Elevated Liver Enzymes: Unusual Presentation of Anti-MDA5 Antibody Associated Juvenile Dermatomyositis

Abstract

Anti-melanoma differentiation-associated gene 5 antibody positive juvenile dermatomyositis (Anti-MDA5 JDM) is a subtype of JDM characterized by cutaneous ulcerations, arthritis, weight loss and progressive interstitial lung disease that can lead to significant morbidity and mortality, often warranting early aggressive treatment. It can present without the classical features of JDM (proximal muscle weakness, heliotrope rash and Gottron’s papules), making diagnosis challenging. We describe a 4-year-old male with Anti-MDA5 JDM who presented with significantly elevated liver enzymes, arthralgia, ecchymotic macules, oral ulcers, and intermittent fevers without significant muscle weakness whose unusual presentation delayed his diagnosis and treatment. He underwent extensive work-up for differential diagnoses including multisystemic inflammatory syndrome in children, non-accidental trauma, and autoimmune hepatitis. His liver biopsy showed extensive hepatocyte swelling and focal hepatocyte cholestasis which has been described in Anti-MDA5 dermatomyositis in adults. His ecchymotic macules progressed to ulcers, and skin biopsy showed perivascular and periadnexal dermatitis with increased mucin deposits, seen in autoimmune connective tissue diseases. He eventually developed arthritis, and mild muscle weakness in bilateral shoulders. Right deltoid muscle biopsy showed atrophic and degenerative myofibers and inflammation consistent with immune-mediated myopathy. His myositis-specific autoantibody profile came back positive for Anti-MDA5, enabling the specific diagnosis of Anti-MDA5 JDM. This case illustrates that definitive diagnosis of Anti-MDA5 JDM can be challenging due to unusual presentations such as elevated liver enzymes and illustrates the importance of further studies to understand the different clinical manifestations of Anti-MDA5 JDM.

Introduction

Juvenile Dermatomyositis (JDM) is the most common type of juvenile idiopathic inflammatory myopathies (JIIM). Common manifestations of JDM include proximal muscle weakness, heliotrope rash and Gottron’s papules. Anti-MDA5 JDM patients composed about 7–13% of JDM patients in North America and Europe, and present with more non-typical manifestations such as cutaneous ulcerations, arthritis, weight loss and rapidly progressive interstitial lung disease that is associated with high morbidity and mortality (1–2). It is important to be aware of different features of Anti-MDA5 JDM and have a high index of suspicion to make the diagnosis in a timely manner. We report a case of Anti-MDA5 JDM with initial manifestations of elevated liver enzymes, amyopathy, ecchymotic macules, and oral ulcers, whose diagnosis was delayed due to this unusual presentation.

Clinical vignette

A 4-year-old male presented with chronic abdominal pain, joint pain, bruises, oral ulcers, fatigue, and intermittent fevers with history of recent COVID-19 infection. His Anti-SARS-CoV-2 IgG Antibody level was high (9.5) without vaccination. Echocardiogram and cardiac enzymes (troponin and b-type natriuretic peptide (BNP)) were obtained with a concern for multisystemic inflammatory syndrome in children, which came back with normal results (troponin 0.012ng/mL and BNP 40pg/mL). With ecchymotic lesions on knees, shins, bilateral pinna and left temporal area of the face (Figure 1), the child abuse team was involved, and non-accidental trauma was ruled out. Interferon-induced antinuclear antibody was positive (titer 1:160) with borderline double stranded DNA antibody (56.60IU/mL). He was found to have elevated Aspartate Aminotransferase (AST 1,497 Units/L), Alanine Transaminase (ALT 309 Units/L), Gamma-glutamyl Transferase (GGT 429 Units/L), and total bilirubin (3.93mg/dL). Abdominal ultrasound showed hepatomegaly. His cholestasis continued to worsen (total bilirubin 6.06mg/dL) with rising AST (2,075 Units/L), which led to a liver biopsy. The biopsy showed nonspecific extensive hepatocyte swelling and focal hepatocyte cholestasis. Magnetic resonance cholangiopancreatography did not demonstrate an etiology of the elevated liver enzymes. With no clear diagnosis to explain his liver injury, ursodiol 20mg/kg/day, prednisone 2mg/kg/day, and azathioprine 20mg/day were started with a presumed diagnosis of autoimmune hepatitis. However, the cholestasis did not resolve despite the treatment. Two months after initial presentation, he was readmitted with fevers, worsening weight loss, difficulty breathing, significant bilateral arm weakness, arthritis on bilateral elbows and ulcerating lesions. Magnetic Resonance Imaging (MRI) of bilateral shoulders showed edema and inflammation in the bilateral rotator cuff and deltoid with confluent edema and inflammation within the soft tissues, suggestive of dermatomyositis. Right deltoid muscle biopsy was obtained and showed scattered atrophic and degenerative myofibers, CD4-T-lymphocyte predominant inflammation, increased expression of MHC Class I molecules, and capillaries with endothelial swelling, consistent with an immune-mediated myopathy (Figure 2). Dermatology obtained a skin biopsy of the hyperpigmented lesion which showed perivascular and periadnexal dermatitis with increased dermal mucin deposits concerning for a connective tissue disorder. Computed tomography (CT) of chest showed scattered peripheral tree-in-bud nodular opacities and symmetric intralobular septal thickening involving the inferior aspects of lower lobes (Figure 3), concerning for interstitial lung disease (ILD). Myositis-specific autoantibody profile from Oklahoma Medical Research Foundation was resulted after 7 weeks of processing and was positive for Anti-melanoma differentiation-associated gene 5 antibody, enabling a formal diagnosis of Anti-MDA5 Antibody JDM.

Figure 1.

Initial mucocutaneous features of the patient. A. Violaceous and ecchymotic thin papules and macules on helix. B. Circular erosion on lower mucosal lip and tip of tongue. C-D. Violaceous and ecchymotic thin papules and patches on right arm and bilateral lower extremities.

Figure 2.

CT Chest with Contrast of the patient. Scattered peripheral tree-in-bud nodular opacities and symmetric intralobular septal thickening involving the inferior aspects of lower lobes.

Figure 3.

Deltoid muscle biopsy findings of the patient. A-B. Biopsy showed skeletal muscle with numerous atrophic fibers and perifascicular atrophy. (A; 20x magnification; B; 60x magnification) C. Increased membranous staining was seen with immunohistochemistry for MHC Class I with accentuation of atrophic perifascicular muscle fibers. D. A focus of perivascular lymphocytic inflammation was noted. E. Immunohistochemistry for CD4 highlights a predominance of CD4 positive T-lymphocytes. F. Immunohistochemistry for CD20 highlights positive B-lymphocytes. G-H. Fiber type-specific immunohistochemistry highlights scattered Type II muscle fibers and accentuates perifascicular atrophy (G), while type I myofibers predominate in number (H). I. Electron microscopy examination showed a perimysial capillary with endothelial cell hyperplasia.

Discussion

Anti-MDA5 JDM is a distinct subgroup of JDM that is differentiated by its atypical presentation of cutaneous ulcerations, arthritis, weight loss, decreased muscle involvement, and progressive ILD (3). ILD is a commonly reported and defining complication of Anti-MDA5 JDM which can lead to significant morbidity and mortality (1, 2). It is important to diagnose Anti-MDA5 JDM in a prompt manner and start intensive immunomodulating treatment to avoid rapidly progressive ILD (5). This patient’s diagnosis was delayed due to an unusual presentation of hepatitis as a major component of the initial presentation. The elevated liver enzymes and hepatocyte changes were likely secondary to his anti-MDA5 JDM. Liver dysfunction and hepatocyte ballooning on liver biopsy have been described in Anti-MDA5 dermatomyositis and polymyositis in adults (6–7). A Japanese cohort of 115 adult patients with Anti-MDA5 dermatomyositis or polymyositis noted liver dysfunction in 14 of these patients with maximum AST, ALT, and GGT levels of 204 Unit/L, 212 Unit/L, and 47 Unit/L, respectively (7). A North American cohort of 35 patients with Anti-MDA5 associated JDM or juvenile connective tissue disease showed a single case of autoimmune hepatitis (1). A United Kingdom cohort of 21 patients with Anti-MDA5 JDM did not note any hepatic findings (3). To our knowledge, this is the first report of significant liver enzyme elevation as a major component of the initial presentation of Anti-MDA5 JDM.

In addition to liver dysfunction, our patient also presented with unusual hyperpigmented macules which delayed clinical suspicion for JDM until they started to ulcerate. He did not present with muscle weakness or muscle enzyme elevation that is typically expected in JDM patients, which is concordant with prior studies showing that amyopathic myositis and ILD are common in patients with Anti-MDA5 dermatomyositis (4). Our patient’s arthralgia did not progress to arthritis until the time of diagnosis. Arthritis (89%) and arthralgias (88%) were common characteristics of Anti-MDA5 JDM from the North American registry (1). The lack of classical JDM features such as significant myopathy, Gottron’s papules, Heliotrope rash in the setting of Anti-MDA5 JDM makes diagnosis challenging and can result in a delay to definitive treatment. This case illustrates the value of studies such as MRI and muscle biopsy for unusual presentations of JIIM. While CT of the chest is not frequently utilized in the pediatric population due to the concern of radiation exposure, it should be considered for pediatric patients with concerns for Anti-MDA5 JDM given the risk of rapidly progressive ILD (6). Myositis-specific autoantibodies are emerging as a standard of care in evaluation for inflammatory myopathy amongst rheumatologists and, as in this case, are critical to establish the correct diagnosis. However, the myositis-specific antibody testing takes a prolonged period (6–8 weeks) to be resulted (7). Our hope is that identification of additional cases will lead to better understanding of the full spectrum of clinical features of Anti-MDA5 JDM and reach an efficient diagnosis.