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The Terrible Triad of Checkpoint Inhibition: A Case Report of Myasthenia Gravis, Myocarditis, and Myositis Induced by Cemiplimab in a Patient with Metastatic Cutaneous Squamous Cell Carcinoma

The Terrible Triad of Checkpoint Inhibition: A Case Report of Myasthenia Gravis, Myocarditis, and... Hindawi Case Reports in Immunology Volume 2020, Article ID 5126717, 4 pages https://doi.org/10.1155/2020/5126717 Case Report The Terrible Triad of Checkpoint Inhibition: A Case Report of Myasthenia Gravis, Myocarditis, and Myositis Induced by Cemiplimab in a Patient with Metastatic Cutaneous Squamous Cell Carcinoma 1 1 2 3 3 Nikeshan Jeyakumar , Mikel Etchegaray, Jason Henry, Laura Lelenwa, Bihong Zhao, 4 4 Ana Segura, and L. Maximilian Buja Division of Internal Medicine, e University of Texas M.D. Anderson Cancer Center, 1400 Pressler Drive, Unit 1463, Houston, Texas 77030, USA Division of Cancer Medicine, e University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA Department of Pathology and Laboratory Medicine, e University of Texas Health Science Center at Houston, McGovern Medical School, 6431 Fannin Street, P.O. Box 20708, Houston, Texas 77225, USA Department of Cardiovascular Pathology, Texas Heart Institute, 6770 Bertner Avenue, Houston, Texas 77030, USA Correspondence should be addressed to Nikeshan Jeyakumar; njeyakumar@mdanderson.org Received 10 January 2020; Revised 16 June 2020; Accepted 18 June 2020; Published 4 July 2020 Academic Editor: Eisei Kondo Copyright © 2020 Nikeshan Jeyakumar et al. 'is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. We report a case of a patient with squamous cell carcinoma (SCC) who developed myasthenia gravis (MG), myositis, and myocarditis after receiving cemiplimab, an anti-PD-1 immune checkpoint inhibitor (ICI). Case Presentation. An 86-year-old man with metastatic periocular SCC presented with decreased vision in the left eye, severe fatigue, and lower back and bilateral hip pain 3 weeks after receiving cemiplimab. Within hours, he developed dysphonia, pharyngeal secretions, and dysphagia, ne- cessitating intubation. Endomyocardial biopsy revealed active lymphocyte-mediated necrosis consistent with ICI-induced myocarditis. Anti-striated muscle and anti-acetylcholine receptor antibodies were elevated, consistent with myositis and my- asthenia gravis. Despite plasma exchange therapy, steroids, and intravenous immunoglobulin, he died from cardiac arrest. Conclusions. 'e presence of myasthenia gravis, myocarditis, or myositis should prompt evaluation for all three toxicities as they may represent an overlap syndrome. 'e severity of these immunotoxicities highlights the need for clinicians to suspect multiple simultaneous adverse effects of ICIs. most common immune-related adverse events (irAEs) 1. Introduction were diarrhea, fatigue, constipation, and rash [2]. Neu- Cemiplimab is a programmed cell death protein 1 (PD-1) romuscular irAEs occur in <1% of patients treated with immune checkpoint inhibitor (ICI) approved in September ICIs overall [3], but due to the nonspecific nature of their 2018 for the treatment of locally advanced or metastatic symptoms, it is likely that many cases go unreported [4]. cutaneous squamous cell carcinoma (SCC) in patients that Myasthenia gravis (MG) is the most commonly reported did not qualify for curative surgery or radiation [1]. Phase 2 neuromuscular irAE associated with PD-1 inhibitors, with studies of patients with metastatic disease demonstrated a incidence ranging from 0.12 to 0.2% [5]. PD-1 inhibitor- response rate of 47% (28/59), with 16 (57%) of these pa- related MG tends to be more severe, with 40–50% of pa- tients having duration of response at 6 months [2]. 'e tients requiring ventilatory support (7 times higher than in 2 Case Reports in Immunology An electrocardiogram was suggestive of inferior wall typical MG) [5]. 'ere also appears to be a distinct cor- relation between PD-1 inhibition and MG, as MG is rarely ischemia and showed a new right bundle-branch block. Transthoracic echocardiogram showed a normal ejection seen in association with anticytotoxic T-lymphocyte-as- sociated protein 4 (CTLA-4) therapy. In a review of over fraction without pericardial effusion. 10,000 patients treated with nivolumab or ipilimumab in Several hours after initial presentation, the patient de- Japan, 12 cases of MG occurred in patients who received veloped dysphonia, increasing pharyngeal secretions and nivolumab, while none occurred with ipilimumab [6]. Ten difficulty swallowing, and new shortness of breath with of these 12 were seropositive for acetylcholine receptor worsening fatigue. He was urgently transferred to the in- (AChR) antibodies [6]. ICI-related MG is also strongly tensive care unit, given 1 g intravenous methylprednisolone, associated with elevated creatine kinase (CK) levels, in- and was electively intubated. Left and right heart cathe- dicating the presence of simultaneous muscle or cardiac terization with endomyocardial biopsy was performed and revealed an active necrotizing lymphocytic myocarditis dysfunction [5]. 'e rare and generally fatal triad of ICI- related MG, myocarditis, and myositis has been described (Figure 1). His bypass grafts were patent, and he had normal ventricular pressures. Results of autoimmune antibody with nivolumab/ipilimumab dual therapy [3] and pem- brolizumab [7] and nivolumab monotherapy [6, 8] but has testing are shown in Table 1. Muscle-specific kinase anti- not previously been reported with cemiplimab. bodies were negative. He received plasma exchange therapy for 5 days, was continued on high-dose methylprednisolone, and received 2. Case Presentation one dose of intravenous immunoglobulin. However, his An 86-year-old man with periocular SCC involving the left troponin-T levels continued rising over 3000 ng/L, his lower and upper eyelids status after Mohs surgery, recon- troponin-I levels peaked at 6.9 ng/L, and he began devel- struction, and adjuvant radiation therapy was referred to the oping worsening kidney function necessitating initiation of continuous renal replacement therapy. Despite these mea- MD Anderson Cancer Center due to local recurrence of SCC to the left lateral canthus and orbit. He had a prior history of sures, he suffered pulseless electrical activity arrest from hyperkalemia and severe metabolic acidosis and could not be numerous cutaneous carcinomas (basal cell, spindle cell, and squamous cell) on the head and face, removed surgically. His resuscitated. Based on his clinical signs and symptoms, el- evations in anti-AChR antibodies, anti-striated muscle an- comorbidities included a 4-vessel coronary artery bypass graft in 2016, sick sinus syndrome status after pacemaker tibodies, CK, and urine myoglobin, and with characteristic placement, hypertension, hyperlipidemia, and chronic findings on endomyocardial biopsy, he was diagnosed with kidney disease (CKD) with creatinine clearance (CrCl) cemiplimab-related MG, myositis, and myocarditis. 22 mL/min. Outpatient ultrasound-guided biopsy of left parotid and submandibular nodules revealed metastatic SCC 3. Discussion in both areas. After discussion with head and neck medical oncology, the patient elected to start cemiplimab and re- 'is case was illustrative of the varied and often vague ceived one 350 mg dose. presentations of irAEs. 'is patient did not have chest pain, 'ree weeks later, he reported to the emergency room dyspnea, or any other symptoms consistent with cardiac with 5 days of decreased vision in the left eye and a 48-hour damage despite his significant cardiac history and highly history of severe fatigue accompanied by lower back and elevated troponins on presentation. His echocardiogram was bilateral hip pain. He had difficulty arising from his chair but also normal, which necessitated cardiac catheterization and denied double vision, difficulty swallowing or walking, endomyocardial biopsy for diagnosis. Another remarkable muscle aches or tenderness, shortness of breath, chest pain, finding was the speed of his clinical deterioration; over a few fevers, chills, nausea, vomiting, diarrhea, or bowel/bladder hours, he went from being minimally symptomatic to dysfunction. Vital signs were normal. Physical exam was needing intubation for deteriorating pulmonary mechanics notable for right-sided ptosis and a large, firm mass lateral to and bulbar dysfunction. His rapid decline required swift the left orbit, causing unilateral proptosis and extending coordination of various hospital services for him to receive through the ipsilateral parotid and submandibular region. emergent plasma exchange and immunosuppression. Distance vision in the left eye was slightly diminished, but 'is patient’s renal function was below the limit tested in pupillary responses and extraocular reflexes were intact cemiplimab clinical trials (CrCl> 25 mL/min) [1]. However, bilaterally. ICIs are typically broken down and cleared by phagocytic Cranial nerve testing was unremarkable. Cardiac, lung, cells, so renal function is not expected to affect drug activity and abdominal exams were within normal limits. He had or metabolism [9]. A study of 27 patients with preexisting proximal muscle weakness primarily in the lower extremities renal, hepatic, and/or cardiac dysfunction showed that but did not have tenderness to palpation of major muscle treatment with PD-1 inhibitors does not typically result in groups or fatiguability. He demonstrated a normal gait. excessive irAEs or increased organ damage [10]. Nonethe- Computed tomography imaging of the hip and lumbar less, the combination of this patient’s advanced age, frailty, spine did not show any metastatic disease or cord com- and multiple comorbidities likely predisposed him to a pression (magnetic resonance imaging could not be done worse outcome. due to the patient’s pacemaker). Notable initial laboratory To our knowledge, this is the first reported case of si- abnormalities are listed in Table 1. multaneous MG, myocarditis, and myositis occurring Case Reports in Immunology 3 Table 1: Notable abnormal labs on admission and results of autoimmune testing. Labs on admission Recorded values Normal values Creatine kinase (CK) 6,407 IU/L 22–198 IU/L High-sensitivity troponin-T 1,557 ng/L < ng/L Potassium 5.8 mEq/L 3.5–5.0 mEq/L Aspartate aminotransferase 532 IU/L <40 IU/L Alanine aminotransferase 214 IU/L <40 IU/L Urine myoglobin 20 ng/mL <5 ng/mL Creatinine 2.14 mg/dL 1.5 mg/dL (for this patient) Autoimmune antibody testing Anti-striated muscle antibody titers 1:15,360 <1:120 Acetylcholine receptor antibody levels 9.34 nmol/L <0.02 nmol/L Anti-Ro antibody levels 51 U/mL <20 U/mL also had elevated anti-striated muscle antibodies [14]. Several other groups have also noted increases in anti- striated muscle antibodies associated with myopathy after PD-1 ICI therapy [15–17]. Our case adds to this growing body of evidence suggesting that anti-striated muscle an- tibodies are sensitive markers of PD-1 myopathy and should be checked in patients with symptoms of myositis in the context of recent PD-1 ICI exposure. Neuromuscular irAEs such as MG may be part of an overlap syndrome with myocarditis and myositis [4]. MG has also been seen more frequently with anti-PD-1 and anti- programmed cell death ligand 1 (PD-L1) ICIs compared to anti-CTLA-4 ICIs [11]. Mechanistically, this may be partially explained by the differing distribution of PD-1 and CTLA-4 in immune cells. PD-1 is expressed on B cells, T cells, and 10μm myeloid cells, whereas CTLA-4 is typically localized to T cells Figure 1: Endomyocardial biopsy showing evidence of acute [18]. 'e increased incidence of MG in anti-PD-1 therapy necrotizing myocarditis with inflammatory cellular infiltrate and compared to anti-CTLA-4 therapy thus may in part be due to cardiomyocyte necrosis (arrowheads) and focal replacement fi- PD-1 blockade on B cells, resulting in proliferation of brosis (arrows) indicative of previous damage and healing. autoreactive B cells that create antibodies to self-antigens on the AChR and neuromuscular junction. Evidence for this mechanism comes from an in vitro study showing that B cells secondary to cemiplimab. A recent review of ICI-related widely express both PD-1 and PD-L1, and that PD-1/PD-L1 neuromuscular toxicities reports that MG is the most binding decreases B-cell activation, proliferation, and inter- common neuromuscular irAE (26.8%, n � 22), followed by leukin-6 synthesis [19]. PD-1 blockade then restores and myositis (25.6%, n � 21) and Guillain–Barre syndrome enhances B-cell proliferation and cytokine production [19]. In (18.3%, n � 15) [4]. Myositis (16.2%) and myocarditis (8.8%) contrast, CTLA-4 blockade results in broad activation and were the most common immunotoxicities accompanying proliferation of T cells and simultaneous reduction of regu- cases of ICI-induced MG [11]. 'e presence of all 3 toxicities latory T-cell-mediated immunosuppression [18], without was associated with a significantly higher risk of death (5/8 direct impact on B cells. In general, irAEs from both anti-PD- patients; 62.5%) than MG alone (29/179; 16.2%), 1/PD-L1 and anti-CTLA-4 therapies are largely similar and MG + myositis (6/29; 20.7%), or myocarditis alone (4/12; most commonly impact the gastrointestinal, dermatologic, 33%) [11]. MG also tended to occur earlier (median 29 days and endocrine systems [20], indicating that T cells are the after immunotherapy) than other neurotoxicities [11]. A primary driver of both efficacy and toxicity. However, rit- report of 101 cases of ICI-related myocarditis showed that uximab has been shown to be useful in resolving immune myositis (25%) and MG (10%) were the two most common thrombocytopenic purpura after ICI therapy [21], suggesting concurrent irAEs [12]. Complicating this picture is that ICI- that abrogating B-cell activity may have some benefit in related myositis often presents with oculomotor weakness treating similar antibody-mediated conditions such as ICI- [13], which can confound the diagnosis of MG. Our patient’s related MG. Further investigation into the dynamics between laboratory and pathologic findings are consistent with prior PD-1 inhibitors and B cells is warranted. reports of “PD-1 myopathy,” a discrete inflammatory my- 'e presence of any one of MG, myocarditis, or myositis opathy observed in patients who received nivolumab or should prompt immediate evaluation for all three toxicities. pembrolizumab and subsequently developed muscle Both troponin-T and troponin-I should be ordered to better weakness. 'ese patients had an average CK of 5247 IU/L differentiate cardiac from skeletal muscle damage. Anti- and multifocal myonecrosis with endomysial inflammation striated muscle, anti-AChR, and muscle-specific kinase on histologic examination [14]. 'irteen of 19 patients (68%) 4 Case Reports in Immunology [7] T. Liewluck, J. C. Kao, and M. L. Mauermann, “PD-1 in- antibodies may be helpful in differentiating specific toxic- hibitor-associated myopathies,” Journal of Immunotherapy, ities. Endomyocardial biopsy should also be performed for vol. 41, no. 4, pp. 208–211, 2018. diagnosis as electro- and echocardiogram may not reveal [8] T. Kimura, S. Fukushima, A. Miyashita et al., “Myasthenic dysfunction. 'e rapid progression of these adverse effects crisis and polymyositis induced by one dose of nivolumab,” requires quick identification and initiation of immuno- Cancer Science, vol. 107, no. 7, pp. 1055–1058, 2016. suppression and plasma exchange. 'e unusual presentation [9] D. B. Johnson, R. J. Sullivan, and A. M. Menzies, “Immune and severity of this triad of immunotoxicities also highlight checkpoint inhibitors in challenging populations,” Cancer, the need for physicians to be alert for multiple simultaneous vol. 123, no. 11, pp. 1904–1911, 2017. irAEs after ICI therapy. [10] B. A. Kanz, M. H. Pollack, R. Johnpulle et al., “Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or hepatic dysfunction,” Journal for Immunoerapy of Abbreviations Cancer, vol. 4, no. 1, p. 60, 2016. [11] D. B. Johnson, A. Manouchehri, A. M. Haugh et al., “Neu- AChR: Acetylcholine receptor rologic toxicity associated with immune checkpoint inhibi- CK: Creatine kinase tors: a pharmacovigilance study,” Journal for Immunoerapy CKD: Chronic kidney disease of Cancer, vol. 7, no. 1, p. 134, 2019. CrCl: Creatinine clearance [12] J. J. Moslehi, J.-E. Salem, J. A. Sosman, B. Lebrun-Vignes, and CTLA-4: Cytotoxic T-lymphocyte-associated protein 4 D. B. Johnson, “Increased reporting of fatal immune ICI: Immune checkpoint inhibitor checkpoint inhibitor-associated myocarditis,” e Lancet, irAE: Immune-related adverse event vol. 391, no. 10124, p. 933, 2018. MG: Myasthenia gravis [13] M. Touat, T. Maisonobe, S. Knauss et al., “Immune check- PD-1/PD- Programmed cell death protein 1/ligand 1 point inhibitor-related myositis and myocarditis in patients L1: with cancer,” Neurology, vol. 91, no. 10, pp. e985–e994, 2018. [14] M. Seki, A. Uruha, Y. Ohnuki et al., “Inflammatory myopathy SCC: Squamous cell carcinoma. associated with PD-1 inhibitors,” Journal of Autoimmunity, vol. 100, pp. 105–113, 2019. Data Availability [15] C. L. Haddox, N. Shenoy, K. K. Shah et al., “Pembrolizumab induced bulbar myopathy and respiratory failure with nec- Primary data about the patient were obtained from the rotizing myositis of the diaphragm,” Annals of Oncology, electronic medical record of the University of Texas MD vol. 28, no. 3, pp. 673–675, 2017. Anderson Cancer Center. Cited manuscripts were found on [16] M. A. Bilen, S. K. Subudhi, J. Gao, N. M. Tannir, S.-M. Tu, and PubMed. P. Sharma, “Acute rhabdomyolysis with severe polymyositis following ipilimumab-nivolumab treatment in a cancer pa- tient with elevated anti-striated muscle antibody,” Journal for Conflicts of Interest Immunoerapy of Cancer, vol. 4, no. 1, p. 36, 2016. [17] K. Takamatsu, S. Nakane, S. Suzuki et al., “Immune check- None of the authors have any conflicts of interest relevant to point inhibitors in the onset of myasthenia gravis with this study. hyperCKemia,” Annals of Clinical and Translational Neu- rology, vol. 5, no. 11, pp. 1421–1427, 2018. References [18] E. I. Buchbinder and A. Desai, “CTLA-4 and PD-1 pathways,” American Journal of Clinical Oncology, vol. 39, no. 1, [1] A. Markham and S. Duggan, “Cemiplimab: first global ap- pp. 98–106, 2016. proval,” Drugs, vol. 78, no. 17, pp. 1841–1846, 2018. [19] M.-L. 'ibult, E. Mamessier, J. Gertner-Dardenne et al., “PD- [2] M. R. Migden, D Rischin, C. D Schmults et al., “PD-1 blockade 1 is a novel regulator of human B-cell activation,” Interna- with cemiplimab in advanced cutaneous squamous-cell car- tional Immunology, vol. 25, no. 2, pp. 129–137, 2013. cinoma,” e New England Journal of Medicine, vol. 379, no. 4, [20] S. Das and D. B. Johnson, “Immune-related adverse events pp. 341–351, 2018. and anti-tumor efficacy of immune checkpoint inhibitors,” [3] M. Fazel and P. M. Jedlowski, “Severe myositis, myocarditis, Journal for Immuno erapy of Cancer, vol. 7, no. 1, p. 306, and myasthenia gravis with elevated anti-striated muscle antibody following single dose of ipilimumab-nivolumab [21] E. Shiuan, K. E. Beckermann, A. Ozgun et al., “'rombo- therapy in a patient with metastatic melanoma,” Case Reports cytopenia in patients with melanoma receiving immune Immunology, vol. 2019, p. 3, 2019. checkpoint inhibitor therapy,” Journal for Immuno erapy of [4] N. Mohn, G. Beutel, R. Gutzmer, P. Ivanyi, I. Satzger, and Cancer, vol. 5, no. 1, p. 8, 2017. T. Skripu, “Neurological immune related adverse events as- sociated with nivolumab, ipilimumab, and pembrolizumab therapy-review of the literature and future outlook,” Journal of Clinical Medicine, vol. 8, no. 11, 2019. [5] J. C. Kao, A. Brickshawana, and T. Liewluck, “Neuromuscular complications of programmed cell death-1 (PD-1) inhibitors,” Current Neurology and Neuroscience Reports, vol. 18, no. 10, p. 63, 2018. [6] S. Suzuki, N. Ishikawa, F. Konoeda et al., “Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan,” Neurology, vol. 89, no. 11, pp. 1127–1134, 2017. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Immunology Hindawi Publishing Corporation

The Terrible Triad of Checkpoint Inhibition: A Case Report of Myasthenia Gravis, Myocarditis, and Myositis Induced by Cemiplimab in a Patient with Metastatic Cutaneous Squamous Cell Carcinoma

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Hindawi Case Reports in Immunology Volume 2020, Article ID 5126717, 4 pages https://doi.org/10.1155/2020/5126717 Case Report The Terrible Triad of Checkpoint Inhibition: A Case Report of Myasthenia Gravis, Myocarditis, and Myositis Induced by Cemiplimab in a Patient with Metastatic Cutaneous Squamous Cell Carcinoma 1 1 2 3 3 Nikeshan Jeyakumar , Mikel Etchegaray, Jason Henry, Laura Lelenwa, Bihong Zhao, 4 4 Ana Segura, and L. Maximilian Buja Division of Internal Medicine, e University of Texas M.D. Anderson Cancer Center, 1400 Pressler Drive, Unit 1463, Houston, Texas 77030, USA Division of Cancer Medicine, e University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77030, USA Department of Pathology and Laboratory Medicine, e University of Texas Health Science Center at Houston, McGovern Medical School, 6431 Fannin Street, P.O. Box 20708, Houston, Texas 77225, USA Department of Cardiovascular Pathology, Texas Heart Institute, 6770 Bertner Avenue, Houston, Texas 77030, USA Correspondence should be addressed to Nikeshan Jeyakumar; njeyakumar@mdanderson.org Received 10 January 2020; Revised 16 June 2020; Accepted 18 June 2020; Published 4 July 2020 Academic Editor: Eisei Kondo Copyright © 2020 Nikeshan Jeyakumar et al. 'is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. We report a case of a patient with squamous cell carcinoma (SCC) who developed myasthenia gravis (MG), myositis, and myocarditis after receiving cemiplimab, an anti-PD-1 immune checkpoint inhibitor (ICI). Case Presentation. An 86-year-old man with metastatic periocular SCC presented with decreased vision in the left eye, severe fatigue, and lower back and bilateral hip pain 3 weeks after receiving cemiplimab. Within hours, he developed dysphonia, pharyngeal secretions, and dysphagia, ne- cessitating intubation. Endomyocardial biopsy revealed active lymphocyte-mediated necrosis consistent with ICI-induced myocarditis. Anti-striated muscle and anti-acetylcholine receptor antibodies were elevated, consistent with myositis and my- asthenia gravis. Despite plasma exchange therapy, steroids, and intravenous immunoglobulin, he died from cardiac arrest. Conclusions. 'e presence of myasthenia gravis, myocarditis, or myositis should prompt evaluation for all three toxicities as they may represent an overlap syndrome. 'e severity of these immunotoxicities highlights the need for clinicians to suspect multiple simultaneous adverse effects of ICIs. most common immune-related adverse events (irAEs) 1. Introduction were diarrhea, fatigue, constipation, and rash [2]. Neu- Cemiplimab is a programmed cell death protein 1 (PD-1) romuscular irAEs occur in <1% of patients treated with immune checkpoint inhibitor (ICI) approved in September ICIs overall [3], but due to the nonspecific nature of their 2018 for the treatment of locally advanced or metastatic symptoms, it is likely that many cases go unreported [4]. cutaneous squamous cell carcinoma (SCC) in patients that Myasthenia gravis (MG) is the most commonly reported did not qualify for curative surgery or radiation [1]. Phase 2 neuromuscular irAE associated with PD-1 inhibitors, with studies of patients with metastatic disease demonstrated a incidence ranging from 0.12 to 0.2% [5]. PD-1 inhibitor- response rate of 47% (28/59), with 16 (57%) of these pa- related MG tends to be more severe, with 40–50% of pa- tients having duration of response at 6 months [2]. 'e tients requiring ventilatory support (7 times higher than in 2 Case Reports in Immunology An electrocardiogram was suggestive of inferior wall typical MG) [5]. 'ere also appears to be a distinct cor- relation between PD-1 inhibition and MG, as MG is rarely ischemia and showed a new right bundle-branch block. Transthoracic echocardiogram showed a normal ejection seen in association with anticytotoxic T-lymphocyte-as- sociated protein 4 (CTLA-4) therapy. In a review of over fraction without pericardial effusion. 10,000 patients treated with nivolumab or ipilimumab in Several hours after initial presentation, the patient de- Japan, 12 cases of MG occurred in patients who received veloped dysphonia, increasing pharyngeal secretions and nivolumab, while none occurred with ipilimumab [6]. Ten difficulty swallowing, and new shortness of breath with of these 12 were seropositive for acetylcholine receptor worsening fatigue. He was urgently transferred to the in- (AChR) antibodies [6]. ICI-related MG is also strongly tensive care unit, given 1 g intravenous methylprednisolone, associated with elevated creatine kinase (CK) levels, in- and was electively intubated. Left and right heart cathe- dicating the presence of simultaneous muscle or cardiac terization with endomyocardial biopsy was performed and revealed an active necrotizing lymphocytic myocarditis dysfunction [5]. 'e rare and generally fatal triad of ICI- related MG, myocarditis, and myositis has been described (Figure 1). His bypass grafts were patent, and he had normal ventricular pressures. Results of autoimmune antibody with nivolumab/ipilimumab dual therapy [3] and pem- brolizumab [7] and nivolumab monotherapy [6, 8] but has testing are shown in Table 1. Muscle-specific kinase anti- not previously been reported with cemiplimab. bodies were negative. He received plasma exchange therapy for 5 days, was continued on high-dose methylprednisolone, and received 2. Case Presentation one dose of intravenous immunoglobulin. However, his An 86-year-old man with periocular SCC involving the left troponin-T levels continued rising over 3000 ng/L, his lower and upper eyelids status after Mohs surgery, recon- troponin-I levels peaked at 6.9 ng/L, and he began devel- struction, and adjuvant radiation therapy was referred to the oping worsening kidney function necessitating initiation of continuous renal replacement therapy. Despite these mea- MD Anderson Cancer Center due to local recurrence of SCC to the left lateral canthus and orbit. He had a prior history of sures, he suffered pulseless electrical activity arrest from hyperkalemia and severe metabolic acidosis and could not be numerous cutaneous carcinomas (basal cell, spindle cell, and squamous cell) on the head and face, removed surgically. His resuscitated. Based on his clinical signs and symptoms, el- evations in anti-AChR antibodies, anti-striated muscle an- comorbidities included a 4-vessel coronary artery bypass graft in 2016, sick sinus syndrome status after pacemaker tibodies, CK, and urine myoglobin, and with characteristic placement, hypertension, hyperlipidemia, and chronic findings on endomyocardial biopsy, he was diagnosed with kidney disease (CKD) with creatinine clearance (CrCl) cemiplimab-related MG, myositis, and myocarditis. 22 mL/min. Outpatient ultrasound-guided biopsy of left parotid and submandibular nodules revealed metastatic SCC 3. Discussion in both areas. After discussion with head and neck medical oncology, the patient elected to start cemiplimab and re- 'is case was illustrative of the varied and often vague ceived one 350 mg dose. presentations of irAEs. 'is patient did not have chest pain, 'ree weeks later, he reported to the emergency room dyspnea, or any other symptoms consistent with cardiac with 5 days of decreased vision in the left eye and a 48-hour damage despite his significant cardiac history and highly history of severe fatigue accompanied by lower back and elevated troponins on presentation. His echocardiogram was bilateral hip pain. He had difficulty arising from his chair but also normal, which necessitated cardiac catheterization and denied double vision, difficulty swallowing or walking, endomyocardial biopsy for diagnosis. Another remarkable muscle aches or tenderness, shortness of breath, chest pain, finding was the speed of his clinical deterioration; over a few fevers, chills, nausea, vomiting, diarrhea, or bowel/bladder hours, he went from being minimally symptomatic to dysfunction. Vital signs were normal. Physical exam was needing intubation for deteriorating pulmonary mechanics notable for right-sided ptosis and a large, firm mass lateral to and bulbar dysfunction. His rapid decline required swift the left orbit, causing unilateral proptosis and extending coordination of various hospital services for him to receive through the ipsilateral parotid and submandibular region. emergent plasma exchange and immunosuppression. Distance vision in the left eye was slightly diminished, but 'is patient’s renal function was below the limit tested in pupillary responses and extraocular reflexes were intact cemiplimab clinical trials (CrCl> 25 mL/min) [1]. However, bilaterally. ICIs are typically broken down and cleared by phagocytic Cranial nerve testing was unremarkable. Cardiac, lung, cells, so renal function is not expected to affect drug activity and abdominal exams were within normal limits. He had or metabolism [9]. A study of 27 patients with preexisting proximal muscle weakness primarily in the lower extremities renal, hepatic, and/or cardiac dysfunction showed that but did not have tenderness to palpation of major muscle treatment with PD-1 inhibitors does not typically result in groups or fatiguability. He demonstrated a normal gait. excessive irAEs or increased organ damage [10]. Nonethe- Computed tomography imaging of the hip and lumbar less, the combination of this patient’s advanced age, frailty, spine did not show any metastatic disease or cord com- and multiple comorbidities likely predisposed him to a pression (magnetic resonance imaging could not be done worse outcome. due to the patient’s pacemaker). Notable initial laboratory To our knowledge, this is the first reported case of si- abnormalities are listed in Table 1. multaneous MG, myocarditis, and myositis occurring Case Reports in Immunology 3 Table 1: Notable abnormal labs on admission and results of autoimmune testing. Labs on admission Recorded values Normal values Creatine kinase (CK) 6,407 IU/L 22–198 IU/L High-sensitivity troponin-T 1,557 ng/L < ng/L Potassium 5.8 mEq/L 3.5–5.0 mEq/L Aspartate aminotransferase 532 IU/L <40 IU/L Alanine aminotransferase 214 IU/L <40 IU/L Urine myoglobin 20 ng/mL <5 ng/mL Creatinine 2.14 mg/dL 1.5 mg/dL (for this patient) Autoimmune antibody testing Anti-striated muscle antibody titers 1:15,360 <1:120 Acetylcholine receptor antibody levels 9.34 nmol/L <0.02 nmol/L Anti-Ro antibody levels 51 U/mL <20 U/mL also had elevated anti-striated muscle antibodies [14]. Several other groups have also noted increases in anti- striated muscle antibodies associated with myopathy after PD-1 ICI therapy [15–17]. Our case adds to this growing body of evidence suggesting that anti-striated muscle an- tibodies are sensitive markers of PD-1 myopathy and should be checked in patients with symptoms of myositis in the context of recent PD-1 ICI exposure. Neuromuscular irAEs such as MG may be part of an overlap syndrome with myocarditis and myositis [4]. MG has also been seen more frequently with anti-PD-1 and anti- programmed cell death ligand 1 (PD-L1) ICIs compared to anti-CTLA-4 ICIs [11]. Mechanistically, this may be partially explained by the differing distribution of PD-1 and CTLA-4 in immune cells. PD-1 is expressed on B cells, T cells, and 10μm myeloid cells, whereas CTLA-4 is typically localized to T cells Figure 1: Endomyocardial biopsy showing evidence of acute [18]. 'e increased incidence of MG in anti-PD-1 therapy necrotizing myocarditis with inflammatory cellular infiltrate and compared to anti-CTLA-4 therapy thus may in part be due to cardiomyocyte necrosis (arrowheads) and focal replacement fi- PD-1 blockade on B cells, resulting in proliferation of brosis (arrows) indicative of previous damage and healing. autoreactive B cells that create antibodies to self-antigens on the AChR and neuromuscular junction. Evidence for this mechanism comes from an in vitro study showing that B cells secondary to cemiplimab. A recent review of ICI-related widely express both PD-1 and PD-L1, and that PD-1/PD-L1 neuromuscular toxicities reports that MG is the most binding decreases B-cell activation, proliferation, and inter- common neuromuscular irAE (26.8%, n � 22), followed by leukin-6 synthesis [19]. PD-1 blockade then restores and myositis (25.6%, n � 21) and Guillain–Barre syndrome enhances B-cell proliferation and cytokine production [19]. In (18.3%, n � 15) [4]. Myositis (16.2%) and myocarditis (8.8%) contrast, CTLA-4 blockade results in broad activation and were the most common immunotoxicities accompanying proliferation of T cells and simultaneous reduction of regu- cases of ICI-induced MG [11]. 'e presence of all 3 toxicities latory T-cell-mediated immunosuppression [18], without was associated with a significantly higher risk of death (5/8 direct impact on B cells. In general, irAEs from both anti-PD- patients; 62.5%) than MG alone (29/179; 16.2%), 1/PD-L1 and anti-CTLA-4 therapies are largely similar and MG + myositis (6/29; 20.7%), or myocarditis alone (4/12; most commonly impact the gastrointestinal, dermatologic, 33%) [11]. MG also tended to occur earlier (median 29 days and endocrine systems [20], indicating that T cells are the after immunotherapy) than other neurotoxicities [11]. A primary driver of both efficacy and toxicity. However, rit- report of 101 cases of ICI-related myocarditis showed that uximab has been shown to be useful in resolving immune myositis (25%) and MG (10%) were the two most common thrombocytopenic purpura after ICI therapy [21], suggesting concurrent irAEs [12]. Complicating this picture is that ICI- that abrogating B-cell activity may have some benefit in related myositis often presents with oculomotor weakness treating similar antibody-mediated conditions such as ICI- [13], which can confound the diagnosis of MG. Our patient’s related MG. Further investigation into the dynamics between laboratory and pathologic findings are consistent with prior PD-1 inhibitors and B cells is warranted. reports of “PD-1 myopathy,” a discrete inflammatory my- 'e presence of any one of MG, myocarditis, or myositis opathy observed in patients who received nivolumab or should prompt immediate evaluation for all three toxicities. pembrolizumab and subsequently developed muscle Both troponin-T and troponin-I should be ordered to better weakness. 'ese patients had an average CK of 5247 IU/L differentiate cardiac from skeletal muscle damage. Anti- and multifocal myonecrosis with endomysial inflammation striated muscle, anti-AChR, and muscle-specific kinase on histologic examination [14]. 'irteen of 19 patients (68%) 4 Case Reports in Immunology [7] T. Liewluck, J. C. Kao, and M. L. 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Case Reports in ImmunologyHindawi Publishing Corporation

Published: Jul 4, 2020

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