XML Template (2015) [16.5.2015–8:03am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/LUPJ/Vol00000/150069/APPFile/SG-LUPJ150069.3d
(LUP)
[1–6] [PREPRINTER stage]
Lupus (2015) 0,
1–6
http://lup.sagepub.com
PAPER
Autoimmune markers and autoimmune disorders in patients with postural tachycardia syndrome (POTS) S Blitshteyn Department of Neurology, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY, USA
Objective: In recent years, there have been a number of studies suggesting that POTS may have an autoimmune etiology. This study examined whether the prevalence of antinuclear antibodies (ANA), other markers of autoimmunity and co-morbid autoimmune disorders is higher in patients with POTS than in the general population. Methods and results: Medical records of 100 consecutive patients with POTS evaluated at our clinic were reviewed. In this cohort (90% females, mean age 32, range 13–54 years), 25% had positive ANA, 7% had at least one positive aPL antibody and 31% had markers of autoimmunity. When compared to the general population, patients with POTS had a higher prevalence of ANA (25% vs. 16%, OR 1.8, CI 1.1–2.8, p < 0.05), aPL antibody (7% vs. 1%, OR 7.5, CI 3.4–16.1, p < 0.001) and co-morbid autoimmune disorders (20% vs. highest estimated 9.4%, OR 2.4, CI 1.5–3.9, p < 0.001). The most prevalent autoimmune disorder was Hashimoto’s thyroiditis (11% vs. up to 2%, OR 6.1, CI 3.2–11.3, p < 0.001), followed by RA (4% vs. up to 1%, OR 4.1, CI 1.5–11.2, p < 0.01) and SLE (2% vs. up to 0.12%, OR 17, CI 4.1–69.7, p < 0.001). The prevalence of CVID was very high (2% vs. 0.004%, OR 510.2, CI 92.4–2817.8, p < 0.001), while celiac disease showed a nonsignificant trend toward increased prevalence. Conclusion: Patients with POTS have a higher prevalence of autoimmune markers and co-morbid autoimmune disorders than the general population. One in four patients have positive ANA, almost one in three have some type of autoimmune marker, one in five have a co-morbid autoimmune disorder, and one in nine have Hashimoto’s thyroiditis. Lupus (2015) 0, 1–6. Key words: Postural tachycardia syndrome (POTS); autoimmune disorders; antinuclear antibodies (ANA); antiphospholipid antibodies (aPL Ab); Hashimoto’s thyroiditis
Introduction Postural tachycardia syndrome (POTS) is a disorder of the autonomic nervous system characterized by orthostatic tachycardia, symptoms of orthostatic intolerance, such as lightheadedness, pre-syncope, weakness and palpitations and nonorthostatic symptoms, such as fatigue, myofascial pain, nausea and migraine headache.1 Although POTS is a heterogeneous disorder with various pathophysiologic mechanisms and etiologies, there has been more evidence in recent years that POTS may have an autoimmune etiology.1–4 We have observed at our clinic that a subset of patients with POTS have a positive antinuclear Correspondence to: S Blitshteyn, State University of New York at Buffalo School of Medicine and Biomedical Sciences, 100 High St., Buffalo, NY 14203, USA. Email: [email protected] Received 15 February 2015; accepted 28 April 2015
antibodies (ANA) test and/or other markers of autoimmunity. We have also observed that a co-morbid autoimmune disorder, such as Hashimoto’s thyroiditis, celiac disease, antiphospholipid syndrome (APS), rheumatoid arthritis (RA), and Sjo¨gren’s syndrome, often precedes and sometimes develops after symptoms of POTS occur. The aim of this study is to determine the prevalence of positive ANA and other autoantibodies and to assess the prevalence of co-morbid autoimmune disorders that exist in patients with POTS.
Methods One hundred consecutive patients with POTS who were evaluated and followed by the author at the Dysautonomia Clinic between October 2012 and March 2013 were included in the study. Diagnosis of POTS was made either through a tilt
! The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at UNIVERSITE LAVAL on October 4, 2015
10.1177/0961203315587566
XML Template (2015) [16.5.2015–8:03am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/LUPJ/Vol00000/150069/APPFile/SG-LUPJ150069.3d
(LUP)
[1–6] [PREPRINTER stage]
Autoimmunity in POTS S Blitshteyn
2
table test or a 10-minute standing test demonstrating a greater than 30 beats per minute (bpm) increase in heart rate from supine to standing position within 10 minutes of tilting or standing.5 All patients had a greater than six-month history of symptoms of POTS. Exclusion criteria 1. Patients with orthostatic intolerance who did not fulfill diagnostic criteria for POTS. 2. Syncope and other symptoms of orthostatic intolerance secondary to medication side effect, anemia, dehydration, diabetes, malignancy, stroke, cardiac arrhythmia, cardiac valvular disease or a neurodegenerative condition, such as Parkinson disease, pure autonomic failure or multiple system atrophy. Patient records were reviewed and information regarding ANA status, any other available markers of autoimmunity, such as rheumatoid factor, antidouble-stranded DNA antibody (anti-dsDNA Ab), anti-Ro/anti-Sjo¨gren’s-syndrome-related antigen A (anti-SSA Ab) and anti-La/anti-Sjo¨gren’s-syndromerelated antigen B antibodies (anti-SSB Ab), antiphospholipid antibodies (aPL Ab) and celiac disease antibodies were documented in the medical records. Co-morbid autoimmune conditions were extracted from the records and verified with the patient when necessary. Since we routinely obtain serum autoimmune markers in patients with POTS, all patients at our clinic have had at least one serum ANA test as part of their evaluation. Where ANA was missing in the records, it was performed through Quest Diagnostics Laboratory. ANA screen was performed via enzyme immunoassay, and if positive, ANA titer was evaluated by indirect immunofluorescence performed on human epithelial cells (HEp-2). This technique requires a multistage process consistent with visual determination of the staining pattern, serial titrations of positive sera, followed by a second test in which autoantigen specificity is determined.6 Titers were reported as 1:40, 1:80, etc., and a pattern was also noted. An elevated antibody level was considered for ANA greater than 1:80, a low antibody level for ANA between 1:40 to 1:80, and a negative antibody level for ANA less than 1:40. When available, other autoimmune markers, such as atypical antineutrophil cytoplasmic antibody (ANCA), tissue transglutaminase, aPL Ab, and anti-SSA and anti-SSB antibodies were extracted from the patient’s charts, but not all patients had these additional markers obtained. Diagnosis of co-morbid autoimmune diseases, such as Hashimoto’s thyroiditis, RA, celiac
disease, APS, systemic lupus erythematosus (SLE) or Sjo¨gren’s syndrome were made or confirmed by the patient’s specialist, such as endocrinologist, rheumatologist, gastroenterologist or primary care physician. A diagnosis of celiac disease was confirmed via small intestine biopsy in all such diagnosed patients. A diagnosis of APS was made using Sapporo criteria, and diagnoses of SLE and Sjo¨gren’s syndrome were made using standard diagnostic criteria. Data were collected and analyzed using standard statistical methods. The odds and prevalence of positive ANA, aPL Ab and comorbid autoimmune conditions in patients with POTS were compared to the odds and prevalence of positive ANA and autoimmune disorders in the general population using odds ratio (OR), confidence interval (CI), p value, and binomial exact calculation. For statistical analysis, we used the highest estimated prevalence of antibody or autoimmune disorder in the general population in order to decrease overestimation of the prevalence in our cohort.
Results In a cohort of 100 consecutive patients with POTS, mean age 32 (age range 13–54 years), 91 were females and nine were males. A positive ANA was found in 25/100 patients (25%), with mostly low titers ranging from 1:40 to 1:320 (Table 1). There were also seven of 100 (7%) patients who had at least one elevated aPL Ab, but only five patients fulfilled a diagnosis of APS by Sapporo criteria. Four of 100 (4%) patients had positive tissue transglutaminase antibodies, three of 100 (3%) had positive anti-SSB antibody, one had elevated anti-dsDNA Ab and one had atypical ANCA (Table 1). When ANA prevalence was combined with these more disease-specific autoantibodies, 31/100 (31%) patients had one or more positive marker of autoimmunity (Table 1). In terms of co-morbid autoimmune conditions, an autoimmune disorder was present in 20/100 (20%) patients. The most frequent autoimmune disorder was Hashimoto’s thyroiditis (11 of 100), followed by APS (five of 100), RA (four of 100), celiac disease (three of 100), SLE (two of 100), and Sjo¨gren’s syndrome (two of 100) (Table 2). Five patients had more than one co-morbid autoimmune disease, and two of these five patients had positive ANA. Additionally, in this 100-patient cohort, two patients had common variable immunodeficiency (CVID); three patients had pacemakers implanted
Lupus Downloaded from lup.sagepub.com at UNIVERSITE LAVAL on October 4, 2015
XML Template (2015) [16.5.2015–8:04am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/LUPJ/Vol00000/150069/APPFile/SG-LUPJ150069.3d
(LUP)
[1–6] [PREPRINTER stage]
Autoimmunity in POTS S Blitshteyn
3
Table 1 Prevalence (percentage (%)) of ANA and other autoimmune markers in patients with POTS (N ¼ 100) POTS (%) ANA aPL Ab Tissue transglutaminase Ab Anti-SSB Ab Anti-SSA Ab Anti-dsDNA Ab Atypical ANCA Any autoimmune marker
25 7 4 3 0 1 1 31
ANA: antinuclear antibodies; POTS: postural tachycardia syndrome; aPL Ab: antiphospholipid antibodies; Anti-SSB Ab: anti-Sjo¨gren’s-syndromerelated antigen B antibody; Anti-SSA Ab: anti-Sjo¨gren’s-syndromerelated antigen A antibody; Anti-dsDNA Ab: anti-double-stranded DNA antibody; ANCA: antineutrophil cytoplasmic antibody.
Table 2 Prevalence of antibodies and co-morbid disorders in patients with POTS compared to the general population POTS Gen. pop. % %ref OR ANA 25 aPL Ab 7 Any autoimmune 20 Hashimoto’s 11 APS 5 RA 4 Celiac 3 SLE 2 Sjo¨gren’s 2 CVID 2
16.06 1.07 9.48 2.09 4.013 1.010 1.012 0.111 1.3914 0.00415
CI CI (lower) (upper) p
1.8 1.1 7.5 3.4 2.4 1.5 6.1 3.2 1.3 0.5 4.1 1.5 3.1 1.0 17.0 4.1 1.4 0.4 510.2 92.4
2.8 16.1 3.9 11.3 3.1 11.2 9.7 69.7 5.9 2817.8
(LUP)
[1–6] [PREPRINTER stage]
Lupus (2015) 0,
1–6
http://lup.sagepub.com
PAPER
Autoimmune markers and autoimmune disorders in patients with postural tachycardia syndrome (POTS) S Blitshteyn Department of Neurology, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY, USA
Objective: In recent years, there have been a number of studies suggesting that POTS may have an autoimmune etiology. This study examined whether the prevalence of antinuclear antibodies (ANA), other markers of autoimmunity and co-morbid autoimmune disorders is higher in patients with POTS than in the general population. Methods and results: Medical records of 100 consecutive patients with POTS evaluated at our clinic were reviewed. In this cohort (90% females, mean age 32, range 13–54 years), 25% had positive ANA, 7% had at least one positive aPL antibody and 31% had markers of autoimmunity. When compared to the general population, patients with POTS had a higher prevalence of ANA (25% vs. 16%, OR 1.8, CI 1.1–2.8, p < 0.05), aPL antibody (7% vs. 1%, OR 7.5, CI 3.4–16.1, p < 0.001) and co-morbid autoimmune disorders (20% vs. highest estimated 9.4%, OR 2.4, CI 1.5–3.9, p < 0.001). The most prevalent autoimmune disorder was Hashimoto’s thyroiditis (11% vs. up to 2%, OR 6.1, CI 3.2–11.3, p < 0.001), followed by RA (4% vs. up to 1%, OR 4.1, CI 1.5–11.2, p < 0.01) and SLE (2% vs. up to 0.12%, OR 17, CI 4.1–69.7, p < 0.001). The prevalence of CVID was very high (2% vs. 0.004%, OR 510.2, CI 92.4–2817.8, p < 0.001), while celiac disease showed a nonsignificant trend toward increased prevalence. Conclusion: Patients with POTS have a higher prevalence of autoimmune markers and co-morbid autoimmune disorders than the general population. One in four patients have positive ANA, almost one in three have some type of autoimmune marker, one in five have a co-morbid autoimmune disorder, and one in nine have Hashimoto’s thyroiditis. Lupus (2015) 0, 1–6. Key words: Postural tachycardia syndrome (POTS); autoimmune disorders; antinuclear antibodies (ANA); antiphospholipid antibodies (aPL Ab); Hashimoto’s thyroiditis
Introduction Postural tachycardia syndrome (POTS) is a disorder of the autonomic nervous system characterized by orthostatic tachycardia, symptoms of orthostatic intolerance, such as lightheadedness, pre-syncope, weakness and palpitations and nonorthostatic symptoms, such as fatigue, myofascial pain, nausea and migraine headache.1 Although POTS is a heterogeneous disorder with various pathophysiologic mechanisms and etiologies, there has been more evidence in recent years that POTS may have an autoimmune etiology.1–4 We have observed at our clinic that a subset of patients with POTS have a positive antinuclear Correspondence to: S Blitshteyn, State University of New York at Buffalo School of Medicine and Biomedical Sciences, 100 High St., Buffalo, NY 14203, USA. Email: [email protected] Received 15 February 2015; accepted 28 April 2015
antibodies (ANA) test and/or other markers of autoimmunity. We have also observed that a co-morbid autoimmune disorder, such as Hashimoto’s thyroiditis, celiac disease, antiphospholipid syndrome (APS), rheumatoid arthritis (RA), and Sjo¨gren’s syndrome, often precedes and sometimes develops after symptoms of POTS occur. The aim of this study is to determine the prevalence of positive ANA and other autoantibodies and to assess the prevalence of co-morbid autoimmune disorders that exist in patients with POTS.
Methods One hundred consecutive patients with POTS who were evaluated and followed by the author at the Dysautonomia Clinic between October 2012 and March 2013 were included in the study. Diagnosis of POTS was made either through a tilt
! The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at UNIVERSITE LAVAL on October 4, 2015
10.1177/0961203315587566
XML Template (2015) [16.5.2015–8:03am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/LUPJ/Vol00000/150069/APPFile/SG-LUPJ150069.3d
(LUP)
[1–6] [PREPRINTER stage]
Autoimmunity in POTS S Blitshteyn
2
table test or a 10-minute standing test demonstrating a greater than 30 beats per minute (bpm) increase in heart rate from supine to standing position within 10 minutes of tilting or standing.5 All patients had a greater than six-month history of symptoms of POTS. Exclusion criteria 1. Patients with orthostatic intolerance who did not fulfill diagnostic criteria for POTS. 2. Syncope and other symptoms of orthostatic intolerance secondary to medication side effect, anemia, dehydration, diabetes, malignancy, stroke, cardiac arrhythmia, cardiac valvular disease or a neurodegenerative condition, such as Parkinson disease, pure autonomic failure or multiple system atrophy. Patient records were reviewed and information regarding ANA status, any other available markers of autoimmunity, such as rheumatoid factor, antidouble-stranded DNA antibody (anti-dsDNA Ab), anti-Ro/anti-Sjo¨gren’s-syndrome-related antigen A (anti-SSA Ab) and anti-La/anti-Sjo¨gren’s-syndromerelated antigen B antibodies (anti-SSB Ab), antiphospholipid antibodies (aPL Ab) and celiac disease antibodies were documented in the medical records. Co-morbid autoimmune conditions were extracted from the records and verified with the patient when necessary. Since we routinely obtain serum autoimmune markers in patients with POTS, all patients at our clinic have had at least one serum ANA test as part of their evaluation. Where ANA was missing in the records, it was performed through Quest Diagnostics Laboratory. ANA screen was performed via enzyme immunoassay, and if positive, ANA titer was evaluated by indirect immunofluorescence performed on human epithelial cells (HEp-2). This technique requires a multistage process consistent with visual determination of the staining pattern, serial titrations of positive sera, followed by a second test in which autoantigen specificity is determined.6 Titers were reported as 1:40, 1:80, etc., and a pattern was also noted. An elevated antibody level was considered for ANA greater than 1:80, a low antibody level for ANA between 1:40 to 1:80, and a negative antibody level for ANA less than 1:40. When available, other autoimmune markers, such as atypical antineutrophil cytoplasmic antibody (ANCA), tissue transglutaminase, aPL Ab, and anti-SSA and anti-SSB antibodies were extracted from the patient’s charts, but not all patients had these additional markers obtained. Diagnosis of co-morbid autoimmune diseases, such as Hashimoto’s thyroiditis, RA, celiac
disease, APS, systemic lupus erythematosus (SLE) or Sjo¨gren’s syndrome were made or confirmed by the patient’s specialist, such as endocrinologist, rheumatologist, gastroenterologist or primary care physician. A diagnosis of celiac disease was confirmed via small intestine biopsy in all such diagnosed patients. A diagnosis of APS was made using Sapporo criteria, and diagnoses of SLE and Sjo¨gren’s syndrome were made using standard diagnostic criteria. Data were collected and analyzed using standard statistical methods. The odds and prevalence of positive ANA, aPL Ab and comorbid autoimmune conditions in patients with POTS were compared to the odds and prevalence of positive ANA and autoimmune disorders in the general population using odds ratio (OR), confidence interval (CI), p value, and binomial exact calculation. For statistical analysis, we used the highest estimated prevalence of antibody or autoimmune disorder in the general population in order to decrease overestimation of the prevalence in our cohort.
Results In a cohort of 100 consecutive patients with POTS, mean age 32 (age range 13–54 years), 91 were females and nine were males. A positive ANA was found in 25/100 patients (25%), with mostly low titers ranging from 1:40 to 1:320 (Table 1). There were also seven of 100 (7%) patients who had at least one elevated aPL Ab, but only five patients fulfilled a diagnosis of APS by Sapporo criteria. Four of 100 (4%) patients had positive tissue transglutaminase antibodies, three of 100 (3%) had positive anti-SSB antibody, one had elevated anti-dsDNA Ab and one had atypical ANCA (Table 1). When ANA prevalence was combined with these more disease-specific autoantibodies, 31/100 (31%) patients had one or more positive marker of autoimmunity (Table 1). In terms of co-morbid autoimmune conditions, an autoimmune disorder was present in 20/100 (20%) patients. The most frequent autoimmune disorder was Hashimoto’s thyroiditis (11 of 100), followed by APS (five of 100), RA (four of 100), celiac disease (three of 100), SLE (two of 100), and Sjo¨gren’s syndrome (two of 100) (Table 2). Five patients had more than one co-morbid autoimmune disease, and two of these five patients had positive ANA. Additionally, in this 100-patient cohort, two patients had common variable immunodeficiency (CVID); three patients had pacemakers implanted
Lupus Downloaded from lup.sagepub.com at UNIVERSITE LAVAL on October 4, 2015
XML Template (2015) [16.5.2015–8:04am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/LUPJ/Vol00000/150069/APPFile/SG-LUPJ150069.3d
(LUP)
[1–6] [PREPRINTER stage]
Autoimmunity in POTS S Blitshteyn
3
Table 1 Prevalence (percentage (%)) of ANA and other autoimmune markers in patients with POTS (N ¼ 100) POTS (%) ANA aPL Ab Tissue transglutaminase Ab Anti-SSB Ab Anti-SSA Ab Anti-dsDNA Ab Atypical ANCA Any autoimmune marker
25 7 4 3 0 1 1 31
ANA: antinuclear antibodies; POTS: postural tachycardia syndrome; aPL Ab: antiphospholipid antibodies; Anti-SSB Ab: anti-Sjo¨gren’s-syndromerelated antigen B antibody; Anti-SSA Ab: anti-Sjo¨gren’s-syndromerelated antigen A antibody; Anti-dsDNA Ab: anti-double-stranded DNA antibody; ANCA: antineutrophil cytoplasmic antibody.
Table 2 Prevalence of antibodies and co-morbid disorders in patients with POTS compared to the general population POTS Gen. pop. % %ref OR ANA 25 aPL Ab 7 Any autoimmune 20 Hashimoto’s 11 APS 5 RA 4 Celiac 3 SLE 2 Sjo¨gren’s 2 CVID 2
16.06 1.07 9.48 2.09 4.013 1.010 1.012 0.111 1.3914 0.00415
CI CI (lower) (upper) p
1.8 1.1 7.5 3.4 2.4 1.5 6.1 3.2 1.3 0.5 4.1 1.5 3.1 1.0 17.0 4.1 1.4 0.4 510.2 92.4
2.8 16.1 3.9 11.3 3.1 11.2 9.7 69.7 5.9 2817.8
