International Journal of Rheumatic Diseases 2015; 18: 800–806
APLAR GRAND ROUND CASE
Cardiac arrhythmias as the initial manifestation of adult € gren’s syndrome: a case report and literature primary Sjo review Minrui LIANG,1,2* Liwen BAO,3* Nanqing XIONG,3 Bo JIN,3 Huanchun NI,3 Jinjin ZHANG,3 Hejian ZOU,1,2 Xinping LUO3 and Jian LI3 1
Division of Rheumatology, Huashan Hospital, 2Institute of Rheumatology, Immunology and Allergy, and 3Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, China
Abstract Two middle-aged female patients presenting with heart palpitation and electrocardiogram revealed complex cardiac arrhythmias. A review of systems was positive for dry mouth and transient arthralgia, while laboratory and instrumental tests enabled us to make the diagnosis of primary Sj€ ogren’s syndrome (pSS). Cardiac electrophysiology revealed atrioventricular node dysfunction and impaired intraventricular conduction. Prednisone therapy induced a significant improvement in symptoms and electrocardiographic readings. The diagnosis of pSS should be considered in a patient presenting with complex cardiac arrhythmias. Key words: Sj€ ogren’s syndrome, cardiac arrhythmias, anti-SSA/Ro antibodies, anti-SSB/La antibodies.
INTRODUCTION
CASE REPORT
Primary Sj€ ogren’s syndrome (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands accompanied by a variety of extraglandular manifestations. Female patients with Sj€ ogren’s syndrome and antibodies against SSA/Ro and SSB/La have significant increased risk of giving birth to children with neonatal conduction abnormalities in the heart, especially complete congenital heart block. It is supposed that the conduction system in the adult heart is relatively resistant to injury by anti-SSA and anti-SSB antibodies. Here we report two cases of combined pSS with the predominant initial manifestation of complex cardiac arrhythmias.
Case I
Correspondence: Professor Jian Li, M.D., Department of Cardiology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China. Email: [email protected] *These authors contribute equally.
A 48-year-old woman, with a 3-month history of heart palpitations, was admitted to the cardiology department of Huashan Hospital (Shanghai, China) for further assessment. She had no medical history of hypertension, diabetes, hyperlipidemia or obesity. She was a housewife and never smoked. At presentation, physical examination demonstrated irregular heart rhythms without heart murmur or crackle. Serial 12lead electrocardiography showed frequent premature ventricular contraction (PVC) and intraventricular conductional block (Fig. 1). Chest radiography showed enlarged heart shadow. Echocardiography indicated bilateral atrial enlargement, pericardial effusion of very small size, pulmonary hypertension (pulmonary artery systolic pressure [PASP] was estimated as 49 mmHg), impaired diastolic function of left ventricular and decreased left ventricular ejection fraction (LVEF) of 47%. She was diagnosed with cardiac arrhythmias resulting from PVC and intraventricular conductional
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Arrhythmias as initial exhibition in adult pSS
Figure 1 Serial 12-lead electrocardiography showed frequent premature ventricular contraction (PVC) and intraventricular conductional block.
block. However, there was no history of arrhythmias nor was there any hints that an overdose of medication caused the arrhythmias. Further tests were performed to determine an underlying cause for these findings. By a careful review of systems, positive for dry mouth and transient arthralgia of both elbow joints was found. Laboratory tests showed increased serum troponin T (TnT) of 0.027 ng/mL (normal ≤ 0.014), myoglobin of 97.61 ng/mL (25–58), creatine kinase (CK) of 296 U/L (26–192), lactate dehydrogenase (LDH) of 220 U/L (135–214) and normal serum brain natriuretic peptide (BNP). Furthermore, she had increased erythrocyte sedimentation rate (ESR) of 64 mm/h, hyperimmunglobulinemia (IgG 19.90 g/L [normal 7.51–15.6], IgA 8.11 g/L [0.82–4.53]). The leukocyte count was not raised, with a normal white cell differential and normal serum C-reactive protein (CRP). As the patient’s complaints, physical findings and primary laboratory tests pointed toward a potential autoimmune disease background, several tests were subsequently conducted. She had positive antinuclear antibody (titer, 1 : 1000, HEp-2), positive anti-SSA (Ro-52) antibodies, and positive IgM rheumatoid factor (RF) with negative anti-SSA (Ro-60), SSB, cyclic citrullinated peptide (CCP), Sm, double-stranded DNA (dsDNA), Scl-70, PM-Scl, antine-
International Journal of Rheumatic Diseases 2015; 18: 800–806
utrophil cytoplasmic antibodies (cANCA), perinuclear ANCA antibodies (pANCA) and normal levels of C3 and C4 complement factors. Serum cytomegaovirus (CMV) DNA and Epstein–Barr virus (EBV) DNA detected by real-time reverse transcription – polymerase chain reaction, adenovirus (ADV) IgM/IgG and Coxsachie virus (CSV) IgM/IgG detected by enzyme-linked immunosorbent assay were all negative. Thyroid function was euthyroid. No monoclonal immunoglobulin was found in the serum or urine by immunofixation electrophoresis. Technetium scintigraphy revealed the reduction of radiotracer uptake and intake in glands of both sides. Biopsy of a minor labial gland showed typical lymphocytic infiltrates (Fig. 2a,b). The lymphocytes were positive for T lymphocyte marker CD3 (Fig. 2c) and B lymphocyte marker CD19 (Fig. 2d). No other abnormal laboratory findings were noted. A diagnosis of pSS was confirmed following the positive findings, including hyposalivation, positive salivary scintigraphy, positive anti-SSA/Ro, and histopathological signs (focus score, ≥ 1/4 mm2) according to American College of Rheumatology (ACR) 2012 classification criteria for pSS.1 Based on the diagnostic criteria for myocarditis proposed by the European Society of Cardiology Working
801
M. Liang et al.
(a)
(b)
(c)
(d)
Figure 2 Biopsy of a minor labial gland was collected from this patient and the histopathologic findings are shown. (a) Hematoxylin and eosin (H&E) staining (original magnification 1009); (b) H&E staining (original magnification 4009); (c) immunohistochemical staining for T lymphocyte marker CD3 (original magnification 4009); (d) and B lymphocyte marker CD19 (original magnification 4009); H&E staining for labial gland biopsy showed lymphocyte-rich inflammatory infiltrate, which was positive for CD3 and CD19.
Group in 2012,2 this patient was diagnosed with immune-mediated myocarditis due to pSS. Continuous 24-h Holter captured complex cardiac arrhythmias, including PVC (8472 beats/24 h), premature superventricular contraction (1992 beats/24 h), and complete right bundle branch block. Heart biopsy was not done because the patient did not consent. In order to evaluate the electrophysiological changes in her heart, cardiac electrophysiology was performed. The Hisventricular (HV) interval was 69.44 ms (normal 35–55) (Fig. 3) and the atrioventricular node effective refractory period (AVN-ERP) was 380.56 ms (normal 250– 365) (Fig. 4), which indicated atrioventricular node dysfunction and impaired intraventricular conduction. The patient was treated with prednisone 1.5 mg/kg/ day for 5 days, with improvement in clinical and electrocardiographic readings. Also, the serum troponin T, myoglobin, CK, LDH, IgG and ESR levels returned to normal. After discharge, the patient tapered the dose of
802
prednisone 10% per month; in the meantime, she was also treated with sotalol (80 mg/day). Repeated continuous 24-h Holter 3 months later showed decreased PVC (1068 times/24 h). And repeated echocardiography was also performed with normal results (PASP estimated as 38 mmHg and LVEF of 63%).
Case II A 61-year-old woman with a 4-year history of heart palpitation was admitted to the cardiology department of Huashan Hospital. She did not have hypertension, diabetes, hyperlipidemia or obesity, and she had a negative finding in coronary angiography 4 years ago. The treatment of metoprolol 12.5 mg per day could relieve her symptom to a certain extent. Further 12-lead electrocardiography showed frequent ventricular contraction, intra-atrial conductional block and intraventricular conductional block. In addition, she had elevated BNP of
International Journal of Rheumatic Diseases 2015; 18: 800–806
Arrhythmias as initial exhibition in adult pSS
Figure 3 Cardiac electrophysiology was performed to evaluate the electrophysiological changes in the heart of this patient. The atrial-His (AH) interval was 93.18 ms and HIS-ventricular (HV) interval was 69.44 ms (as indicated by arrows). In our center, the normal range of AH interval is 60–125 ms, HV interval is 35–55 ms.
857.5 pg/mL (normal < 300) and normal TnT. A chest X-ray revealed borderline cardiomegaly. Echocardiography showed impaired systolic function of the left ventricle with the LVEF of 38%. Continuous 24-h Holter captured multifocal PVC (6378 times/24 h), premature superventricular contraction (107 times/24 h) and complete left bundle branch block. Repeated coronary angiography showed tiny plaques in the left anterior descending artery, left circumflex artery and right coronary artery with 30% stenosis. Therefore, this patient was diagnosed with coronary artery atherosclerosis; however, the severity of coronary stenosis could not explain her complex cardiac arrhythmias and cardiac insufficiency. By a careful review of systems, she complained of dry mouth and described a migratory arthralgia lasting for 4 years. In order to reveal the underling etiology, further tests were performed. Results of further investigations were as follows: positive for the anti-SSA (Ro-52) antibody, negative for the
International Journal of Rheumatic Diseases 2015; 18: 800–806
antibodies against SSA (Ro-60), SSB, RF, CCP, Sm, dsDNA, Scl-70, PM-Scl, cANCA, pANCA, and normal levels of IgG, IgM, IgA, C3 and C4 complement factors. Serological tests for viral infection were all negative. Technetium scintigraphy also revealed the reduction of radiotracer uptake and intake in glands of both sides. Biopsy of labial gland showed a typical lymphocytic infiltration. Therefore, this patient was also diagnosed with pSS. Ruling out infection, medication, or coronary heart disease-induced cardiac arrhythmias, clinical findings suggested her complex cardiac arrhythmias and cardiac insufficiency were closely associated with pSS. After starting prednisone therapy 0.5 mg/kg/day and sotalol 80 mg/day, her palpitation and dryness gradually improved. Repeated 24-h Holter 1 month later revealed decreased PVC (703 times/24 h) and premature superventricular contraction (58 times/24 h). Repeated echocardiography showed improved LVEF of 46%.
803
M. Liang et al.
Figure 4 Cardiac electrophysiology was performed to evaluate the electrophysiological changes in the heart of this patient. The atrioventricular node effective refractory period (AVN-ERP) was 380.56 ms (as indicated by arrows). In our center, the normal range of AVN-ERP is 250–365 ms.
Table 1 Summary of cases of cardiac arrhythmias in Sj€ ogren’s syndrome (SS) Country
No. SS cases
Types of cardiac arrhythmias
Anti-SSA/SSB antibodies
References
USA Korea USA Turkey Italy
1 1 1 40 12
SSA (Ro-52 and Ro-60) SSA SSA (Ro-60) and SSB No association SSA
Lee et al.6 Sung et al.7 Baumgart et al.8 Akyel et al.9 Lazzerini et al.10
Italy
16
Complete atrioventricular block Complete atrioventricular block Complete atrioventricular block Atrial electromechanical delay QT interval prolongation Complex ventricular arrhythmias (Lown classes 2–5) QT interval prolongation
SSA (Ro-52)
Lazzerini et al.11
DISCUSSION This case report of two patients illustrates the association of pSS and complex cardiac arrhythmias. To our knowledge, this is the first case report in the literature
804
of pSS patients presenting complex cardiac arrhythmias as their significant initial manifestation. On the other hand, the detailed description of the functions of impulse formation and the conduction system of the heart in adult pSS patients has not been reported. For
International Journal of Rheumatic Diseases 2015; 18: 800–806
Arrhythmias as initial exhibition in adult pSS
the first case, cardiac electrophysiology was performed and showed atrioventricular node dysfunction and impaired intraventricular conduction, which provides additional support for the hypothesis that anti-SSA (Ro52) was associated with conduction defect in adult pSS patients, although the adult conduct system was thought to be relatively resistant to anti-SSA/Ro antibody damage. Also, the treatment of prednisone induced significant symptomatic and laboratory improvement in these two patients. Obvious cardiac arrhythmia is rare in pSS, so their associations and clinical significance are not well defined. Based on this clinical report, pSS with cardiac arrhythmias are summarized here (Table 1). Patients with pSS, compared with health controls, were more likely to have cardiac arrhythmias.3 Also a Sj€ ogren’s syndrome mother with anti-SSA antibodies is associated with congenital heart block in newborns.4 However, anti-SSA autoantibody is believed to be safe from damaging the adult atrioventricular (AV) node.5 Nevertheless, there are some reports of an adult AV block in Sj€ ogren’s syndrome.6–8 Interestingly, the clinical manifestations of cardiac arrhythmias and the associated antibodies in Sj€ ogren’s syndrome remain a debated issue (Table 1). However, the pathological basis of cardiac arrhythmias in pSS is far from clear. It is described an autopsy case following the sudden death of a young female patient with pSS, and the autopsy showed that the stenosis of the lumen in both sinoatrial (SA) node and AV node arteries and lymphocyte infiltration in the bundle of His, which may have led to fatal arrhythmias.12 The role of anti-SSA/SSB autoantibodies in the pathogenesis of heart block needs to be discussed. Maternal sera containing antibodies against SSA and SSB ribonucleoproteins (positive IgG) inhibited L-type Ca current in isolated cardiac myocytes and induced sinus bradycardia in a murine model of congenital heart block (CHB), and further study showed that maternal antibodies interact directly with the pore-forming alpha (1)-subunit of Ca channels.13,14 And rather than a 60kDa anti-Ro antibody, a 52-kDa antibody was a more specific cause of the conduction abnormality.15 On the basis of our observations in these two cases, the significance of cardiac involvement must be interpreted cautiously for patients with pSS in the light of the clinical scenario. Also, the possibility of pSS should be given attention in patients with complex cardiac arrhythmias, and corticosteroid therapy seemed to elicit good response in these patients.
International Journal of Rheumatic Diseases 2015; 18: 800–806
CONFLICTS OF INTEREST The authors have no competing interests to declare.
REFERENCES 1 Shiboski SC, Shiboski CH, Criswell L et al. (2012) American College of Rheumatology classification criteria for Sjogren’s syndrome: a data-driven, expert consensus approach in the Sjogren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 64, 475–87. 2 Caforio AL, Pankuweit S, Arbustini E et al. (2013) Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 34, 2636–48, 48a–48d. 3 Kang JH, Lin HC (2010) Comorbidities in patients with primary Sjogren’s syndrome: a registry-based case-control study. J Rheumatol 37, 1188–94. 4 Lee LA (2005) Transient autoimmunity related to maternal autoantibodies: neonatal lupus. Autoimmun Rev 4, 207–13. 5 Boutjdir M (2000) Molecular and ionic basis of congenital complete heart block. Trends Cardiovasc Med 10, 114–22. 6 Lee LA, Pickrell MB, Reichlin M (1996) Development of complete heart block in an adult patient with Sjogren’s syndrome and anti-Ro/SS-A autoantibodies. Arthritis Rheum 39, 1427–9. 7 Sung MJ, Park SH, Kim SK, Lee YS, Park CY, Choe JY (2011) Complete atrioventricular block in adult Sjogren’s syndrome with anti-Ro autoantibody. Korean J Intern Med 26, 213–5. 8 Baumgart DC, Gerl H, Dorner T (1998) Complete heart block caused by primary Sjogren’s syndrome and hypopituitarism. Ann Rheum Dis 57, 635. 9 Akyel A, Tavil Y, Tufan A et al. (2012) Atrial electromechanical delay and diastolic dysfunction in primary Sjogren syndrome. Clin Invest Med 35, E303. 10 Lazzerini PE, Capecchi PL, Guideri F et al. (2007) Comparison of frequency of complex ventricular arrhythmias in patients with positive versus negative anti-Ro/SSA and connective tissue disease. Am J Cardiol 100, 1029– 34. 11 Lazzerini PE, Capecchi PL, Acampa M et al. (2011) AntiRo/SSA-associated corrected QT interval prolongation in adults: the role of antibody level and specificity. Arthritis Care Res (Hoboken) 63, 1463–70. 12 Inoue H, Kinoshita K, Sugiyama M, Funauchi M, Hanagama M, Nata M (2008) Sudden death from ischaemic heart disease in a female patient with Sjogren syndrome: a case report. Med Sci Law 48, 261–5.
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13 Qu Y, Xiao GQ, Chen L, Boutjdir M (2001) Autoantibodies from mothers of children with congenital heart block downregulate cardiac L-type Ca channels. J Mol Cell Cardiol 33, 1153–63. 14 Xiao GQ, Hu K, Boutjdir M (2001) Direct inhibition of expressed cardiac l- and t-type calcium channels by igg
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from mothers whose children have congenital heart block. Circulation 103 (11), 1599–604. 15 Xiao GQ, Qu Y, Hu K, Boutjdir M (2001) Down-regulation of L-type calcium channel in pups born to 52 kDa SSA/Ro immunized rabbits. FASEB J 15, 1539–45.
International Journal of Rheumatic Diseases 2015; 18: 800–806
APLAR GRAND ROUND CASE
Cardiac arrhythmias as the initial manifestation of adult € gren’s syndrome: a case report and literature primary Sjo review Minrui LIANG,1,2* Liwen BAO,3* Nanqing XIONG,3 Bo JIN,3 Huanchun NI,3 Jinjin ZHANG,3 Hejian ZOU,1,2 Xinping LUO3 and Jian LI3 1
Division of Rheumatology, Huashan Hospital, 2Institute of Rheumatology, Immunology and Allergy, and 3Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, China
Abstract Two middle-aged female patients presenting with heart palpitation and electrocardiogram revealed complex cardiac arrhythmias. A review of systems was positive for dry mouth and transient arthralgia, while laboratory and instrumental tests enabled us to make the diagnosis of primary Sj€ ogren’s syndrome (pSS). Cardiac electrophysiology revealed atrioventricular node dysfunction and impaired intraventricular conduction. Prednisone therapy induced a significant improvement in symptoms and electrocardiographic readings. The diagnosis of pSS should be considered in a patient presenting with complex cardiac arrhythmias. Key words: Sj€ ogren’s syndrome, cardiac arrhythmias, anti-SSA/Ro antibodies, anti-SSB/La antibodies.
INTRODUCTION
CASE REPORT
Primary Sj€ ogren’s syndrome (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands accompanied by a variety of extraglandular manifestations. Female patients with Sj€ ogren’s syndrome and antibodies against SSA/Ro and SSB/La have significant increased risk of giving birth to children with neonatal conduction abnormalities in the heart, especially complete congenital heart block. It is supposed that the conduction system in the adult heart is relatively resistant to injury by anti-SSA and anti-SSB antibodies. Here we report two cases of combined pSS with the predominant initial manifestation of complex cardiac arrhythmias.
Case I
Correspondence: Professor Jian Li, M.D., Department of Cardiology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China. Email: [email protected] *These authors contribute equally.
A 48-year-old woman, with a 3-month history of heart palpitations, was admitted to the cardiology department of Huashan Hospital (Shanghai, China) for further assessment. She had no medical history of hypertension, diabetes, hyperlipidemia or obesity. She was a housewife and never smoked. At presentation, physical examination demonstrated irregular heart rhythms without heart murmur or crackle. Serial 12lead electrocardiography showed frequent premature ventricular contraction (PVC) and intraventricular conductional block (Fig. 1). Chest radiography showed enlarged heart shadow. Echocardiography indicated bilateral atrial enlargement, pericardial effusion of very small size, pulmonary hypertension (pulmonary artery systolic pressure [PASP] was estimated as 49 mmHg), impaired diastolic function of left ventricular and decreased left ventricular ejection fraction (LVEF) of 47%. She was diagnosed with cardiac arrhythmias resulting from PVC and intraventricular conductional
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Arrhythmias as initial exhibition in adult pSS
Figure 1 Serial 12-lead electrocardiography showed frequent premature ventricular contraction (PVC) and intraventricular conductional block.
block. However, there was no history of arrhythmias nor was there any hints that an overdose of medication caused the arrhythmias. Further tests were performed to determine an underlying cause for these findings. By a careful review of systems, positive for dry mouth and transient arthralgia of both elbow joints was found. Laboratory tests showed increased serum troponin T (TnT) of 0.027 ng/mL (normal ≤ 0.014), myoglobin of 97.61 ng/mL (25–58), creatine kinase (CK) of 296 U/L (26–192), lactate dehydrogenase (LDH) of 220 U/L (135–214) and normal serum brain natriuretic peptide (BNP). Furthermore, she had increased erythrocyte sedimentation rate (ESR) of 64 mm/h, hyperimmunglobulinemia (IgG 19.90 g/L [normal 7.51–15.6], IgA 8.11 g/L [0.82–4.53]). The leukocyte count was not raised, with a normal white cell differential and normal serum C-reactive protein (CRP). As the patient’s complaints, physical findings and primary laboratory tests pointed toward a potential autoimmune disease background, several tests were subsequently conducted. She had positive antinuclear antibody (titer, 1 : 1000, HEp-2), positive anti-SSA (Ro-52) antibodies, and positive IgM rheumatoid factor (RF) with negative anti-SSA (Ro-60), SSB, cyclic citrullinated peptide (CCP), Sm, double-stranded DNA (dsDNA), Scl-70, PM-Scl, antine-
International Journal of Rheumatic Diseases 2015; 18: 800–806
utrophil cytoplasmic antibodies (cANCA), perinuclear ANCA antibodies (pANCA) and normal levels of C3 and C4 complement factors. Serum cytomegaovirus (CMV) DNA and Epstein–Barr virus (EBV) DNA detected by real-time reverse transcription – polymerase chain reaction, adenovirus (ADV) IgM/IgG and Coxsachie virus (CSV) IgM/IgG detected by enzyme-linked immunosorbent assay were all negative. Thyroid function was euthyroid. No monoclonal immunoglobulin was found in the serum or urine by immunofixation electrophoresis. Technetium scintigraphy revealed the reduction of radiotracer uptake and intake in glands of both sides. Biopsy of a minor labial gland showed typical lymphocytic infiltrates (Fig. 2a,b). The lymphocytes were positive for T lymphocyte marker CD3 (Fig. 2c) and B lymphocyte marker CD19 (Fig. 2d). No other abnormal laboratory findings were noted. A diagnosis of pSS was confirmed following the positive findings, including hyposalivation, positive salivary scintigraphy, positive anti-SSA/Ro, and histopathological signs (focus score, ≥ 1/4 mm2) according to American College of Rheumatology (ACR) 2012 classification criteria for pSS.1 Based on the diagnostic criteria for myocarditis proposed by the European Society of Cardiology Working
801
M. Liang et al.
(a)
(b)
(c)
(d)
Figure 2 Biopsy of a minor labial gland was collected from this patient and the histopathologic findings are shown. (a) Hematoxylin and eosin (H&E) staining (original magnification 1009); (b) H&E staining (original magnification 4009); (c) immunohistochemical staining for T lymphocyte marker CD3 (original magnification 4009); (d) and B lymphocyte marker CD19 (original magnification 4009); H&E staining for labial gland biopsy showed lymphocyte-rich inflammatory infiltrate, which was positive for CD3 and CD19.
Group in 2012,2 this patient was diagnosed with immune-mediated myocarditis due to pSS. Continuous 24-h Holter captured complex cardiac arrhythmias, including PVC (8472 beats/24 h), premature superventricular contraction (1992 beats/24 h), and complete right bundle branch block. Heart biopsy was not done because the patient did not consent. In order to evaluate the electrophysiological changes in her heart, cardiac electrophysiology was performed. The Hisventricular (HV) interval was 69.44 ms (normal 35–55) (Fig. 3) and the atrioventricular node effective refractory period (AVN-ERP) was 380.56 ms (normal 250– 365) (Fig. 4), which indicated atrioventricular node dysfunction and impaired intraventricular conduction. The patient was treated with prednisone 1.5 mg/kg/ day for 5 days, with improvement in clinical and electrocardiographic readings. Also, the serum troponin T, myoglobin, CK, LDH, IgG and ESR levels returned to normal. After discharge, the patient tapered the dose of
802
prednisone 10% per month; in the meantime, she was also treated with sotalol (80 mg/day). Repeated continuous 24-h Holter 3 months later showed decreased PVC (1068 times/24 h). And repeated echocardiography was also performed with normal results (PASP estimated as 38 mmHg and LVEF of 63%).
Case II A 61-year-old woman with a 4-year history of heart palpitation was admitted to the cardiology department of Huashan Hospital. She did not have hypertension, diabetes, hyperlipidemia or obesity, and she had a negative finding in coronary angiography 4 years ago. The treatment of metoprolol 12.5 mg per day could relieve her symptom to a certain extent. Further 12-lead electrocardiography showed frequent ventricular contraction, intra-atrial conductional block and intraventricular conductional block. In addition, she had elevated BNP of
International Journal of Rheumatic Diseases 2015; 18: 800–806
Arrhythmias as initial exhibition in adult pSS
Figure 3 Cardiac electrophysiology was performed to evaluate the electrophysiological changes in the heart of this patient. The atrial-His (AH) interval was 93.18 ms and HIS-ventricular (HV) interval was 69.44 ms (as indicated by arrows). In our center, the normal range of AH interval is 60–125 ms, HV interval is 35–55 ms.
857.5 pg/mL (normal < 300) and normal TnT. A chest X-ray revealed borderline cardiomegaly. Echocardiography showed impaired systolic function of the left ventricle with the LVEF of 38%. Continuous 24-h Holter captured multifocal PVC (6378 times/24 h), premature superventricular contraction (107 times/24 h) and complete left bundle branch block. Repeated coronary angiography showed tiny plaques in the left anterior descending artery, left circumflex artery and right coronary artery with 30% stenosis. Therefore, this patient was diagnosed with coronary artery atherosclerosis; however, the severity of coronary stenosis could not explain her complex cardiac arrhythmias and cardiac insufficiency. By a careful review of systems, she complained of dry mouth and described a migratory arthralgia lasting for 4 years. In order to reveal the underling etiology, further tests were performed. Results of further investigations were as follows: positive for the anti-SSA (Ro-52) antibody, negative for the
International Journal of Rheumatic Diseases 2015; 18: 800–806
antibodies against SSA (Ro-60), SSB, RF, CCP, Sm, dsDNA, Scl-70, PM-Scl, cANCA, pANCA, and normal levels of IgG, IgM, IgA, C3 and C4 complement factors. Serological tests for viral infection were all negative. Technetium scintigraphy also revealed the reduction of radiotracer uptake and intake in glands of both sides. Biopsy of labial gland showed a typical lymphocytic infiltration. Therefore, this patient was also diagnosed with pSS. Ruling out infection, medication, or coronary heart disease-induced cardiac arrhythmias, clinical findings suggested her complex cardiac arrhythmias and cardiac insufficiency were closely associated with pSS. After starting prednisone therapy 0.5 mg/kg/day and sotalol 80 mg/day, her palpitation and dryness gradually improved. Repeated 24-h Holter 1 month later revealed decreased PVC (703 times/24 h) and premature superventricular contraction (58 times/24 h). Repeated echocardiography showed improved LVEF of 46%.
803
M. Liang et al.
Figure 4 Cardiac electrophysiology was performed to evaluate the electrophysiological changes in the heart of this patient. The atrioventricular node effective refractory period (AVN-ERP) was 380.56 ms (as indicated by arrows). In our center, the normal range of AVN-ERP is 250–365 ms.
Table 1 Summary of cases of cardiac arrhythmias in Sj€ ogren’s syndrome (SS) Country
No. SS cases
Types of cardiac arrhythmias
Anti-SSA/SSB antibodies
References
USA Korea USA Turkey Italy
1 1 1 40 12
SSA (Ro-52 and Ro-60) SSA SSA (Ro-60) and SSB No association SSA
Lee et al.6 Sung et al.7 Baumgart et al.8 Akyel et al.9 Lazzerini et al.10
Italy
16
Complete atrioventricular block Complete atrioventricular block Complete atrioventricular block Atrial electromechanical delay QT interval prolongation Complex ventricular arrhythmias (Lown classes 2–5) QT interval prolongation
SSA (Ro-52)
Lazzerini et al.11
DISCUSSION This case report of two patients illustrates the association of pSS and complex cardiac arrhythmias. To our knowledge, this is the first case report in the literature
804
of pSS patients presenting complex cardiac arrhythmias as their significant initial manifestation. On the other hand, the detailed description of the functions of impulse formation and the conduction system of the heart in adult pSS patients has not been reported. For
International Journal of Rheumatic Diseases 2015; 18: 800–806
Arrhythmias as initial exhibition in adult pSS
the first case, cardiac electrophysiology was performed and showed atrioventricular node dysfunction and impaired intraventricular conduction, which provides additional support for the hypothesis that anti-SSA (Ro52) was associated with conduction defect in adult pSS patients, although the adult conduct system was thought to be relatively resistant to anti-SSA/Ro antibody damage. Also, the treatment of prednisone induced significant symptomatic and laboratory improvement in these two patients. Obvious cardiac arrhythmia is rare in pSS, so their associations and clinical significance are not well defined. Based on this clinical report, pSS with cardiac arrhythmias are summarized here (Table 1). Patients with pSS, compared with health controls, were more likely to have cardiac arrhythmias.3 Also a Sj€ ogren’s syndrome mother with anti-SSA antibodies is associated with congenital heart block in newborns.4 However, anti-SSA autoantibody is believed to be safe from damaging the adult atrioventricular (AV) node.5 Nevertheless, there are some reports of an adult AV block in Sj€ ogren’s syndrome.6–8 Interestingly, the clinical manifestations of cardiac arrhythmias and the associated antibodies in Sj€ ogren’s syndrome remain a debated issue (Table 1). However, the pathological basis of cardiac arrhythmias in pSS is far from clear. It is described an autopsy case following the sudden death of a young female patient with pSS, and the autopsy showed that the stenosis of the lumen in both sinoatrial (SA) node and AV node arteries and lymphocyte infiltration in the bundle of His, which may have led to fatal arrhythmias.12 The role of anti-SSA/SSB autoantibodies in the pathogenesis of heart block needs to be discussed. Maternal sera containing antibodies against SSA and SSB ribonucleoproteins (positive IgG) inhibited L-type Ca current in isolated cardiac myocytes and induced sinus bradycardia in a murine model of congenital heart block (CHB), and further study showed that maternal antibodies interact directly with the pore-forming alpha (1)-subunit of Ca channels.13,14 And rather than a 60kDa anti-Ro antibody, a 52-kDa antibody was a more specific cause of the conduction abnormality.15 On the basis of our observations in these two cases, the significance of cardiac involvement must be interpreted cautiously for patients with pSS in the light of the clinical scenario. Also, the possibility of pSS should be given attention in patients with complex cardiac arrhythmias, and corticosteroid therapy seemed to elicit good response in these patients.
International Journal of Rheumatic Diseases 2015; 18: 800–806
CONFLICTS OF INTEREST The authors have no competing interests to declare.
REFERENCES 1 Shiboski SC, Shiboski CH, Criswell L et al. (2012) American College of Rheumatology classification criteria for Sjogren’s syndrome: a data-driven, expert consensus approach in the Sjogren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 64, 475–87. 2 Caforio AL, Pankuweit S, Arbustini E et al. (2013) Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 34, 2636–48, 48a–48d. 3 Kang JH, Lin HC (2010) Comorbidities in patients with primary Sjogren’s syndrome: a registry-based case-control study. J Rheumatol 37, 1188–94. 4 Lee LA (2005) Transient autoimmunity related to maternal autoantibodies: neonatal lupus. Autoimmun Rev 4, 207–13. 5 Boutjdir M (2000) Molecular and ionic basis of congenital complete heart block. Trends Cardiovasc Med 10, 114–22. 6 Lee LA, Pickrell MB, Reichlin M (1996) Development of complete heart block in an adult patient with Sjogren’s syndrome and anti-Ro/SS-A autoantibodies. Arthritis Rheum 39, 1427–9. 7 Sung MJ, Park SH, Kim SK, Lee YS, Park CY, Choe JY (2011) Complete atrioventricular block in adult Sjogren’s syndrome with anti-Ro autoantibody. Korean J Intern Med 26, 213–5. 8 Baumgart DC, Gerl H, Dorner T (1998) Complete heart block caused by primary Sjogren’s syndrome and hypopituitarism. Ann Rheum Dis 57, 635. 9 Akyel A, Tavil Y, Tufan A et al. (2012) Atrial electromechanical delay and diastolic dysfunction in primary Sjogren syndrome. Clin Invest Med 35, E303. 10 Lazzerini PE, Capecchi PL, Guideri F et al. (2007) Comparison of frequency of complex ventricular arrhythmias in patients with positive versus negative anti-Ro/SSA and connective tissue disease. Am J Cardiol 100, 1029– 34. 11 Lazzerini PE, Capecchi PL, Acampa M et al. (2011) AntiRo/SSA-associated corrected QT interval prolongation in adults: the role of antibody level and specificity. Arthritis Care Res (Hoboken) 63, 1463–70. 12 Inoue H, Kinoshita K, Sugiyama M, Funauchi M, Hanagama M, Nata M (2008) Sudden death from ischaemic heart disease in a female patient with Sjogren syndrome: a case report. Med Sci Law 48, 261–5.
805
M. Liang et al.
13 Qu Y, Xiao GQ, Chen L, Boutjdir M (2001) Autoantibodies from mothers of children with congenital heart block downregulate cardiac L-type Ca channels. J Mol Cell Cardiol 33, 1153–63. 14 Xiao GQ, Hu K, Boutjdir M (2001) Direct inhibition of expressed cardiac l- and t-type calcium channels by igg
806
from mothers whose children have congenital heart block. Circulation 103 (11), 1599–604. 15 Xiao GQ, Qu Y, Hu K, Boutjdir M (2001) Down-regulation of L-type calcium channel in pups born to 52 kDa SSA/Ro immunized rabbits. FASEB J 15, 1539–45.
International Journal of Rheumatic Diseases 2015; 18: 800–806
