Cardiac side effect of rituximab

Vaibhav Bansidhar Patil; Snehal Balvant Lunge; Bhavana Ravindra Doshi

doi:10.4103/ijdd.ijdd_64_19

MANAGING A SIDE EFFECT

Year : 2020 | Volume : 6 | Issue : 1 | Page : 49-52

Cardiac side effect of rituximab

Vaibhav Bansidhar Patil¹, Snehal Balvant Lunge², Bhavana Ravindra Doshi²
¹ Department of Cardiology, Venereology and Leprosy, J. N. Medical College, Belagavi, Karnataka, India
² Department of Dermatology, Venereology and Leprosy, J. N. Medical College, Belagavi, Karnataka, India

Date of Submission	16-Nov-2019
Date of Decision	18-Apr-2020
Date of Acceptance	04-May-2020
Date of Web Publication	23-Jun-2020

Correspondence Address:
Dr. Snehal Balvant Lunge
Assistant Professor, Department of Dermatology, Venereology and Leprosy, J. N. Medical College, Belagavi - 590 010, Karnataka
India

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/ijdd.ijdd_64_19

Abstract

Rituximab is an anti-CD20 monoclonal antibody frequently used for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and anti-neutrophilic cytoplasmic antibody-associated vasculitis. In addition, rituximab has recently been increasingly used as an off-label treatment in a number of inflammatory and systemic autoimmune diseases. Its side effect profile includes infusion-related reactions and adverse cardiac effects such as arrhythmia and angina, particularly in patients with prior history of cardiovascular diseases. However, its detailed cardiotoxicity profile, effects on cardiac function, and its management are not well described in the literature. As the utility of rituximab expands, primary physicians, intensivist, dermatologist who use drug should be made of these serious cardiovascular adverse effect.

Keywords: Cardiac side effects, hypotension, rituximab

How to cite this article:
Patil VB, Lunge SB, Doshi BR. Cardiac side effect of rituximab. Indian J Drugs Dermatol 2020;6:49-52

How to cite this URL:
Patil VB, Lunge SB, Doshi BR. Cardiac side effect of rituximab. Indian J Drugs Dermatol [serial online] 2020 [cited 2023 Dec 9];6:49-52. Available from: https://www.ijdd.in/text.asp?2020/6/1/49/287439

Introduction

Rituximab, a chimeric monoclonal anti-CD20 antibody, is currently approved by the US Food and Drug Administration (FDA) for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (RA), antineutrophil cytoplasmic antibody-associated vasculitis including granulomatosis with polyangiitis and microscopic polyangiitis.^{[1],[2],[3],[4],[5]} In addition to these indications, it has been used for off-label treatment of many diseases including systemic lupus erythematosus, Sjögren's syndrome, idiopathic thrombocytopenic purpura, bullous dermatologic diseases, membranous nephropathy, steroid-dependent or frequently relapsing idiopathic nephrotic syndrome, treatment in recurrent and de novo glomerular disease after renal transplantation, and others.^{[6],[7],[8],[9]}

Dosing Recommended for Dermatological Disorders

There are two broadly accepted protocols for the drug in adults:

RA protocol-rituximab as an infusion of 1 g every 2 weeks for two doses
Lymphoma protocol-rituximab at 375 mg/m² body-surface area doses every week for 4 weeks.^[10]

Adverse effect

Despite its relative safety profile, infusion-related side effects of rituximab, such as fevers, chills, and rigors are common and reported to be as high as 87%.^{[2],[3],[4],[5],[11],[12]} Due to the reported cases of angina, acute coronary syndrome (ACS), and arrhythmias related to rituximab infusion, caution for its use is advised by FDA in patients with a history of cardiovascular disease.^[13] However, its detailed cardiotoxicity profile and effects on cardiac function are not clearly described in the medical literature.

The most lethal cardiac issues with rituximab are encountered during an infusion reaction, in which the patient may develop hypotension, hypoxia, acute myocardial infarction (MI), arrythymias, and cardiogenic shock.^{[10],[11],[13]}

Infusion-related reactions to rituximab are common (30% with the first infusion).^[14]

Hence, premedication with paracetamol, hydrocortisone 100 mg, and pheniramine maleate 22.75 mg intravenously needs to be given before each infusion.^[10],[14]

Benign cardiac side effects of rituximab include hypertension (between approximately 6%–12% of patients) and transient hypotension (approximately 10% of patients).^[10]

Rituximab is available as a 50 ml vial of liquid containing 500 mg of the drug to be infused. It is mixed with 450 ml saline to create a concentration of 1 mg/ml. The infusion rate is 50 ml/h in 1½ h and increased by 50 ml every ½ h till you finish the infusion.

The maximum infusion rate is 400 ml/h, and the total infusion time would be 5–6 h.

Infusion reactions can be seen up to 24 h after the infusion is over.

For subsequent infusions, the dose is 100 ml/h with a 30-min escalation of 50 ml/h to a maximum infusion rate of 400 ml/h.^[10]

Preexisting cardiovascular disease is not an absolute contraindication to rituximab use; however, these patients should be monitored closely during all infusions, especially the first one.

Pathophysiology

Rituximab is well known to cause infusion-related side effects from cytokine release, such as fevers and rigors within the first few hours, especially during the first infusion. These symptoms are associated with cytokine release, particularly interleukin 6. Most of these cases resolve promptly with supportive management. Hypotension, angioedema, hypoxia, and bronchospasm can also be seen in up to 10% of cases.^{[11],[12],[13]}

Cardiovascular toxicity in the form of cardiac arrhythmias has been reported in 8% of patients treated with rituximab.^[2] These include monomorphic ventricular tachycardia, polymorphic ventricular tachycardia, supraventricular tachycardia, trigeminy, bradycardia, atrial fibrillation, and nonspecific dysrhythmias or tachycardia.^{[2],[15],[16],[17],[18],[19],[20]} It is postulated that the CD-20 antigen also may affect the calcium-ion channel.^[15] The therapeutic action of rituximab may act by cell lysis through complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and apoptosis. The CD20 antigen is present on immune-effector cells and after cytotoxic-mediated lysis; it could sequester itself in normal tissues of the body, including cardiac myocytes. It is possible that rituximab affects conduction by inhibiting the calcium-ion channel properties of the CD20 antigen. The inhibition of calcium-ion channels in cardiac myocytes could lead to the formation of early after depolarization.^[15]

After rituximab infusion, patients' cardiac myocytes were noted to have diffuse amounts of reticulin fiber along with increased serum-transforming growth factor-β levels. The transforming growth factor-β levels could lead to increased reticulin fiber formation causing a decrease in myocardial contractility leading to non-ischemic cardiomyopathy.^[21] Furthermore, Takotsubo cardiomyopathy (stress cardiomyopathy), an important type of non-ischemic cardiomyopathy has recently been reported after rituximab infusion.^[22]

In addition to ACS and arrhythmia, rituximab-induced cardiogenic shock, delayed reduction in left ventricular ejection fraction (LVEF), Takotsubo's and non-ischemic cardiomyopathies have also been described,^{[15],[21],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32]} as summarized in [Table 1].

Table 1: Summary of cardiovascular adverse effects related to rituximab treatment

Click here to view

Risk factors for developing adverse effect

Age >60 years
Previous cardiovascular disease
Severe left ventricular (LV) dysfunction.

Signs and symptoms of cardiotoxicity

Chest pain
Breathlessness
Palpitations
Nausea and emesis.

Diagnostic evaluation

All patients should undergo prior cardiac clinical evaluation with the assessment of cardiovascular risk factors and undergo baseline Echocardiogram (ECG), two dimensional (2D) echocardiography (ECHO), and treadmill test.

Ideally, all rituximab infusions need to be given with cardiac monitoring in intensive cardiac care unit setup, so that any untoward cardiac arrhythmias can be tackled timely and treated promptly.

Monitoring for chest pain, breathlessness, palpitations, giddiness, or syncope during the infusion should be done and treated promptly so that any untoward complication can be avoided.

ECG and clinic cardiovascular evaluation to screen the signs of cardiomyopathy, conduction disturbances, QT interval, baseline Doppler echocardiogram (2D Echo) to assess cardiac functioning patients undergoing therapy in the presence of CV risk factors, age >60 years, previous CVD, LV fractional shortening and ejection fraction (LVEF) are the most common indexes for cardiac function assessment before starting the oncological therapy.^{[15],[21],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32]}

Prevention

High index of suspension in patients who are known case of coronary artery disease or cardiomyopathy are taken into consideration before starting of infusion

In patients who develop chest pain during rituximab administration, this possibility of ACS should be considered and appropriate cardiac investigation should be undertaken, even if patients have no history of or risk factors for cardiac disease.

In the absence of significant coronary artery disease, rechallenging with rituximab may be possible following optimal premedication in a monitored setting in selected cases where benefit of rituximab overweighs the risk of recurrent of cardiac ischemia.

Treatment of Side Effects

With previously reported cases of angina, ACS, and arrhythmias with rituximab infusion,^{[15],[21],[23],[24],[25],[26],[27],[28],[29],[30],[31]} FDA has cautiously provided recommendations to discontinue the infusions for serious or life-threatening cardiac arrhythmias and perform cardiac monitoring during and after all infusions of rituximab for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina.^[13] In addition to ACS and arrhythmia, rituximab-induced cardiogenic shock, delayed reduction in LVEF, Takotsubo's and non-ischemic cardiomyopathies have also been described.^{[15],[21],[23],[24],[25],[26],[27],[28],[29],[30],[31]}

Hypotension after starting IV injection for initial period patients' blood pressure (BP) monitoring had to be mandatory, as hypotension may occur, so that 1 hourly BP monitoring is required or use of noninvasive BP monitoring. It should be treated with the judicious use of intravenous (IV) fluids. IV fluid should be given as per the ejection fraction of the patient. If patient is having severe LV dysfunction, IV fluid should not exceed the rate of 30 ml/hour
Cardiogenic shock-IV fluids, inotropic agents (injection dopamine 5–15 μg/kg/min IV, injection dobutamin 0.5–1 μg/kg/min IV continuous infusion initially, then 2–20 μg/kg/min; not to exceed 40 μg/kg/min), and vasopressors (norepinephrine initial dose: 8–12 μg/min continuous IV infusion maintenance dose: 2–4 μg/min continuous IV infusion duration of therapy: Continue infusion until adequate BP and tissue perfusion are maintained without therapy.
ACS (unstable angina, ST-elevation MI, and non-ST-elevation MI) – ECG, 2D ECHO and cardiac enzymes should be done. If the patient had ACS, he should be treated with nitrates, antiplatelets, statins, antithrombotic agent, B-blockers (sublingual or IV nitroglycerin, soluble aspirin 162–325 mg, and clopidogrel with a 300–600 mg, atorvastatin 40–80 mg, and metaprolol succinate 25–100 mg). Loading dose is given as initial treatment
Arrhythmia (monomorphic ventricular tachycardia, polymorphic ventricular tachycardia, supraventricular tachycardia, trigeminy, bradycardia, atrial fibrillation, and nonspecific dysrhythmias or tachycardia) calcium-channel blocker or antiarrhythmic drugs need to be given

Reduction in LVEF (may occur within the first few hours after the initial infusion dose or after subsequent doses) diuretics (injection lasix 40–100 mg/day)
Non-ischemic cardiomyopathy – 2D ECHO is diagnostic modality, it shows reduced LV function and can be managed with B-blockers, diuretics, and ACE inhibitors
Takotsubo's cardiomyopathy (stress-induced cardiomyopathy) 2D ECHO is a diagnostic modality, it shows reduced LV function, will be managed with B blockers, diuretics, and ACE inhibitors.^[33]

Previously reported cases of cardiac toxicity^[23],[31]

ACS/Unstable angina-NO of patient = 4 onset was 4 h after first dose. Treated with sublingual nitroglycerin
Cardiogenic shock-NO of patient = 1, onset was 6 h after first dose, Echo-LVEF = 10%, which was normalized after 1 week
Delayed reduction in LV function-NO of patient = 3

^th

Polymorphic ventricular tachycardia–30 min after infusion of rituximab, case of post AV nodal ablation and post-pacemaker. pacemaker interrogation revealed polymorphic VT.
Atrial fibrillation – onset-immediately after the end of first infusion, coronary angiography shows multivessel disease, underwent angioplasty
Fulminant viral myocarditis 13 months after rituximab infusion in a 7-year-old boy underwent heart transplant
Takotsubo cardiomyopathy during infusion of rituximab, ECG–ST elevation V1-V6 2D echo–Apical ballooning with EF 20%–25%. Rituximab was stopped. ACE inhibitors and B-blockers were given
MI-(NO 2)

Non-ischemic cardiomyopathy – No of patient = 2.

Case 1: During the second and third cycle, echo-dilated LV severely reduced LV function EF of 20% after second cycle and 10% after third cycle, no regional wall motion abnormality, CAG – Normal epicardial coronaries, patient treated with medical line of management for cardiomyopathy but required Implantable cardioverter defibrillator for symptomatic bradycardia.^[34]

Case 2 – 48 h after infusion, ECG-LBBB, ECHO–LVEF-30% with hypokinesis of anteroseptal myocardium, CAG – Normal epicardial coronaries.

Conclusion

In summary, the awareness of cardiotoxicity profile of rituximab is important to minimize the risk of treatment-related morbidity/mortality. In addition to ACS and cardiac arrhythmia, nonischemic cardiomyopathy can be associated with the infusion of rituximab. This condition may occur early within 48 h. The occurrence of symptoms that could be ascribed to an ACS or heart failure with reduced ejection fraction (HFrEF) should always be taken seriously during the rituximab infusion and carefully investigated. Patients should be aware that this is a rare, although serious, complication of treatment with rituximab. Pretreatment ECG may be helpful when considering rituximab treatment in patients who have a family history of cardiomyopathy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Specks U, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med 2013;369:417-27.
2.	Foran JM, Rohatiner AZ, Cunningham D, Popescu RA, Solal-Celigny P, Ghielmini M, et al. European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol 2000;18:317-24.
3.	Kilickap S, Yavuz B, Aksoy S, Sahiner L, Dincer M, Harputluoglu H. et al. Addition of rituximab to chop does not increase the risk of cardiotoxicity in patients with non-Hodgkin's lymphoma. Med Oncol 2008;25:437-42.
4.	Ganjoo KN, An CS, Robertson MJ, Gordon LI, Sen JA, Weisenbach J,et al. Rituximab, bevacizumab and CHOP (RA-CHOP) in untreated diffuse large B-cell lymphoma: Safety, biomarker and pharmacokinetic analysis. Leuk Lymphoma 2006;47:998-1005.
5.	Drapkin R, Di Bella NJ, Faragher DC, Harden E, Matei C, Hyman W, et al. Results of a phase II multicenter trial of pentostatin and rituximab in patients with low grade B-cell non-Hodgkin's lymphoma: An effective and minimally toxic regimen. Clin Lymphoma 2003;4:169-75.
6.	Ruggenenti P, Ruggiero B, Cravedi P, Vivarelli M, Massella L, Marasà M, et al. Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. J Am Soc Nephrol 2014;25:850-63.
7.	Ponticelli C, Glassock RJ. Posttransplant recurrence of primary glomerulonephritis. Clin J Am Soc Nephrol 2010;5:2363-72.
8.	Kattah AG, Fervenza FC, Roccatello D. Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases. Autoimmun Rev 2013;12:854-9.
9.	Rigal D, Meyer F. Autoimmune haemolytic anemia: Diagnosis strategy and new treatments. Transfus Clin Biol 2011;18:277-85.
10.	Rajagopalan M, Vasani R. Rituximab in the treatment of skin diseases. Indian J Drugs Dermatol 2017;3:105-9. [Full text]
11.	Monsuez JJ, Charniot JC, Vignat N, Artigou JY. Cardiac side-effects of cancer chemotherapy. Int J Cardiol 2010;144:3-15.
12.	Cersosimo RJ. Monoclonal antibodies in the treatment of cancer, Part 2. Am J Health Syst Pharm 2003;60:1631-41.
13.	Rituxan-FDA Prescribing Information, Side Effects and Uses. Available from: http://www.drugs.com/pro/rituxan.html. [Last accessed on 2020 Apr 16].
14.	Randall KL. Rituximab in autoimmune diseases. Aust Prescr 2016;39:131-4.
15.	Poterucha JT, Westberg M, Nerheim P, Lovell JP. Rituximab-induced polymorphic ventricular tachycardia. Tex Heart Inst J 2010;37:218-20.
16.	Arunprasath P, Gobu P, Dubashi B, Satheesh S, Balachander J. Rituximab induced myocardial infarction: A fatal drug reaction. J Cancer Res Ther 2011;7:346-8.
17.	Arai Y, Tadokoro J, Mitani K. Ventricular tachycardia associated with infusion of rituximab in mantle cell lymphoma. Am J Hematol 2005;78:317-8.
18.	Dillman RO. Infusion reactions associated with the therapeutic use of monoclonal antibodies in the treatment of malignancy. Cancer Metastasis Rev 1999;18:465-71.
19.	Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE,et al. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: A phase II trial of the minnie pearl cancer research network. J Clin Oncol 2003;21:1746-51.
20.	Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-42.
21.	Kanamori H, Tsutsumi Y, Mori A, Kawamura T, Obara S, Shimoyama N, et al. Delayed reduction in left ventricular function following treatment of non-Hodgkin's lymphoma with chemotherapy and rituximab, unrelated to acute infusion reaction. Cardiology 2006;105:184-7.
22.	Smith SA, Auseon AJ. Chemotherapy-induced takotsubo cardiomyopathy. Heart Fail Clin 2013;9:233-42, x.
23.	Garypidou V, Perifanis V, Tziomalos K, Theodoridou S. Cardiac toxicity during rituximab administration. Leuk Lymphoma 2004;45:203-4.
24.	Millward PM, Bandarenko N, Chang PP, Stagg KF, Afenyi-Annan A, Hay SN, et al. Cardiogenic shock complicates successful treatment of refractory thrombotic thrombocytopenia purpura with rituximab. Transfusion 2005;45:1481-6.
25.	Armitage JD, Montero C, Benner A, Armitage JO, Bociek G. Acute coronary syndromes complicating the first infusion of rituximab. Clin Lymphoma Myeloma 2008;8:253-5.
26.	Lee L, Kukreti V. Rituximab-induced coronary vasospasm. Case Rep Hematol 2012;2012:984-86.
27.	Passalia C, Minetto P, Arboscello E, Balleari E, Bellodi A, Del Corso L, et al. Cardiovascular adverse events complicating the administration of rituximab: Report of two cases. Tumori 2013;99:288e-92e.
28.	Sellier-Leclerc AL, Belli E, Guérin V, Dorfmüller P, Deschênes G. Fulminant viral myocarditis after rituximab therapy in pediatric nephrotic syndrome. Pediatr Nephrol 2013;28:1875-9.
29.	van Sijl AM, van der Weele W, Nurmohamed MT. Myocardial infarction after rituximab treatment for rheumatoid arthritis: Is there a link? Curr Pharm Des 2014;20:496-9.
30.	Mulay S, Boruchov A. Recurrent and partially reversible cardiomyopathy occurring during treatment with bendamustine and rituximab. Leuk Lymphoma 2015;56:805-7.
31.	Ng KH, Dearden C, Gruber P. Rituximab-induced Takotsubo syndrome: More cardiotoxic than it appears? BMJ Case Rep 2015;2015. pii: bcr2014208203.
32.	Tournamille JF, Rigal-Huguet F, Pathak A, Montastruc JL, Lapeyre-Mestre M. Cardiac effects of cytokines produced after rituximab infusion. Bull Cancer 2005;92:769-71.
33.	Mega JL, Marrow DA. ST-Elevation myocardial infarction: Management. In: Mann DL, Zips DP, Libby P, Bonow RO, Braunwald E, editors. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 10^th ed. Philadelphia: Saunders an Imprint of Elseveir; 2015. p. 1147-77.
34.	Cheungpasitporn W, Kopecky SL, Specks U, Bharucha K, Fervenza FC. Non-ischemic cardiomyopathy after rituximab treatment for membranous nephropathy. J Renal Inj Prev 2016;6:18-25.

Tables

[Table 1]

This article has been cited by
1	Reversible Cardiomyopathy after Rituximab Treatment in a Chronic Lymphocytic Leukemia Patient
	Nishat Girkar, Saba Zaki, Sunita Pawar, Priti Dhande
	Journal of Oncology Pharmacy Practice. 2022; : 1078155222
	[Pubmed] \| [DOI]