Journal of Clinical Medicine Case Report Heart–Lung–Muscle Anti-SAE Syndrome: An Atypical Severe Combination Elisabet Zamora 1,2,3, *, Elena Seder-Colomina 1 , Susana Holgado 4 , Bibiana Quirant-Sanchez 5,6 , José Luis Mate 7 , Eva M. Martínez-Cáceres 5,6 , Ivette Casafont 4 and Antoni Bayés-Genís 1,2,3 1 Cardiology Department, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain; elena.seder@gmail.com (E.S.-C.); abayesgenis@gmail.com (A.B.-G.) 2 Departament de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain 3 CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain 4 Rheumatology Department, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain; susholgado@gmail.com (S.H.); ivette.casafont@gmail.com (I.C.) 5 Immunology Department, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain; bquirant@gmail.com (B.Q.-S.); evmcaceres@gmail.com (E.M.M.-C.) 6 Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain 7 Pathology Department, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain; jlmate.germanstrias@gencat.cat * Correspondence: e.zamora@telefonica.net; Tel.: +34-934-978-915  Received: 23 November 2018; Accepted: 21 December 2018; Published: 23 December 2018  Abstract: A 78-year-old man with 3 months of progressive dyspnea, dysphony, dysgeusia, and proximal muscle weakness was diagnosed of probably idiopathic inflammatory myopathy with nonspecific interstitial pneumonia. Variable degrees of atrioventricular block and persistently elevated cardiac enzymes indicated a diagnosis of myocarditis, confirmed with cardiac magnetic resonance imaging and endomyocardial biopsy. A comprehensive immune work-up revealed anti-small ubiquitin-like modifier-1 activating enzyme (anti-SAE) antibody, a novel myositis-specific antibody, previously described mainly with overt cutaneous dermatomyositis and late skeletal muscle manifestations. Here, heart–lung–muscle involvement combined with anti-SAE antibodies was a severe combination. Keywords: myocarditis; idiopathic inflammatory myopathy; anti-SAE antibody 1. Case Report A 78-year-old man with a previous history of hypertension presented with progressive dyspnea, unexpected weight loss, Raynaud phenomenon, muscle weakness, dysphony, dysgeusia, and right hemifacial hypoesthesia, which had persisted for 3 months. A physical examination revealed bi-basal fine crackles and bilateral proximal muscle weakness in the upper and lower extremities. A dermatological examination revealed no cutaneous abnormalities. An electrocardiogram showed low voltages, sinus rhythm, first degree atrioventricular block, and QS-wave morphology in the anterior precordial leads. Bilateral interstitial infiltrates were found in the chest X-ray, and biochemical tests showed elevations in C-reactive protein (76 mg/L) and skeletal muscle and cardiac enzymes (creatine kinase: 1942 U/L, creatine kinase–muscle/brain: 50 ng/mL, and hs-troponin I: 31,125 pg/mL). The patient was admitted. An electromyogram showed signs of chronic radiculopathy L4–L5–S1 without acute axonal damage and primary affectation of muscular fiber in inferior extremities (fibrillation and positive waves in right psoas). During voluntary contraction, we observed many small polyphase complexes with an early recruitment pattern. The vastus lateralis and medial right J. Clin. Med. 2019, 8, 20; doi:10.3390/jcm8010020 www.mdpi.com/journal/jcm J. Clin. Med. 2019, 8, 20 2 of 6 J. Clin. Med. 2018, 7, x FOR PEER REVIEW 2 of 6 gastrocnemius showed showed complex a big polyphasic a big polyphasic complexpattern with a reduced with a without reduced spontaneous pattern without spontaneous activity. activity. The deltoid The deltoid and right biceps muscles had an interferential pattern without spontaneous and right biceps muscles had an interferential pattern without spontaneous activity. Capillaroscopy activity. Capillaroscopy showed a reduced showed number aofreduced number capillaries of capillaries and avascular areas,and andavascular areas, and central nervous central system nervous magnetic system magnetic resonance imaging (MRI) results were unremarkable. Thoracoabdominal resonance imaging (MRI) results were unremarkable. Thoracoabdominal computed tomography computed tomography (CT) (CT) revealed revealed nonspecific nonspecific interstitial interstitial pneumonia pneumoniapositron-emission and whole-body and whole-bodytomography/CT positron-emission tomography/CT revealed revealed diffuse myocardial diffuse uptake. myocardial A cardiac uptake. mild MRI revealed A cardiac systolic MRI revealeddysfunction, biventricular mild systolic biventricular dysfunction, inferoseptal hypokinesia, biatrial dilatation, diffuse edema, inferoseptal hypokinesia, biatrial dilatation, diffuse edema, and fibrosis in the atrial walls and and fibrosis right in the atrial ventricle. walls These and right features ventricle. fulfilled These the Lake features Louise fulfilled criteria the Lake Louise for myocarditis (Figurecriteria 1). for myocarditis (Figure 1). Figure 1. Cardiac magnetic resonance imaging (MRI). Diffuse myocardial edema in T2-weighted edema Figure 1. Cardiac images magnetic (SA, short axis; LA,resonance long axis;imaging 3C, three(MRI). Diffuse chamber; myocardial 4C, four edema in T2-weighted chamber). edema images (SA, short axis; LA, long axis; 3C, three chamber; 4C, four chamber). Coronary CT angiography ruled out coronary artery disease. An endomyocardial biopsy (EMB) was performed and showed Dallas Coronary CT angiography criteria ruled out for myocarditis, coronary withAn artery disease. lymphocytic myocardial endomyocardial biopsyinfiltration (EMB) wasand moderateand performed fibrosis showed(Figure 2A–C); Dallas microbiological criteria tests for myocarditis, were with negative. myocardial infiltration lymphocytic and moderate fibrosis (Figure 2A–C); microbiological tests were negative. J. Clin. Med. 2018, 7, x FOR PEER REVIEW 3 of 6 J. Clin. Med. 2019, 8, 20 3 of 6 Figure 2. Endomyocardial biopsy. (A) Moderate fibrosis. Hematoxylin and eosin staining. (B) Lymphocyte myocardial infiltration. Immunohistochemical staining shows positive staining for CD3 (brown), which confirms the T-cell phenotype. (C) Macrophage myocardial infiltration. Immunohistochemical staining Figure 2. Endomyocardial biopsy. (A) Moderate fibrosis. Hematoxylin and eosin staining. (B) shows positive staining for CD68 (brown). Lymphocyte myocardial infiltration. Immunohistochemical staining shows positive staining for CD3 (brown), which confirms A comprehensive the T-cellstudy immunology phenotype. revealed(C)a high Macrophage myocardial antibodies titer of antinuclear infiltration. (1/640), Immunohistochemical staining shows positive staining for CD68 (brown). and indirect immunofluorescence showed a nucleoplasm with a speckled pattern. Antinuclear antibodies (ANA) were detected by indirect immunofluorescence (IFL) using ready-made slides A comprehensive immunology study revealed a high titer of antinuclear antibodies (1/640), and from commercial sources of fixed HEp-2 cells (Nova Lite range of reagents, Inova Diagnostics). indirect immunofluorescence showed a nucleoplasm with a speckled pattern. Antinuclear antibodies The study of autoantibodies related to the ANA pattern found was performed using a monospecific (ANA) were detected by indirect immunofluorescence (IFL) using ready-made slides from assay by inmunoblot (Euroline range of reagents, Euroimmun) in the patient’s serum being negative commercial sources of fixed HEp-2 cells (Nova Lite range of reagents, Inova Diagnostics). The study for Ro60, Ro52, La, RNP, and Sm. Nevertheless, given a high suspicion of autoimmune disease, of autoantibodies related to the ANA pattern found was performed using a monospecific assay by the immunological study was extended to autoantibodies associated with scleroderma, such as: inmunoblot (Euroline range of reagents, Euroimmun) in the patient’s serum being negative for Ro60, Scl70, PM-Scl75, PMScl100, Th/To, RNA pol III, CENP B, CENP A, fibrillarin, and Ku, using a Ro52, La, RNP, and Sm. Nevertheless, given a high suspicion of autoimmune disease, the monospecific assay by immunoblot (Euroline range of reagents, Euroimmun); being all negative. immunological study was extended to autoantibodies associated with scleroderma, such as: Scl70, For the association of interstitial lung disease (ILD) and positive ANA pattern, we analyzed PM-Scl75, PMScl100, Th/To, RNA pol III, CENP B, CENP A, fibrillarin, and Ku, using a monospecific myositis-specific autoantibodies (MSA) specificities: Mi-2, MDA-5, TIF1-gamma, NXP and SAE-1, assay by immunoblot (Euroline range of reagents, Euroimmun); being all negative. For the and SAE-2, the latter being positive for SAE1/SAE2, suggestive of a systemic autoimmune disease, association of interstitial lung disease (ILD) and positive ANA pattern, we analyzed myositis-specific probably inflammatory myopathy (IMM). Anti-SAE antibodies were determined using a monospecific autoantibodies (MSA) specificities: Mi-2, MDA-5, TIF1-gamma, NXP and SAE-1, and SAE-2, the latter assay by dot blot for the detection in human sera of IgG autoantibodies (Myositis12 SAE IgG, D-Tek). being positive for SAE1/SAE2, suggestive of a systemic autoimmune disease, probably inflammatory Human leukocyte antigen (HLA) genotyping revealed the presence of the HLA-DQB1*03:02 allele myopathy (IMM). Anti-SAE antibodies were determined using a monospecific assay by dot blot for (measured with a real-time polymerase chain reaction assay [GenVitSet, BDR]). the detection in human sera of IgG autoantibodies (Myositis12 SAE IgG, D-Tek). Treatment was initiated with pulse-dose corticosteroid therapy for 3 days, followed by a second Human leukocyte antigen (HLA) genotyping revealed the presence of the HLA-DQB1*03:02 line immunosuppressive therapy with intravenous cyclophosphamide (900 mg), which failed to slow allele (measured with a real-time polymerase chain reaction assay [GenVitSet, BDR]). disease progression. Indeed, cardiac involvement symptoms prevailed in the form of variable types Treatment was initiated with pulse-dose corticosteroid therapy for 3 days, followed by a second of arrhythmia, including atypical atrial flutter, alternating with atrial fibrillation, and second- and line immunosuppressive therapy with intravenous cyclophosphamide (900 mg), which failed to slow third-degree atrioventricular block, with an intermittent left bundle branch block; moreover, cardiac disease progression. Indeed, cardiac involvement symptoms prevailed in the form of variable types enzymes remained persistently high. Third- and fourth-line therapies with immunoglobulins and of arrhythmia, including atypical atrial flutter, alternating with atrial fibrillation, and second- and rituximab (500mg) were started, respectively. On day 28 after admission, the patient evolved with third-degree atrioventricular block, with an intermittent left bundle branch block; moreover, cardiac progressive breathlessness, due to progression of the interstitial infiltrate and heart failure. He required enzymes remained persistently high. Third- and fourth-line therapies with immunoglobulins and intubation but remained hypoxemic, despite mechanical ventilation, and died on day 30. The necropsy J. Clin. Med. 2018, 7, x FOR PEER REVIEW 4 of 6 rituximab (500mg) were started, respectively. On day 28 after admission, the patient evolved with J. Clin. Med. 2019, 8, 20 4 of 6 progressive breathlessness, due to progression of the interstitial infiltrate and heart failure. He required intubation but remained hypoxemic, despite mechanical ventilation, and died on day 30. The necropsy pointed to acutepointed to acute respiratory respiratory distress syndromedistress syndrome (ARDS) (ARDS) cause as the primary as theofprimary cause death. It also of death. revealed It also vast revealedfibrosis, pulmonary vast pulmonary fibrosis, consistent with consistent an evolved, with aninterstitial nonspecific evolved,pneumonia nonspecificandinterstitial areas of pneumonia diffuse and damage, alveolar areas of with diffuse alveolar edema and damage, withrelated hemorrhage edematoandARDShemorrhage (Figure 3),related to ARDS confirming the (Figure 3),ofconfirming diagnosis the diagnosis rapidly progressive of rapidly interstitial lungprogressive interstitial disease (RP-ILD). lung diseasethoracic The authorized (RP-ILD). The limited authorized necropsy thoracic revealed thelimited indemnitynecropsy revealed the of the intercostal indemnity muscular of Cardiac tissue. the intercostal histologymuscular tissue. showed diffuse Cardiac histology myocarditis showed and large diffuse fibrotic myocarditis and large fibrotic areas. areas. Figure Figure 3.3. Necropsy. Necropsy. Pulmonary Pulmonary tissue. tissue. Nonspecific Nonspecific interstitial interstitial pneumonia pneumonia consistent consistent with with evolved evolved interstitial interstitial fibrosis fibrosis(arrow) combined (arrow) with areas combined with ofareas diffuseofalveolar diffusedamage (arrowhead). alveolar Hematoxylin damage (arrowhead). and eosin staining. Hematoxylin and eosin staining. 2. Discussion 2. Discussion Idiopathic inflammatory myopathy is a heterogeneous group of immune mediated disorders. Idiopathic inflammatory myopathy is a heterogeneous group of immune mediated disorders. They are defined as chronic inflammatory muscle diseases characterized by muscle weakness and They are defined as chronic inflammatory muscle diseases characterized by muscle weakness and frequent extramuscular involvement [1]. The diagnosis of the different subtypes of IIM is given by the frequent extramuscular involvement [1]. The diagnosis of the different subtypes of IIM is given by combination of clinical history, pattern of muscle involvement, and immunological profile. the combination of clinical history, pattern of muscle involvement, and immunological profile. Over the last decade, several myositis-specific antibodies have been described, including Over the last decade, several myositis-specific antibodies have been described, including anti- anti-SAE antibodies. The small ubiquitin-like modifier is a small protein, structurally similar to SAE antibodies. The small ubiquitin-like modifier is a small protein, structurally similar to ubiquitin, ubiquitin, involved in post-translational protein modifications. It is involved in several cell processes, involved in post-translational protein modifications. It is involved in several cell processes, including including gene transcription and genome stability [2]. Anti-SAE antibodies were first described gene transcription and genome stability [2]. Anti-SAE antibodies were first described by Betteridge by Betteridge et al. [3] in 2007 and since then, they have been identified in some IIM cohorts [4]. et al. [3] in 2007 and since then, they have been identified in some IIM cohorts [4]. In one of those In one of those cohorts [5], a human leukocyte antigen (HLA) profile showed that all patients with cohorts [5], a human leukocyte antigen (HLA) profile showed that all patients with anti-SAE anti-SAE antibodies had at least one copy of HLA-DQB1*03. The patient presented here also carried antibodies had at least one copy of HLA-DQB1*03. The patient presented here also carried the HLA- the HLA-DQB1*03 gene. DQB1*03 gene. To date, anti-SAE antibodies have only been associated with dermatomyositis (DM), with a To date, anti-SAE antibodies have only been associated with dermatomyositis (DM), with a frequency range of 1%–10% [4]. Although data are scarce and heterogeneous, patients with anti-SAE frequency range of 1%–10% [4]. Although data are scarce and heterogeneous, patients with anti-SAE antibodies have a clinical phenotype defined by prominent and often severe dermatological lesions, antibodies have a clinical phenotype defined by prominent and often severe dermatological lesions, mild muscular symptoms, and infrequently, interstitial lung disease (ILD) and dysphagia [4]. mild muscular symptoms, and infrequently, interstitial lung disease (ILD) and dysphagia [4]. Extramuscular symptoms have consistently been reported to be mild and nonfatal; thus, the anti-SAE Extramuscular symptoms have consistently been reported to be mild and nonfatal; thus, the anti-SAE syndrome was considered to have a benign course and prognosis. To our knowledge, the present syndrome was considered to have a benign course and prognosis. To our knowledge, the present study was the first to describe a case of anti-SAE probable IIM without dermatological manifestations, but with fatal RP-ILD and myocarditis. J. Clin. Med. 2019, 8, 20 5 of 6 RP-ILD is more frequently associated with amyopathic dermatomyositis, an atypical form of DM without muscular symptoms [6]. Patients with RP-ILD responded poorly to even aggressive treatment and have shown a high mortality rate. A less-studied, but critical extramuscular condition is IIM-associated cardiomyopathy. In IIMs, cardiac involvement is typically subclinical, and it can include myocarditis, rhythm disturbances, and congestive heart failure. The prevalence is difficult to estimate, due to the wide range of clinical manifestations and the lack of a systematic cardiac assessment at diagnosis. When myocarditis is suspected, a cardiac MRI is currently the main diagnostic tool [7], as highlighted by the International Consensus Group on Cardiac MR in Rheumatology [8]. A small prospective study found 55% of cardiac MRI-proven myocarditis in patients with IIM at diagnosis [9]. A complementary tool, the EMB, allows tissue microbiological testing and characterization of the inflammatory response [10]. A recent literature review found myocarditis in 38% of IIM pathology reports [11]. The clinical course and severity of IIM-related myocarditis are not well established. Our case is an example of how early, mild cardiac manifestations may lead to diffuse, persistent overt myocarditis (including arrhythmias and heart failure). To our knowledge, no previous reports have described anti-SAE antibodies associated with cardiac involvement. Indeed, the fatal outcome we observed has raised concern regarding the risk of this IIM subset, which was previously considered benign. Taking these data into account, we suggest including heart and lung work-ups in all patients with a diagnosis of IIM, regardless of the immunologic profile. 3. Conclusions To date, the presence of the anti-SAE antibody has been mainly reported as an indication of DM with mild extramuscular involvement. Here, we described a case of an anti-SAE unrelated to DM, with fatal RP-ILD, and biopsy-proven myocarditis. Further research is needed to fully understand the anti-SAE syndrome and its unpredictable outcome. This clinical case report fulfills the Spanish Protection of Personal Data Law (15/1999). Witnessed oral consent by the patient and their family were obtained. Author Contributions: E.Z., E.S.-C., A.B.-G.—collection and interpretation of data, first draft; S.H., I.C.— rheumatology data; critical review of the manuscript; B.Q.-S., E.M.M.-C.—immunology data; critical review of the manuscript; J.L.M.—pathology data; critical review of the manuscript. Funding: A.B.-G. was supported by grants from CIBER Cardiovascular (CB16/11/00403). Acknowledgments: None. Conflicts of Interest: The authors declare no conflict of interest. Abbreviations IIM idiopathic inflammatory myopathy ILD interstitial lung disease SAE small ubiquitin-like modifier-1 activating enzyme References 1. Lundberg, I.E. The heart in dermatomyositis and polymyositis. Rheumatology 2006, 45, 18–21. [CrossRef] [PubMed] 2. Tarricone, E.; Ghirardello, A.; Rampudda, M.; Bassi, N.; Punzi, L.; Doria, A. 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