Successful high-dose glucocorticoid therapy for anti-mitochondrial antibody-positive myocarditis arising during tocilizumab and low-dose glucocorticoid therapy for rheumatoid arthritis

Abstract

Anti-mitochondrial antibody (AMA)-positive myopathy, a recently identified condition with significant cardiac involvement, poses a serious challenge in treatment consensus due to its extreme rarity. While several studies demonstrate the efficacy of high-dose prednisolone in managing this disease, the current literature lacks substantial evidence regarding the effectiveness of biologic therapy or low-dose prednisolone for remission induction. Here, we present a case of AMA-positive myocarditis that emerged during rheumatoid arthritis treatment with tocilizumab (TCZ) and low-dose prednisolone (PSL). Successfully, intensive immunosuppressive therapy with high-dose PSL proved effective in stabilizing this condition. Our case highlights the necessity of a robust immunosuppressive approach, favoring high-dose PSL over the combination of low-dose PSL and TCZ in this disease.

Keywords:

• Anti-mitochondrial antibody
• myocarditis
• tocilizumab
• immunosuppressive therapy

1. Introduction

Anti-mitochondrial antibody (AMA)-positive myopathy is a recently identified subgroup of idiopathic inflammatory myopathy (IIM), characterized by a high frequency of cardiovascular complications and muscle atrophy [1,2], and the occurrence of cardiovascular complications, such as myocarditis and arrhythmia, in patients with AMA-positive myopathy ranges from 33% to 70% in small case series [1,3].

While cardiac involvement poses a life-threatening complication, finding the suitable therapy remains challenging due to the rarity of this disease. Bujo et al. demonstrated the effectiveness of immunosuppressive therapy for cardiac involvement [4], but the appropriate treatment is still unclear, and there are no reports on the effectiveness of biologic therapy.

Our report highlights a compelling case of AMA-positive myocarditis successfully managed with a potent treatment approach involving high-dose prednisolone (PSL). What sets our case apart is the emergence of myocarditis during rheumatoid arthritis (RA) treatment, specifically with low-dose PSL and tocilizumab (TCZ), an anti-interleukin (IL)-6 receptor antibody. Our case advocates for an intensive immunosuppressive regimen, favoring high-dose PSL over the combination of low-dose PSL and TCZ, as the key to effectively stabilize this complex condition.

2. Case report

An 81-year-old female presented to our hospital with joint pain and swelling. She was diagnosed with RA based on the presence of persistent polyarthritis for three months, elevated C-reactive protein (CRP; 0.48 mg/dL, normal range ≤ 0.14 mg/dL), and positive results for rheumatoid factor (RF 28, normal range ≤ 15 U/mL) and anti-citrullinated protein (CCP) antibody (77.4, normal range ≤ 4.4 U/mL) based on the 2010 classification criteria [5]. She did not present with muscle weakness or leg edema at that time. She was treated with iguratimod (50 mg daily) and low-dose PSL (10 mg daily), but her disease activity worsened with a Disease Activity Score 28 (DAS28) of 4.9. Therefore, iguratimod was switched to intravenous TCZ (400 mg monthly), which improved her disease activity to low disease activity with a DAS28 of 2.6, and we gradually tapered the dose of PSL to 3 mg/day.

Seven months after starting treatment for RA, she developed persistent dyspnea, cough, and bilateral leg edema for one week, and was admitted to our hospital. Her vital signs showed a body temperature of 36.2 °C, blood pressure of 151/70 mmHg, and peripheral artery oxygen saturation of 96% on ambient air. Physical examination revealed irregular heart sounds, and pitting leg edema of bilateral legs and coarse crackles on lung auscultation. Manual muscle testing revealed a score of 5 for the deltoid, biceps, wrist extensors, iliopsoas, quadriceps, hamstrings, and ankle dorsiflexors muscle groups. There was no active arthritis and RA was in remission with a DAS28 of 1.41. Blood tests showed elevated levels of creatinine kinase (CK; 396 U/L, normal range ≤ 153 U/L), aldolase (8.0 U/L, normal range ≤ 5.0 U/L), troponin T (32 ng/L, normal range ≤ 14 ng/L), and brain natriuretic peptide (BNP; 408.9 pg/mL, normal range ≤ 18.4 pg/mL), and normal levels of CRP (0.01 mg/dL, normal range ≤ 0.14 mg/dL) and D-dimer (0.8, normal range < 1.0 μg/mL). The electrocardiogram (ECG) was previously normal sinus rhythm, but atrial fibrillation was detected on the ECG at the admission. Chest radiography showed an increased cardiothoracic ratio (CTR) from 53% in the outpatient clinic (Figure 1A) to 62% on admission, along with bilateral pleural effusions (Figure 1B). Cardiac ultrasound revealed a decreased left ventricular ejection fraction (LVEF) to 40%. We diagnosed her with acute heart failure and initiated loop diuretic and angiotensin receptor blocker therapy. Although these treatments reduced the pleural effusions (Figure 1C), her dyspnea persisted and her LVEF worsened to 36%.

Figure 1. Chest radiographic findings in our present case.

Chest radiographs in the outpatient clinic (A), on admission (B), after treatment of heart failure with diuretics (C), and two weeks after the initiation of high-dose PSL therapy (D).

We investigated the etiology of acute heart failure. Cardiac ultrasound revealed no left ventricular asynergy or valvular disease, and acute coronary syndrome was excluded. Immunological tests revealed an anti-nuclear antibody titer of 1:40 (cytoplasmic and nucleolar pattern), along with positive results for AMA-M2 (206 index, normal < 6.9 index). Anti-ds-DNA, anti-aminoacyl tRNA synthetases, anti-Mi-2, anti-transcription intermediary factor 1 gamma, anti-melanoma differentiation-associated gene 5, anti-SS-A, and anti-neutrophil cytoplasmic antibodies were all negative. Considering the positive AMA-M2 antibody, elevated CK and troponin T levels, and cardiac involvement, we suspected AMA-positive myopathy complicated with cardiac involvement [1]. Cardiac magnetic resonance imaging (MRI) revealed hyperintensity in the left ventricular sidewall on fat-suppressed T2-weighted image (Figure 2A) and expansion of extracellular volume fraction consistent with T1 image, so we diagnosed acute myocarditis based on the 2018 Lake Louise criteria [6]. Furthermore, computed tomography (CT) revealed atrophic paraspinal erector spinae muscles (Figure 2C), which is also a disease-specific feature of AMA-positive myopathy [1], while MRI of the bilateral thighs did not show any muscle inflammation. Myocardial biopsy showed no evidence of granuloma or amyloidosis.

Figure 2. Cardiac MRI findings and CT findings.

Cardiac MRI at the time of admission shows hyperintensity in the left ventricular sidewall on T2 image (A), which improved two weeks after the high-dose PSL initiation (B). CT shows atrophy of bilateral paraspinal erector spinae muscles (C).

We diagnosed her with AMA-positive myopathy with myocarditis. She was started on a high dose of PSL (1 mg/kg; 40 mg daily). Two weeks after the treatment initiation, CTR normalized to 52% (Figure 1D), cardiac MRI re-evaluation showed the diminishment of left ventricular sidewall hyperintensity (Figure 2B), and CK level became normalized. Furthermore, LVEF improved dramatically to 52%, while atrial fibrillation persisted. We added azathioprine (50 mg/day) as a glucocorticoid-sparing agent, and PSL was gradually tapered (Figure 3).

Figure 3. Clinical course of a present case.

CK, BNP, and EF improved after high-dose PSL initiation. Her disease status remained stable one year after the treatment initiation.

Abbreviations: AZP, azathioprine; EF, ejection fraction; IGU, iguratimod; PSL, prednisolone; TCZ, tocilizumab.

3. Discussion

We presented a case of AMA-positive myocarditis that emerged during rheumatoid arthritis treatment with TCZ and low-dose PSL, successfully managed with high-dose PSL therapy. With no established consensus on myocarditis treatment in AMA-positive myopathy, our case emphasizes the need for intensive immunosuppressive therapy to stabilize this condition.

AMA-positive myopathy is reported to occur in 2.5–10% of IIM, and is characterized by chronic disease course, muscle atrophy, and cardiac involvement [1,2,7]. Notably, Uenaka et al. reported that among patients with AMA-positive myopathy, limb muscle involvement is rare, and 50% of them present with cardiac symptoms as the first symptom [2]. Our patient was diagnosed with AMA-positive myopathy after the new onset of heart failure. Considering the polyarthritis and positivity of RF and anti-CCP antibody in this case, the diagnosis of RA was valid with a retrospective view. However, it is important to note that the elevation in CK levels was already observed at the time of RA diagnosis, before the onset of acute heart failure (Figure 3). Additionally, Zhang et al. reported that 69% of patients with AMA-positive myopathy took more than three months to develop overt clinical symptoms [7], and the presence of muscle atrophy indicates chronic progression of the disease, as Maeda et al. reported no muscle atrophy in patients with acute onset [1]. Hence, even though the precise onset of the disease in our case is not easily identifiable, we suspect that she already had AMA-positive myopathy when RA treatment began, and myocarditis became overt as the onset of her dyspnea. This implies that the use of low-dose PSL and TCZ for RA was insufficient in managing or preventing the disease progression of AMA-positive myopathy.

There is currently no unanimous agreement on how to treat AMA-positive myopathy and myocarditis. The effectiveness of PSL therapy for AMA-positive myocarditis has been a subject of debate in various case studies [1,3,8]. However, these reports lack specific details on PSL dosage, and the variability of clinical course may have been influenced by differences in the prescribed PSL doses. In a study by Bujo et al. they compared the treatment outcomes of AMA-positive myocarditis patients with and without a reduction in LVEF [4]. The study included three patient groups: those without any immunosuppressive therapy, those treated with PSL alone (at doses ranging from 0.5 to 1 mg/kg), and those receiving additional immunosuppressive agents like methotrexate, azathioprine, mycophenolate mofetil, or tacrolimus alongside PSL. While patients without any immunosuppressive therapy experienced a decline in LVEF, the majority in the latter two groups did not, and none of the patients in the additional immunosuppressive group showed a reduction in LVEF. The researchers suggested that intensive immunosuppression is crucial for treating AMA-positive myocarditis. In alignment with their findings, our case required a more aggressive approach to immunosuppressive therapy with high-dose PSL rather than the combination of low-dose PSL and TCZ.

As an additional immunosuppressive therapy, there are no reports on the efficacy of biologic therapy in cases of myocarditis complicated by IIM. Our case suggests the insufficiency of TCZ with low-dose PSL to prevent the development of AMA-positive myocarditis. However, considering the reported role of IL-6 in myocarditis [9], and the findings by Sizhao et al. demonstrating the efficacy of TCZ in immune-mediated necrotizing myopathies [10], TCZ may be effective for remission induction when used in conjunction with high-dose PSL or for remission maintenance. To establish a treatment strategy, we need accumulation of cases.

In conclusion, we encountered a case of AMA-positive myocarditis that arose during TCZ and low-dose PSL therapy, effectively addressed with high-dose PSL. Our findings highlight the essential role of intensive immunosuppressive therapy, emphasizing the superiority of high-dose PSL over the combination of low-dose PSL and TCZ in stabilizing this condition.

Patient consent

Written informed consent for publication of this report was obtained from the patient.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

None declared.