- Email: [email protected]
A case report of heart failure after therapy with ustekinumab
Available online at www.sciencedirect.com www.jdds.org
ScienceDirect Journal of Dermatology & Dermatologic Surgery 19 (2015) 117–119
Case report
A case report of heart failure after therapy with ustekinumab Kourosh Beroukhim a,b,⇑, Melissa Danesh a, Catherine Nguyen a, John Koo a, Argentina Leon a b
a University of California, San Francisco, Department of Dermatology, 515 Spruce St., San Francisco, CA 94118, United States David Geffen School of Medicine at UCLA, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, United States
Received 13 February 2015; accepted 2 March 2015 Available online 3 April 2015
Abstract Psoriasis is a chronic immune disorder that affects 2–3% of the US population. Ustekinumab, a monoclonal antibody against IL-23/12, has shown great efficacy in treating psoriasis. Here we present a rare finding of a patient with plaque-type psoriasis who was diagnosed with congestive heart failure after initiating treatment with ustekinumab. The patient experienced full recovery of cardiac function upon discontinuation of ustekinumab. Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Psoriasis; Ustekinumab; Congestive heart failure; Adverse drug events
1. Introduction Psoriasis is a chronic, immune disorder that presents as erythematous, indurated, and scaly plaques. The developments of biologic agents that target inflammatory cytokines have provided effective and convenient treatment options for the management of moderate-to-severe plaque-type psoriasis. Ustekinumab is a monoclonal antibody against interluekin-12/23 cytokines that has proven highly efficacious in achieving clearance of psoriasis, with an impressive safety profile thus far based on worldwide use
Abbreviations: CHF, congestive heart failure; IL, interleukin
⇑ Corresponding author at: University of California, San Francisco,
Department of Dermatology, 515 Spruce St., San Francisco, CA 94118, United States. Tel.: +1 (310) 272 6025; fax: +1 (415) 502 4126. E-mail address: [email protected] (K. Beroukhim). Peer review under responsibility of King Saud University.
for approximately 8 years. We report a case of a patient with plaque-type psoriasis who experienced heart failure following the initiation of ustekinumab therapy with full recovery of cardiac function upon discontinuation of ustekinumab. 2. Report of a case A 46-year-old Hispanic female was diagnosed with psoriasis and psoriatic arthritis in 2006. Treatment was initiated with oral methotrexate once weekly and adalimumab biweekly. The patient experienced a generalized desquamating rash that was attributed to the initiation of adalimumab, which was discontinued promptly. The patient was then started on etanercept and continued therapy for 5 months until she developed a persistent cough and fatigue. Workup with chest X-ray showed mediastinal widening, and subsequent biopsy revealed non-Hodgkin lymphoma. She received 6 cycles of R-CHOP (Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone), with successful induction of remission based on PET scan findings.
http://dx.doi.org/10.1016/j.jdds.2015.03.003 2352-2410/Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
118
K. Beroukhim et al. / Journal of Dermatology & Dermatologic Surgery 19 (2015) 117–119
Upon completion of her chemotherapy regimen in 2007, the patient resumed methotrexate therapy for her psoriasis. After failure to improve on multiple trials of methotrexate, prednisone, and rituximab, the patient was started on ustekinumab in 2012. She initially noticed improvement in her psoriasis, but this was accompanied by gradual worsening shortness of breath and bilateral lower extremity edema. Workup with echocardiography confirmed a diagnosis of congestive heart failure (CHF). Ustekinumab was promptly discontinued, and the patient was started on ACE-inhibitor and beta-blocker therapy, resulting in the complete resolution of all her symptoms.
3. Discussion CHF is marked by progressive deterioration of cardiac function, driven in part by a cascade of pro-inflammatory cytokines and neuro-hormones (Sinagra et al., 2013). One notable immune mediator with increased serum levels in patients with CHF is TNF-alpha (Testa et al., 1996). However, randomized, controlled trials with infliximab have shown that anti-TNF-alpha is associated with a worsening of CHF (Chung et al., 2003). Analysis of data from the US FDA Medwatch program revealed a total of 47 patients who developed new-onset heart failure following the initiation of anti-TNF-alpha therapy (Kwon et al., 2003). As a result, the labels of currently available antiTNF-alpha medications, including etanercept, infliximab, and adalimumab, caution against the use of these agents in patients with heart failure or decreased left ventricular function (Sinagra et al., 2013). Ustekinumab is a monoclonal antibody within the class of interleukin (IL)-12/23 inhibitors, which are novel biologic treatment modalities for psoriasis that have proven highly efficacious in randomized controlled trials (Famenini and Wu, 2013; Gordon et al., 2012; Kimball et al., 2012). However, many of the studies that have examined the cardiovascular risk profile of ustekinumab have specified a history of heart failure as an exclusion criterion. Thus, there are scant data from these clinical trials about the relationship between ustekinumab therapy and heart failure. Long-term post-marketing surveillance has provided an additional avenue for determining the association between ustekinumab and rare potential adverse events. The EUV database with 1394 total events includes 16 cases of heart failure (Ustekinumab (Stelara), 2013). Although neither the present case nor data from postmarketing surveillance establishes an unequivocal cause– effect relationship between ustekinumab and heart failure, both may constitute a signal that supports further investigation into this association. Particularly pertinent in this case is the temporal relationship between the initiation of ustekinumab therapy and the onset of heart failure. The patient’s improvement with the cessation of this medication is also supportive, though concurrent beta-blocker and ACE-inhibitor therapy may have contributed to her
recovery as well. Furthermore, the patient had no previous history of cardiovascular abnormalities prior to this event. Other potential causes of CHF in this patient include prior exposure to doxorubicin as a part of her chemotherapy regimen. Doxorubicin-induced cardiomyopathy may occur in as many as a third of patients. However, the majority of cases occur within 1 year of discontinuing the medication, with rare instances of late-onset doxorubicininduced cardiomyopathy, which arises more than 1 year after the completion of chemotherapy, occurring predominantly in pediatric populations (Aiken et al., 2009; Chatterjee et al., 2010; Lipshultz et al., 2008). The onset of CHF in this patient took place over 5 years following the completion of her chemotherapy, making this a less likely cause of her condition. Additionally, this patient was diagnosed with lymphoma prior to experiencing heart failure. In rare cases, lymphoma has been associated with heart failure secondary to metastasis to cardiac tissue (Amirimoghaddam et al., 2010). However, heart metastases from lymphoma are remarkably uncommon, with only a few reported cases worldwide. Furthermore, multiple MRI studies performed on this patient during routine surveillance for recurrence of her lymphoma gave no indication of heart metastases. The mechanistic relationship between anti-IL-12/23 agents and cardiac adverse events such as CHF has yet to be elucidated. We propose the mechanism to be immune-mediated, with potential interactions with the pathway through which TNF-alpha affects cardiac tissue. In light of this potential association, it is essential that physicians take precautions when prescribing ustekinumab for the treatment of psoriasis in patients with a personal or family history of heart disease. We recommend a thorough screening for cardiomyopathy prior to the initiation of therapy in patients with a personal or family history of heart disease, and a complete cardiac evaluation of patients on ustekinumab who report alarming symptoms such as chest pain or shortness of breath. Conflict of interest John Koo is a clinical researcher for Pfizer, Amgen, Janssen and Merck. He is a speaker for Leo Pharma, Abbvie and Celgene. All other authors have no conflicts of interest to declare. References Aiken, M.J., Suhag, V., Garcia, C.A., et al., 2009. Doxorubicin-induced cardiac toxicity and cardiac rest gated blood pool imaging. Clin. Nucl. Med. 34 (11), 762–767. Amirimoghaddam, Z., Khoddami, M., Nayeri, N.D., Molaee, S., 2010. Hodgkin’s lymphoma presenting with heart failure: a case report. J. Med. Case Rep. 4, 14. Chatterjee, K., Zhang, J., Honbo, N., Karliner, J.S., 2010. Doxorubicin cardiomyopathy. Cardiology 115 (2), 155–162. Chung, E.S., Packer, M., Lo, K.H., Fasanmade, A.A., Willerson, J.T., 2003. Anti TNFTACHFI. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to
K. Beroukhim et al. / Journal of Dermatology & Dermatologic Surgery 19 (2015) 117–119 tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial. Circulation 107 (25), 3133–3140. Famenini, S., Wu, J.J., 2013. The efficacy of ustekinumab in psoriasis. J. Drugs Dermatol. 12 (3), 317–320. Gordon, K., Papp, K., Poulin, Y., Gu, Y., Rozzo, S., Sasso, E.H., 2012. Long-term efficacy and safety of adalimumab in patients with moderate to severe psoriasis treated continuously over 3 years: results from an open-label extension study for patients from REVEAL. J. Am. Acad. Dermatol. 66 (2), 241–251. Kimball, A.B., Gordon, K.B., Fakharzadeh, S., et al., 2012. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years. Br. J. Dermatol. 166 (4), 861–872.
119
Kwon, H.J., Cote, T.R., Cuffe, M.S., Kramer, J.M., Braun, M.M., 2003. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann. Intern. Med. 138 (10), 807–811. Lipshultz, S.E., Alvarez, J.A., Scully, R.E., 2008. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 94 (4), 525–533. Sinagra, E., Perricone, G., Romano, C., Cottone, M., 2013. Heart failure and anti tumor necrosis factor-alpha in systemic chronic inflammatory diseases. Eur. J. Intern. Med. 24 (5), 385–392. Testa, M., Yeh, M., Lee, P., et al., 1996. Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J. Am. Coll. Cardiol. 28 (4), 964–971. Ustekinumab (Stelara) Prescribing Information, Janssen, May 2013.
ScienceDirect Journal of Dermatology & Dermatologic Surgery 19 (2015) 117–119
Case report
A case report of heart failure after therapy with ustekinumab Kourosh Beroukhim a,b,⇑, Melissa Danesh a, Catherine Nguyen a, John Koo a, Argentina Leon a b
a University of California, San Francisco, Department of Dermatology, 515 Spruce St., San Francisco, CA 94118, United States David Geffen School of Medicine at UCLA, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, United States
Received 13 February 2015; accepted 2 March 2015 Available online 3 April 2015
Abstract Psoriasis is a chronic immune disorder that affects 2–3% of the US population. Ustekinumab, a monoclonal antibody against IL-23/12, has shown great efficacy in treating psoriasis. Here we present a rare finding of a patient with plaque-type psoriasis who was diagnosed with congestive heart failure after initiating treatment with ustekinumab. The patient experienced full recovery of cardiac function upon discontinuation of ustekinumab. Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Psoriasis; Ustekinumab; Congestive heart failure; Adverse drug events
1. Introduction Psoriasis is a chronic, immune disorder that presents as erythematous, indurated, and scaly plaques. The developments of biologic agents that target inflammatory cytokines have provided effective and convenient treatment options for the management of moderate-to-severe plaque-type psoriasis. Ustekinumab is a monoclonal antibody against interluekin-12/23 cytokines that has proven highly efficacious in achieving clearance of psoriasis, with an impressive safety profile thus far based on worldwide use
Abbreviations: CHF, congestive heart failure; IL, interleukin
⇑ Corresponding author at: University of California, San Francisco,
Department of Dermatology, 515 Spruce St., San Francisco, CA 94118, United States. Tel.: +1 (310) 272 6025; fax: +1 (415) 502 4126. E-mail address: [email protected] (K. Beroukhim). Peer review under responsibility of King Saud University.
for approximately 8 years. We report a case of a patient with plaque-type psoriasis who experienced heart failure following the initiation of ustekinumab therapy with full recovery of cardiac function upon discontinuation of ustekinumab. 2. Report of a case A 46-year-old Hispanic female was diagnosed with psoriasis and psoriatic arthritis in 2006. Treatment was initiated with oral methotrexate once weekly and adalimumab biweekly. The patient experienced a generalized desquamating rash that was attributed to the initiation of adalimumab, which was discontinued promptly. The patient was then started on etanercept and continued therapy for 5 months until she developed a persistent cough and fatigue. Workup with chest X-ray showed mediastinal widening, and subsequent biopsy revealed non-Hodgkin lymphoma. She received 6 cycles of R-CHOP (Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone), with successful induction of remission based on PET scan findings.
http://dx.doi.org/10.1016/j.jdds.2015.03.003 2352-2410/Ó 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
118
K. Beroukhim et al. / Journal of Dermatology & Dermatologic Surgery 19 (2015) 117–119
Upon completion of her chemotherapy regimen in 2007, the patient resumed methotrexate therapy for her psoriasis. After failure to improve on multiple trials of methotrexate, prednisone, and rituximab, the patient was started on ustekinumab in 2012. She initially noticed improvement in her psoriasis, but this was accompanied by gradual worsening shortness of breath and bilateral lower extremity edema. Workup with echocardiography confirmed a diagnosis of congestive heart failure (CHF). Ustekinumab was promptly discontinued, and the patient was started on ACE-inhibitor and beta-blocker therapy, resulting in the complete resolution of all her symptoms.
3. Discussion CHF is marked by progressive deterioration of cardiac function, driven in part by a cascade of pro-inflammatory cytokines and neuro-hormones (Sinagra et al., 2013). One notable immune mediator with increased serum levels in patients with CHF is TNF-alpha (Testa et al., 1996). However, randomized, controlled trials with infliximab have shown that anti-TNF-alpha is associated with a worsening of CHF (Chung et al., 2003). Analysis of data from the US FDA Medwatch program revealed a total of 47 patients who developed new-onset heart failure following the initiation of anti-TNF-alpha therapy (Kwon et al., 2003). As a result, the labels of currently available antiTNF-alpha medications, including etanercept, infliximab, and adalimumab, caution against the use of these agents in patients with heart failure or decreased left ventricular function (Sinagra et al., 2013). Ustekinumab is a monoclonal antibody within the class of interleukin (IL)-12/23 inhibitors, which are novel biologic treatment modalities for psoriasis that have proven highly efficacious in randomized controlled trials (Famenini and Wu, 2013; Gordon et al., 2012; Kimball et al., 2012). However, many of the studies that have examined the cardiovascular risk profile of ustekinumab have specified a history of heart failure as an exclusion criterion. Thus, there are scant data from these clinical trials about the relationship between ustekinumab therapy and heart failure. Long-term post-marketing surveillance has provided an additional avenue for determining the association between ustekinumab and rare potential adverse events. The EUV database with 1394 total events includes 16 cases of heart failure (Ustekinumab (Stelara), 2013). Although neither the present case nor data from postmarketing surveillance establishes an unequivocal cause– effect relationship between ustekinumab and heart failure, both may constitute a signal that supports further investigation into this association. Particularly pertinent in this case is the temporal relationship between the initiation of ustekinumab therapy and the onset of heart failure. The patient’s improvement with the cessation of this medication is also supportive, though concurrent beta-blocker and ACE-inhibitor therapy may have contributed to her
recovery as well. Furthermore, the patient had no previous history of cardiovascular abnormalities prior to this event. Other potential causes of CHF in this patient include prior exposure to doxorubicin as a part of her chemotherapy regimen. Doxorubicin-induced cardiomyopathy may occur in as many as a third of patients. However, the majority of cases occur within 1 year of discontinuing the medication, with rare instances of late-onset doxorubicininduced cardiomyopathy, which arises more than 1 year after the completion of chemotherapy, occurring predominantly in pediatric populations (Aiken et al., 2009; Chatterjee et al., 2010; Lipshultz et al., 2008). The onset of CHF in this patient took place over 5 years following the completion of her chemotherapy, making this a less likely cause of her condition. Additionally, this patient was diagnosed with lymphoma prior to experiencing heart failure. In rare cases, lymphoma has been associated with heart failure secondary to metastasis to cardiac tissue (Amirimoghaddam et al., 2010). However, heart metastases from lymphoma are remarkably uncommon, with only a few reported cases worldwide. Furthermore, multiple MRI studies performed on this patient during routine surveillance for recurrence of her lymphoma gave no indication of heart metastases. The mechanistic relationship between anti-IL-12/23 agents and cardiac adverse events such as CHF has yet to be elucidated. We propose the mechanism to be immune-mediated, with potential interactions with the pathway through which TNF-alpha affects cardiac tissue. In light of this potential association, it is essential that physicians take precautions when prescribing ustekinumab for the treatment of psoriasis in patients with a personal or family history of heart disease. We recommend a thorough screening for cardiomyopathy prior to the initiation of therapy in patients with a personal or family history of heart disease, and a complete cardiac evaluation of patients on ustekinumab who report alarming symptoms such as chest pain or shortness of breath. Conflict of interest John Koo is a clinical researcher for Pfizer, Amgen, Janssen and Merck. He is a speaker for Leo Pharma, Abbvie and Celgene. All other authors have no conflicts of interest to declare. References Aiken, M.J., Suhag, V., Garcia, C.A., et al., 2009. Doxorubicin-induced cardiac toxicity and cardiac rest gated blood pool imaging. Clin. Nucl. Med. 34 (11), 762–767. Amirimoghaddam, Z., Khoddami, M., Nayeri, N.D., Molaee, S., 2010. Hodgkin’s lymphoma presenting with heart failure: a case report. J. Med. Case Rep. 4, 14. Chatterjee, K., Zhang, J., Honbo, N., Karliner, J.S., 2010. Doxorubicin cardiomyopathy. Cardiology 115 (2), 155–162. Chung, E.S., Packer, M., Lo, K.H., Fasanmade, A.A., Willerson, J.T., 2003. Anti TNFTACHFI. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to
K. Beroukhim et al. / Journal of Dermatology & Dermatologic Surgery 19 (2015) 117–119 tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial. Circulation 107 (25), 3133–3140. Famenini, S., Wu, J.J., 2013. The efficacy of ustekinumab in psoriasis. J. Drugs Dermatol. 12 (3), 317–320. Gordon, K., Papp, K., Poulin, Y., Gu, Y., Rozzo, S., Sasso, E.H., 2012. Long-term efficacy and safety of adalimumab in patients with moderate to severe psoriasis treated continuously over 3 years: results from an open-label extension study for patients from REVEAL. J. Am. Acad. Dermatol. 66 (2), 241–251. Kimball, A.B., Gordon, K.B., Fakharzadeh, S., et al., 2012. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years. Br. J. Dermatol. 166 (4), 861–872.
119
Kwon, H.J., Cote, T.R., Cuffe, M.S., Kramer, J.M., Braun, M.M., 2003. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann. Intern. Med. 138 (10), 807–811. Lipshultz, S.E., Alvarez, J.A., Scully, R.E., 2008. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 94 (4), 525–533. Sinagra, E., Perricone, G., Romano, C., Cottone, M., 2013. Heart failure and anti tumor necrosis factor-alpha in systemic chronic inflammatory diseases. Eur. J. Intern. Med. 24 (5), 385–392. Testa, M., Yeh, M., Lee, P., et al., 1996. Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J. Am. Coll. Cardiol. 28 (4), 964–971. Ustekinumab (Stelara) Prescribing Information, Janssen, May 2013.