Medical Resident University of Saskatchewan College of Medicine - - Saskatoon, SK Saskatoon, Saskatchewan, Canada
Case background: Autoimmune polyglandular syndromes (APS) are a group of rare autoimmune diseases that primarily affect the endocrine system. Three major subtypes have been identified based on pattern of disease: APS1, APS2, and APS3. APS1 is characterized by hypoparathyroidism, primary adrenal insufficiency, and chronic mucocutaneous candidiasis, with a global prevalence of less than 1 in 80,000 people [1,2]. This primary immunodeficiency (PID) is inherited in an autosomal recessive pattern [1]. Here, we present the first case in Saskatchewan, Canada of an individual with APS1 presenting with fulminant myocarditis and myositis.
Management Challenges: A patient in their early 30s with a history of autoimmune polyendocrine syndrome type 1 (APS1), autoimmune retinopathy, dyslipidemia, and asthma presented to a local hospital with a 2-day history of diffuse myalgias, arthralgias, and diarrhea. The patient denied chest pain. On admission, vital signs were notable for tachycardia (HR 113), tachypnea (RR 30), hypotension (BP 88/46 mmHg), and an oxygen saturation of 96% on 4L via nasal prongs. Temperature was 37.7°C. Empiric treatment with ceftriaxone was initiated for presumed bacterial infection.
Within hours, the patient developed acute shortness of breath and a diffuse blanching erythematous rash. Chest X-ray revealed pulmonary edema, prompting treatment for decompensated heart failure and transfer to the cardiac critical care unit (CCU).
Initial labs showed leukocytosis (WBC 11.5 x10⁹/L) with marked lymphopenia (0.21 x10⁹/L). Cardiac biomarkers were significantly elevated: troponins at 515 ng/L, creatinine kinase at 2917 U/L, and NT-proBNP at 25,800 ng/L. Inflammatory markers were also high, with C-reactive protein >300 mg/L. Chest X-ray confirmed diffuse pulmonary edema. Electrocardiogram showed sinus tachycardia (HR 109) without ischemic changes. Transthoracic echocardiogram demonstrated an ejection fraction of 35%, moderate global hypokinesis, and biventricular systolic dysfunction with a moderate-sized pericardial effusion, but no signs of tamponade. Cardiac MRI revealed severe LV global hypokinesis, sub-epicardial delayed enhancement in the lateral mid-LV wall, and moderate RV hypokinesis—findings consistent with acute myocarditis (Fig 1).
Given the concurrent myocarditis and myositis picture, further investigation into the etiology was undertaken. Extensive autoimmune and infectious workup—including myositis panel, ENA, anti-Scl 70, vasculitis panel, anti-histone antibodies, cryoglobulins, SSA/SSB, ds-DNA, anti-Smith, ANA, anti-CCP, anti-centromere antibodies, complements, HIV, syphilis, and viral serologies—were all negative.
Endocrine investigations revealed normal TSH (3.87 mIU/L), free T4 (16.8 pmol/L), and cortisol (358 nmol/L), but low PTH (0.64 pmol/L) and low ionized calcium (0.81 mmol/L), consistent with hypoparathyroidism from APS1.
Before CCU transfer, the patient received IV methylprednisolone 250 mg and furosemide 60 mg. Empiric coverage with vancomycin and gentamicin was initiated for possible infectious myocarditis/myositis. Norepinephrine infusion was started for hemodynamic support. As infectious etiology was ruled out, antibiotics were discontinued, and a viral etiology was favored. The patient’s condition improved gradually.
By discharge, a repeat echocardiogram showed normalization of cardiac function with LVEF at 62%, normal biventricular size and function, and no valvular disease. The patient was discharged on metoprolol 25 mg BID and colchicine 0.3 mg daily for three months to treat pericarditis. Follow-up was arranged for three months post-discharge.
This case represents an rare presentation of myocarditis and myositis in a patient with APS1. APS1 is a rare autosomal recessive disorder caused by mutations in the AIRE gene, leading to impaired negative selection of self-reactive T-cells and resulting in systemic autoimmunity [1].
Although the myocardium lacks a structured reticuloendothelial system, it possesses its own immune defense mechanisms that can paradoxically result in autoimmune injury during inflammatory or infectious processes [3]. The pathogenesis of myocarditis in autoimmune conditions remains incompletely understood. Belkaya et al. suggested that silent genetic defects may predispose individuals to acute myocarditis in the context of viral infections [3,4]. Additionally, inherited primary immunodeficiencies (PIDs) like APS1 may confer increased susceptibility to infections known to trigger myocarditis [3,5].
In this patient, despite the extensive negative serologic and autoimmune testing, the constellation of symptoms—including rash, myalgias, and weakness following a diarrheal prodrome—was most consistent with a viral myositis and myocarditis. Although a definitive etiology was not confirmed (no biopsy was performed), the temporal association with a likely viral gastroenteritis suggests a viral trigger. However, an autoimmune mechanism may have contributed as well, particularly given the known immune dysregulation in APS1.
There are reports of myocarditis in patients with immunodeficiencies and autoimmune overlap syndromes. Duda-Seiman et al. reported COVID-19–associated myocarditis and myositis in a patient with anti-synthetase syndrome, an autoimmune condition similar to APS1 [6]. Schuman et al. described idiopathic giant cell myocarditis in a patient with APS1 [7].
The precise mechanism remains elusive. It is postulated that the autoimmune inflammation in APS1 may be driven by persistent interferon-γ (IFN-γ) signaling. Oikonomou et al. found that APS1 is characterized by robust multiorgan IFN-γ responses, and that blockade with JAK inhibitors led to remission in several patients [8]. IFN-γ has also been implicated in cardiac injury—experimental models show that IFN-γ can contribute to myocyte atrophy by reducing myosin heavy chain protein in chronic inflammation [9].
In murine models of viral myocarditis, IFN-γ has been shown to impair cardiac function in the acute phase but paradoxically protect against fibrosis in chronic disease by inhibiting mast cell degranulation and reducing profibrotic cytokines [10,11]. These divergent effects suggest that the timing, context, and underlying immune state all influence the role of IFN-γ in myocarditis.
In our case, chronic immune activation due to APS1 may have created a pro-inflammatory state that predisposed the myocardium to injury, either through a dysregulated immune response to a viral trigger or through direct autoimmune-mediated inflammation. Though rare, this case aligns with the growing recognition of myocarditis as a manifestation of immune dysregulation in PIDs.
Learning Points:
Physicians should consider an underlying PID in patients presenting with myocarditis, especially if it is recurrent
Interferon-γ, a pro-inflammatory mediator, is implicated in the pathogenesis of myocarditis in patients with APS1 and other chronic inflammatory states.
APS1 may represent an “interferon-gammopathy” .
There is heterogeneity in how myocarditis manifests itself in different types of PID with a commonality of increased susceptibility to infections and inflammation
Emerging therapies such as JAK inhibition (e.g., ruxolitinib) may offer benefit in modulating IFN-γ-mediated damage and warrant further exploration.
