serum creatinine 339 mmol/L). Urine microscopy rash involving the face, torso and peripheries but was haemo- showed 36  10 red cells without pyuria. Procalcitonin levels dynamically stable. The presumptive diagnosis was allergic were not tested due to unavailability. Received: December 15, 2016. Editorial decision: June 3, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/51/4080235 by Ed 'DeepDyve' Gillespie user on 16 March 2018 52 | J. Cheong and K. Ooi Table 1. Differential diagnosis of serum sickness Onset Clinical presentation Notable investigations • • Serum sickness Commonly 1–2 weeks, Pruritic urticarial rash from the lower Reduced C3 and C4 in severe episodes rarely 1 month trunk spreading to the back, upper Reduced neutrophils Resolves within a few trunk and extremities Reactive plasmacytoid lymphocytes • • weeks of drug cessation Sparing of mucous membranes Uncommon eosinophilia • • Rapid resolution of rash Elevated CRP, ESR High-grade temperatures Lymphadenopathy Myalgia, arthralgia • • Viral exanthema Variable depending Mucous membranes Reduced C3 and C4 • • on exposure Can cause urticarial rash Positive serology, viral polymerase Low-grade temperatures chain reaction Arthralgia • • Hypersensitivity 7–10 days after Palpable purpuric rash, maculopapular Reduced C3 and C4 vasculitis and exposure rash May have active urinary sediment and urticarial vasculitis Abdominal pain abnormal renal function • • Lymphadenopathy Skin biopsy: neutrophils around vessels Arthralgia High-grade temperatures • • DRESS Delayed reaction 2–6 Morbilliform rash confluent and Eosinophilia weeks after exposure desquamating Elevated transaminases • • Uncommon urticarial rash Atypical lymphocytosis • • Diffuse lymphadenopathy HHV-6 positive (40–60%) No arthralgia • • Reactive arthritis 1–4 weeks after infection Mucosa involved Constitutional symptoms, headache Distinct skin lesions (circinate balanitis) and neck pain common • • Low-grade temperatures Elevated CRP and ESR Joint effusions Arthralgia • • Bacterial endocarditis Variable Typical peripheral stigmata (Oslers’ Positive microbiology nodes, Janeway lesions) Elevated CRP and ESR • • Febrile Echocardiogram diagnostic Cardiac murmur Potential history for initial source (den- tal work, skin cracks) • • Generalized Rapid onset during Typical urticarial rash Eosinophilia • • hypersensitivity course of therapy Angioedema, acute anaphylaxis Elevated serum tryptase and urticarial reactions CRP, C-reactive protein; ESR, erthrocyte sedimentation rate; HHV-6, human herpesvirus 6. Symptoms resolved within 48 h, with inotropic support neutrophil cytoplasmic antibody–associated vasculitis. It is weaned within 24 h. Renal function normalized. Rituximab- not licensed for use in IMN but has been used off label for re- induced serum sickness (RISS) was concluded as the most fractory disease. Dosage regimens have been either four likely diagnosis due to the timeline of medication exposure weekly doses of 375 mg/m or two doses of 1000 mg given a and rapid clinical improvement. Antibiotics were ceased and fortnight apart [1]. hydrocortisone was changed to a 1 week weaning course of Rituximab reactions commonly occur with the first infusion, prednisolone. The patient was rechallenged with trimethoprim- ranging from simple flushing and dyspnoea to anaphylaxis. sulfamethoxazole with no issues. Arrangements were made for Simple reactions are thought to be due to a cytokine release outpatient skin allergen testing. The patient was discharged syndrome [2] potentially triggered by the murine element of the home and follow-up phone calls revealed no recurrence of antibody, with studies looking into reducing reactions with pure symptoms over 3 months. human monoclonal CD20 antibodies (ofatumumab) [3]. RISS was first identified in 2001 and appears to be an im- mune complex–mediated type III hypersensitivity reaction that Discussion results in complement activation and mast cell degranulation. It typically occurs 1 week after exposure but can occur up to a Rituximab is a CD20 mouse monoclonal antibody designed to month after. Incidence ranges between 1 and 20% [4]. eliminate B cells by direct, complement and antibody- The classical syndrome consists of a triad of fever, lymphaden- dependent cellular cytotoxicity. In Australia, it has been opathy and polyarthralgia. Other symptoms can include rash, licenced for use in chronic lymphocytic leukaemia, non- proteinuria and gastrointestinal symptoms. It is often Hodgkin’s lymphoma, rheumatoid arthritis and recently anti- Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/51/4080235 by Ed 'DeepDyve' Gillespie user on 16 March 2018 RISS in IMN treatment | 53 accompanied by elevated inflammatory markers, low comple- Conflict of interest statement ments and lymphocytosis without eosinophilia. K.O. has received travel support and conference sponsorship It can be difficult to differentiate RISS from diagnoses such from Roche. There are no other disclosures. as bacterial infection or anaphylaxis. Table 1 offers a list of dif- ferential diagnoses. To date, there are only a few case reports of this reaction, References confined to haematological and rheumatological populations 1. Bomback AS, Derebail VK, McGregor JG et al. Rituximab ther- [2, 4]. Only one report has documented RISS being associated apy for membranous nephropathy: a systematic review. Clin J with shock requiring inotropic support [5]. A systematic re- Am Soc Nephrol 2009; 4: 734–744 view of 33 haematological and rheumatological patients with 2. Karmacharya P, Poudel DR, Pathak R et al. Rituximab-induced RISS found that the classic triad was only seen in 16 cases serum sickness: a systematic review. Semin Arthritis Rheum (48.5%) and symptoms resolved in 2.156 1.34 days [2]. 2015; 45: 334–340 Corticosteroids were the most commonly used treatment. 3. Haarhaus ML, Svenungsson E, Gunnarsson I. Ofatumumab treat- In total, 4 of the 33 patients were rechallenged with a further ment in lupus nephritis patients. Clin Kidney J 2016; 9: 552–555 infusion. Two patients tolerated it well, one patient had a 4. Le Guenno G, Ruivard M, Charra L et al. Rituximab-induced mild immediate reaction and one patient experienced serum sickness in refractory immune thrombocytopenic pur- RISS again [2]. pura. Intern Med J 2011; 41: 202–205 Currently there are no reports of RISS in a renal 5. Rampurwala M, Kannan S, Gorusu M. Rituximab induced population. Our case demonstrates that serum sickness can serum sickness masquerading as septic shock. Clin Lymphoma occur in this population and it is the second case report of Myeloma Leuk 2010; 10: E41 such severity. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/51/4080235 by Ed 'DeepDyve' Gillespie user on 16 March 2018

Journal

Clinical Kidney JournalOxford University Press

Published: Feb 1, 2018

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