Pembrolizumab-induced Myopathy with Anti-striated Muscle Antibodies Successfully Treated by Plasma Exchange

Abstract

A 70-year-old woman with advanced endometrial cancer developed right ptosis and muscle weakness in the right quadriceps after pembrolizumab administration. Serum creatine kinase (CK) levels were elevated, and anti-striated muscle antibodies were positive. On magnetic resonance imaging, the right vastus lateral muscle showed an abnormal signal. She was diagnosed with pembrolizumab-induced myopathy. We initiated plasma exchange (PE), and the ptosis immediately resolved. We then introduced oral corticosteroids, which improved her muscle weakness. We were able to rapidly diagnose her with ocular symptoms and serum CK level elevation. The early initiation of PE might prevent the exacerbation of pembrolizumab-induced myopathy.

Introduction

Recently, immune checkpoint inhibitors (ICIs) have been widely used in various types of cancer. The efficacy of pembrolizumab plus lenvatinib was proven in endometrial cancer in a recent clinical trial (1). However, pembrolizumab, a monoclonal antibody against programmed cell death protein-1 (PD-1), has been known to cause certain immune-related adverse events (irAEs).

Neuromuscular irAEs are rare but show higher mortality rates than those of other organs (2). The latest guideline recommends prednisolone (PSL) as a first-line treatment depending on the severity of the condition (3). However, irAE myopathy, sometimes complicated with myasthenia gravis (MG) and myocarditis, can have a catastrophic clinical course when it presents with heart or respiratory failure (4). For this reason, an accurate diagnosis of this disease and the early induction of treatment should be performed.

We herein report a case of anti-striated muscle antibody-positive irAE myopathy that showed rapid improvement with plasma exchange (PE) during the early stage of the disease.

Case Report

A 70-year-old woman with advanced endometrial cancer developed ptosis in her right eye 22 days after the first administration of pembrolizumab (200 mg every 3 weeks, intravenously) and lenvatinib (20 mg per day). She was referred to our department with a chief complaint of these symptoms 28 days after chemotherapy. She had a medical history of diabetes mellitus, hypertension, and endometrial cancer. Regarding the endometrial cancer, she had undergone total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy. In addition to the surgery, carboplatin plus paclitaxel and doxorubicin plus cisplatin had been administered. Despite these therapies, she developed multiple bone and lung metastases. Pembrolizumab and lenvatinib were then administered. She was hospitalized for her complaints of neurological symptoms 29 days after receiving the first dose of pembrolizumab. Her neurological examination revealed mild right-dominant ptosis and fluctuating horizontal diplopia. She also had myalgia, tenderness and mild weakness at the right quadriceps muscle, and diminished tendon reflex of the limbs. Her cardiac and respiratory functions were normal.

Laboratory investigations revealed a serum creatine kinase (CK) level of 915 IU/L (normal range: <153 IU/L), aspartate aminotransferase level (AST) of 48 U/L (normal range: <30 U/L), myoglobin level of 287 ng/mL (normal range: <70 ng/mL), and normal cardiac, respiratory, and thyroid function parameters in her blood. Serum muscle-specific antibodies, such as aminoacyl-tRNA synthetase (ARS), melanoma differentiation-associated protein 5 (MDA5), transcriptional intermediary factor 1 (TIF1)-gamma, Mi-2, mitochondrial M2, HMGCR, and signal recognition particle (SRP) antibodies, were negative, and acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) antibodies (for myasthenic syndrome) were also negative. However, serum anti-striated muscle antibodies, including the anti-titin antibody (35.69 A.U., normal range: <1.0 A.U.) and the anti-voltage-gated potassium channel Kv1.4 antibody (30.18 A.U., normal range: <1.0 A.U.), were both positive.

Magnetic resonance imaging (MRI) revealed a high-intensity signal in the right vastus lateralis muscle on short tau inversion recovery (STIR) imaging (Fig. 1a). This lesion showed isointensity on T1-weighted imaging, which excluded chronic fat infiltration change (Fig. 1b). Gadolinium-enhanced head MRI on T1-weighted imaging demonstrated no abnormal intensity in the extraocular muscles and no brain metastasis. Chest computed tomography showed atrophy of the thymus. During the myasthenic syndrome evaluation, the ice pack and edrophonium tests for her fluctuating ptosis and diplopia were negative. Repetitive stimulation tests on the right facial nerve, the right accessory nerve, and the right ulnar nerve revealed neither waning nor waxing. She refused a muscle biopsy, so histopathological examinations could not be performed.

Figure 1.

Muscle MRI and ptosis. The right vastus lateralis muscle shows a high-intensity signal (arrow) on the axial image of STIR imaging of MRI (a), and the red box area in (a) demonstrates isointensity on T1-weighted image (b). On admission, the patient showed right-side-dominant ptosis (c), and the ptosis on both sides improved after initiating plasma exchange (d). MRI: magnetic resonance imaging, STIR: short tau inversion recovery

We clinically diagnosed her with irAE myopathy with myasthenic symptoms. The clinical course and treatment details are shown in Fig. 2. Ten days after the onset of the symptoms, we introduced total PE and performed it six times. After the first session of PE, the ptosis and diplopia immediately and almost fully resolved (Fig. 1c, d). Thereafter, we started oral PSL at a dose of 5 mg/day and gradually increased it to 30 mg/day to avoid initial worsening. The muscle weakness in the right thigh and the elevation of the serum CK level were both improved to the normal level. She was discharged without any neurological sequelae 36 days after the onset. Although no neurological recurrence or serum CK elevation was noted after the discharge, the serum anti-striated muscle antibody titers remained high (anti-titin antibody: 55.77 A.U.; and anti-Kv1.4 antibody: 35.26 A.U.).

Figure 2.

Clinical course and treatment of the patient. CK: creatine kinase, PE: plasma exchange, PSL: prednisolone

Discussion

We encountered a case of pembrolizumab-induced myopathy with myasthenic symptoms that was rapidly diagnosed and successfully treated with PE, thus avoiding life-threatening events, such as respiratory failure or myocarditis. In this case, myopathy was considered because of ptosis and the continuous serum CK elevation. Recent studies have shown that irAE myopathy tends to demonstrate myasthenic symptoms and respiratory failure earlier than idiopathic autoimmune myositis or MG; therefore, the early diagnosis and treatment are very important (4,5). Furthermore, irAEs occur in patients with progressive cancer, meaning that it is also important to differentiate weakness due to irAE symptoms from general weakness due to cancer. Ptosis and fluctuating diplopia are atypical symptoms of myositis but common symptoms of MG. However, persistent serum CK elevation is rare in MG but is usually seen in myositis. Ono et al. reported that anti-striated muscle antibody-positive irAE myopathy was a distinct disease entity from idiopathic MG and myositis and tended to show both ptosis and persistent serum CK elevation (6). The combination of these two findings can be considered an important clue for the early diagnosis of irAE myopathy.

After the diagnosis of irAE myopathy, the early introduction of proper therapy is crucial, and PE was an effective initial treatment in this case. We believe that the early initiation of PE was a successful treatment strategy in this case for two reasons. The first is the fast-acting efficacy of PE. Once administered, PD-1 inhibitors occupy PD-1 on the surface of circulating T cells for more than two months (7). Pembrolizumab is a member of the IgG4 subclass, and the serum component in the sera is expected to be removed by PE. The removal of the monoclonal antibodies of the drug, pathogenic autoantibodies, and other circulating inflammatory factors, such as cytokines, might improve the neurologic symptoms in the present case. Safa et al. reported that the combination therapies of PSL plus PE or intravenous immunoglobulin (IVIg) may lead to more favorable outcomes than PSL monotherapy in irAE MG (8). Furthermore, in idiopathic MG, a prospective study revealed that PE was able to improve the symptoms earlier than IVIg (9). Moreover, PE was unable to be safely introduced under unstable hemodynamic conditions due to the presence of accompanying myocarditis, as PE should be introduced before the progression of irAE myopathy. For these reasons, the early initiation of PE in irAE myopathy is thought to prevent severe clinical conditions and improve the symptoms.

The second reason we believe PE was successful was that this treatment avoided initial worsening related to the introduction of high-dose corticosteroids (HDCS). The previous reports of irAE cases with positive anti-striated muscle antibodies, for which detailed clinical courses are available, are shown in Table. The latest guideline recommends HDCS be administered for irAE myopathy (3). However, 4 out of 11 cases without respiratory failure at initial presentation demonstrated the exacerbation of respiratory failure a few days after HDCS initiation, despite serum CK reduction. Interestingly, all of these cases showed myasthenic symptoms. We speculate that the exacerbation represented initial worsening of the myasthenic symptoms after starting HDCS, which has already been reported in cases of idiopathic MG (26). Preceding treatment with PE could prevent initial worsening in idiopathic MG (27). Onda et al. reported that they successfully administered HDCS without initial worsening by preceding treatment with an ascending-dose regimen of PSL in irAE myopathy with myasthenic syndrome (16). We should recall that a catastrophic clinical course of irAE myopathy with positive anti-striated muscle antibodies can be caused by initial worsening when myasthenic symptoms are observed. PE might therefore be a useful candidate for avoiding the initial worsening.

Table.

Clinical Features and Treatments of the irAE Patients with Anti-striated Muscle Antibodies.

Reference	Immune-checkpoint inhibitor	Age	Sex	Myopathy	Myasthenic syndrome (ocular symptom)	Myocarditis	Anti-striated muscle antibodies	Anti-AChR antibody	Initial serum CK (IU/mL)	First immunotherapy	Additional immunotherapies	Initial corticosteroid dose (/day)	Respiratory failure after HDCS, despite CK reduction	PE initiation day from the admission	Outcome
(10)	Pembrolizumab	75	M	+	+	+	+	-	3,480	HDCS	PE	MP 100 mg	+	6	Improved after PE
(11)	Pembrolizumab	83	M	+	+	+	+	+	5,567	HDCS, PE	-	MP 1,000 mg	-	0	Improved
(12)	Pembrolizumab	69	F	+	+	-	+	-	Slightly elevated	HDCS	PE	MP 1,000 mg	-	ND	Died
(13)	Pembrolizumab	76	F	+	+	+	+	-	3,527	HDCS	IVIg	PSL 65 mg	-	-	Improved
(14)	Pembrolizumab	78	M	+	+	-	+	-	1,284	HDCS	PE	PSL 1 mg/kg	+	10	Died
(15)	Pembrolizumab	69	M	-	+	+	+	+	ND	HDCS	IVIg, MMF	MP 1,000 mg	Already intubated	-	Continued NIV
(16)	Pembrolizumab	73	M	+	+	-	+	-	7,311	CS	HDCS	PSL 5 mg	-	-	Improved
(17)	Pembrolizumab	78	M	+	+	-	+	+	2,015	HDCS	IVIg	MP 1,000 mg	Already use NIV	-	Continued NIV
(18)	Nivolumab	78	M	-	+	-	+	-	Within normal range	HDCS	IVIg, PE	ND	Already intubated	ND	Improved
(19)	Nivolumab	65	M	+	+	-	+	+	2,299	HDCS, IVIg	-	MP 1 mg/kg	-	-	Improved
(20)	Nivolumab	77	F	+	+	+	+	-	11,297	HDCS	IVIg	MP 1,000 mg	-	-	Died
(21)	Ipilimumab/ Nivolumab	78	F	+	+	-	+	ND	9,198	HDCS	IVIg, PE	MP 75 mg	+	7	Improved after PE
(22)	Ipilimumab/ Nivolumab	73	M	+	+	-	+	ND	13,710	HDCS	PE, IFX, IVIg	MP 2 mg/kg	+	4	Improved after PE
(23)	Ipilimumab/ Nivolumab	49	F	-	-	+	+	ND	335	HDCS	IVIg	MP 125 mg	-		Improved
(24)	Atezolizumab	87	M	+	+	+	+	+	1,542	HDCS	IVIg	PSL 60 mg	ND	-	Died in 3 days
(25)	Cemiplimab	86	M	+	+	+	+	+	6,407	HDCS	PE, IVIg	MP 1,000 mg	Already intubated	ND	Died
Our case	Pembrolizumab	70	F	+	+	-	+	-	915	PE	CS	PSL 5 mg	-	3	Improved after PE

AChR: acetylcholine receptor, CK: creatinine kinase, CS: corticosteroid, F: female, HDCS: high-dose corticosteroid, IFX: infliximab, IVIg: intravenous immunoglobulin, M: male, MMF: mycophenolate mofetil, MP: methylprednisolone, ND: not described, NIV: non-invasive ventilation, PE: plasma exchange, PSL: prednisolone

In the present case, fluctuating ocular myasthenic symptoms, such as ptosis and diplopia, immediately improved to normal with the administration of PE before the onset of PSL therapy. This finding strongly suggests that the ocular myasthenic symptoms, including ptosis and fluctuating diplopia, were mediated by humoral factors (including autoantibodies). The presence of anti-AChR antibody is less frequent in irAE myopathy than in idiopathic MG (28), and like in our patient, ocular symptoms sometimes appear in patients with negative anti-AChR antibody (29). This suggests that ocular manifestations are caused by autoantibodies other than the anti-AChR antibody. Seki et al. demonstrated that the anti-striated muscle antibody can be a diagnostic biomarker in irAE myopathy (30). Although the same antibodies were also detected in the present case, those titers did not decrease when ocular myasthenic symptoms and muscle weakness improved. We speculate that the persistent elevation of these antibodies can be explained by two reasons. The first is the long-acting affinity of pembrolizumab on T cells (7). Long-lasting T cell activation can cause persistent B cell stimulation and continuous anti-striated muscle antibody production. The second reason is these antibodies may not have direct toxicity to the skeletal muscle in irAE myopathy. One previous study revealed that irAE myopathy due to ipilimumab and nivolumab was able to be treated successfully with symptomatic resolution. Although the anti-striated muscle antibody titers decreased, they remained positive at one year after the initial therapy (31). The actual pathophysiological implications of these antibodies remain unclear; however, they seemed not to be directly related to the disease severity in irAE myopathy. Other unknown autoantibodies or the cooperation of certain antibodies or humoral factors can directly trigger this disease; therefore, further studies including many irAE myopathy cases are needed.

In conclusion, we should suspect irAE myopathy in cases with fluctuating ocular symptoms and persistent elevations of serum CK levels in patients on ICI treatment. Furthermore, the introduction of PE therapy should be considered during the early phase of this disease.

The authors state that they have no Conflict of Interest (COI).