Indian Journal of Dermatology
ORIGINAL ARTICLE
Year
: 2022  |  Volume : 67  |  Issue : 6  |  Page : 639--644

Risk of atrial fibrillation in pemphigus vulgaris


Nastaran Namazi1, Shahram Ariaeenejad1, Mitra Esmailii Azad2, Mehdi Pishgahi3,  
1 From the Department of Dermatology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3 Department of Cardiology, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Correspondence Address:
Nastaran Namazi
Department of Dermatology, Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran
Iran

Abstract

Background: Pemphigus vulgaris (PV) is a rare immunobullous disease with a higher mortality rate than the general population. The aim of this study was to investigate P-wave duration and P-wave dispersion (PWD) in patients with PV as predictors of atrial fibrillation (AF). Materials and Methods: In this case-control study, the risk of AF development was determined by measuring maximum and minimum P-wave duration (P-max and P-min) and PWD in 45 PV patients and 45 healthy individuals. The incidence of metabolic syndrome was evaluated. Results: PWD and P-max values of the study group were significantly higher than those of the control group. No difference was observed between PWD with regards to disease duration and disease phenotype (p > 0.05). There was no significant difference regarding the prevalence of metabolic syndrome in PV patients compared with the control group. Conclusion: PWD and P-max, which are accepted as risk factors for AF development, were found to be higher in PV patients. Some components of metabolic syndrome were more prevalent in PV patients. It seems that there is an increased risk of CVD and AF in PV patients.



How to cite this article:
Namazi N, Ariaeenejad S, Azad ME, Pishgahi M. Risk of atrial fibrillation in pemphigus vulgaris.Indian J Dermatol 2022;67:639-644


How to cite this URL:
Namazi N, Ariaeenejad S, Azad ME, Pishgahi M. Risk of atrial fibrillation in pemphigus vulgaris. Indian J Dermatol [serial online] 2022 [cited 2023 Mar 31 ];67:639-644
Available from: https://www.e-ijd.org/text.asp?2022/67/6/639/370341


Full Text



 Introduction



Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering disease characterized by autoantibodies targeting desmoglein 3 and to a lesser extent, desmoglein 1, which are engaged in the intercellular junction of keratinocytes.[1] PV is characterized by thin-walled, flaccid bullae that appear on mucous membranes and/or skin evolving into painful non-healing erosions. The mean incidence of the disease varies by geographic location and different ethnic groups and is 0.67-1.6/100,000/year for the overall population in Iran.[2],[3]

Although the prognosis of the condition has considerably improved after the introduction of glucocorticoids and immunosuppressive therapy, some population-based studies revealed that the mortality rate among PV patients is higher than that of the general population. Systemic and respiratory tract infections, cardiovascular diseases (CVDs) and peptic ulcer disease are the main causes of death in these patients.[4],[5] Some investigations have evaluated the risk factors for overall mortality in patients with PV and showed that coronary heart disease and cardiac arrhythmia have a statistically significant association with mortality in PV patients.[6]

While several studies have reported rhythm and conduction disturbances are higher in some inflammatory diseases, there is no study investigating the risk of atrial fibrillation (AF) in PV patients.[7],[8],[9],[10] As we have encountered several cases of de novo AF and sudden death in PV patients without a history of cardiac problems in our practice, we designed a study to investigate the risk of AF in PV patients.

In this study, our aim was to anticipate the risk of AF in PV patients by evaluating electrocardiogram predictors.

P-wave dispersion (PWD) is regarded as an electrocardiographic marker of prolongation of intra-atrial and inter-atrial conduction time in addition to heterogeneous and discontinuous propagation of sinus impulses. Prolongation of PWD has been demonstrated to be an independent risk factor for the development of AF, while P-max and PWD are commonly used to determine the risk of AF in patient populations with inflammatory diseases.[11] Therefore we sought to investigate the risk of developing atrial arrhythmia in PV patients by measuring P-wave duration and PWD.

 Materials and Methods



Forty-five PV patients and 45 healthy control subjects matched for age and sex were included in the study. Participants' age was greater than 18 years, and all provided written informed consent for inclusion in the study. The patients fulfilled the currently accepted criteria for PV, defined as the presence of typical mucocutaneous lesions confirmed by pathology and direct immunofluorescence. They were recruited between January 2014 and January 2016 (Shohada-e- Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran). The institutional ethics committee approved the protocol of the study, which was performed according to the Declaration of Helsinki.

Patients and control subjects with a history of chronic diseases including hypertension, hyperlipidaemia, diabetes mellitus, CVD, heart failure, arrhythmia or valvular heart diseases, lung diseases or pulmonary hypertension, liver/kidney/thyroid diseases, connective tissue diseases, cardiovascular/antiarrhythmia/antihypertensive drug use, obese subjects (BMI ≥30 kg/m2), alcoholics and smokers were excluded from the study. Biochemical variables such as fasting glucose levels and lipid panel were analysed.

All cases and controls underwent echocardiographic evaluation, and everyone with abnormal results, including valvular disease, pulmonary hypertension or atrial/ventricular dysfunction were excluded. A 12-lead ECG of all subjects was recorded in the supine position. ECG recordings were obtained at a paper speed of 50 mm/s and 10 mm/mV amplitude. The beginning of the P-wave was defined as the point where the first atrial deflection crossed the isoelectric line, and the end of the P-wave was defined as the point where the atrial deflection returned to the isoelectric line. The P-wave durations (P-max, P-min) were calculated in all 12 ECG leads. The difference between P-max and P-min was defined as PWD. Two ECG readers, who were blinded to the study, evaluated the ECGs with calipers and magnifying lens. According to the WHO definition, the prevalence of metabolic syndrome was determined.

 Statistical Methods



All data analyses were performed using the statistical software JMP, Version 7. SAS Institute Inc., Cary, NC, 1989-2007. P values less than 0.05 were considered statistically significant. All tests were two-sided.

Continuous variables are presented as mean ± SD or as medians with total and interquartile ranges (25th-75th percentiles). Categorical data are expressed as number (percentage). The normality of continuous variables was checked using the Shapiro–Wilk's W-test.

Chi-square test and Fisher's exact test, wherever appropriate, were performed for data analysis. A comparison of the continuous variable between the two groups was performed using the Mann–Whitney U test. In addition, multiple linear regression analysis was applied to determine the parameters most predictive of the P-min, P-max and PWD. A step-wise forward regression algorithm was used to choose variables entering in the final standard least square model. Regression diagnostics were used to detect violations in regression modelling assumptions.

 Results



Forty-five PV patients with 45 age- and sex-frequency matched healthy controls were recruited for this study. Baseline demographics and laboratory findings of the study groups are presented in [Table 1]. The two groups did not differ significantly in age, gender, systolic and diastolic blood pressure.{Table 1}

The disease duration was 6 months to 23 years. All the patients were in the maintenance phase of treatment. None of them was using high dose corticosteroids at the time of this study. The dose of oral corticosteroid was 0-30 mg/day. Twenty-five patients were taking Azathioprine (50-100 mg/day), 11 were taking Mycophenolate Mofetil (1500-2000 mg/day) and 9 patients were not taking adjuvant drugs. None of them used anti CD20 or other biologic agents during the treatment period.

Waist circumference in PV patients was 95-137 (median 108) in men and 75-130 (median 98) in women. In healthy control, the values were 82-133 (median 95) in men and 74-113 (median 90) in women. PV patients had significantly higher abdominal obesity (p < 0.01). There was no significant difference regarding the prevalence of metabolic syndrome in PV patients compared with controls (40% in PV patients vs. 36% in controls, P = 0.1).

The median serum levels of total cholesterol, LDL and blood sugar were significantly higher in patients with pemphigus in comparison with healthy controls (p = 0.049, P = 0.01 and P = 0.01 respectively). The two groups did not differ significantly in the serum concentrations of HDL (p = 0.24).

Patients with PV had significantly longer P-max duration than healthy controls (p <.0001, [Table 2] and [Figure 1]). However, the two groups were similar in the P-min durations (p = 0.07, [Table 2] and [Figure 2]). Compared to control group, patients had significantly greater PWD (p <.0001, [Table 2] and [Figure 3]).{Table 2}{Figure 1}{Figure 2}{Figure 3}

Multivariable analyses were applied, including all subjects (patients and healthy controls) and introducing 'group of study' to the model as a dummy variable. Total cholesterol was positively associated with P-max (regression summary: adjusted R2 = 0.27, F = 16.44, P <.0001). Controlling for the effect of total cholesterol, P-max duration was significantly longer in patients than in healthy controls (p <.0001). According to the multivariable analyses, PWD was significantly greater in patients with pemphigus compared to the healthy controls (p <.0001). No association was observed between PWD with regards to disease duration, disease phenotype (cutaneous or mucocutaneous), dose of oral corticosteroid and adjuvant drug (p > 0.05).

 Discussion



PV is a potentially life-threatening autoimmune blistering disease. A higher risk of death in PV patients, compared to the general population has been reported. The presence of coronary heart disease and cardiac arrhythmia has a statistically significant association with survival in PV patients.[6] While mutations in the Dsg2 gene were shown to cause arrhythmogenic right ventricular cardiomyopathy/dysplasia, there is no association between Dsg2 and PV.[12]

The increased risk of atrial arrhythmia in PV patients seems to be multifactorial. PV patients usually take several medications, and drug-induced arrhythmia could be a potential mechanism of AF. Long-term use of oral glucocorticoids is associated with adverse effects; including hypertension, hyperglycaemia, dyslipidaemia, obesity and metabolic syndrome that may increase the risk of ischaemic heart disease and heart failure, which are triggers for AF development. The risk of steroid-induced cardiovascular events is higher in people who develop a cushingoid appearance.[13],[14]

The role of corticosteroids in the induction and treatment of AF is not clearly determined.[15] There are reports of AF induced by high doses of corticosteroids probably mediated by a direct effect on the cell membrane that leads to local potassium efflux.[16] Although the risk of arrhythmia is greater with intravenous infusion of corticosteroids due to electrolyte shifts during a rapid rate of infusion, there are reports of AF development following oral low dose corticosteroid treatment.[17] A Danish population-based, case-control study revealed that glucocorticoid prescriptions within 60 days were associated with an almost 2-fold increased risk of atrial fibrillation or flutter.[18] However, some studies have demonstrated that atrial remodelling and AF vulnerability is decreased by prednisone treatment and demonstrated that corticosteroids reduce the risk of postoperative AF[19],[20] maybe because some of the inflammatory cytokines such as IL-8 and TNF-alpha that are contributory to AF pathogenesis are decreased by corticosteroids.[21] It seems that corticosteroids could have various effects on arrhythmia development in different clinical settings.

Another drug that has widespread use in PV patients which been reported to have arrhythmogenic effect is Azathioprine. There are several case reports of AF following Azathioprine administration in patients with no cardiovascular disease. The mechanism of arrhythmia induction during treatment with Azathioprine remains to be established.[22],[23]

Bisphosphonates are the most widely prescribed drugs for the prevention and treatment of glucocorticoid-induced osteoporosis. Some studies have found that use of bisphosphonates is associated with an almost double increase in the risk of AF compared to non-users and those who had stopped this treatment before at least 1 year. Calcification in the conducting system and atria, elevated production of cytokines (including IL-6) and abnormalities in calcium dynamics are proposed mechanisms for bisphosphonate-related AF.[24]

Recent studies have indicated that inflammation might play a significant role in the initiation, maintenance, and preservation of AF. Some inflammatory cytokines such as TNF-α and IL-6 have been shown to be involved in the pathogenesis of PV, as well as atherosclerosis and coronary heart disease.[25],[26],[27] Recent studies have reported that higher TNF-α and IL-6 levels were associated with a greater risk of AF and stroke, and mortality.[28],[29],[30],[31],[32]

Macrophage migration inhibitory factor (MIF) MIF is another inflammatory cytokine which plays an important role in the pathophysiology of cardiovascular diseases and is involved in the pathogenesis of AF. The mean serum MIF levels are reported to be significantly higher in PV patients.[33] A hypothesis for inflammation-related AF is atrial remodelling, oxidative stress and prothrombotic state, which are induced by inflammation and facilitate the development of AF.[16]

P-wave duration and PWD are the most important ECG markers used to evaluate the risk of atrial arrhythmias.[20] Several studies showed that PWD has a predictive value for AF in patients with various conditions such as rheumatoid arthritis, IBD and scleroderma.[7],[8],[9],[10]

Because of confounding effects on CVD and arrhythmia, we excluded cases and controls with apparent hyperlipidaemia, diabetes and BMI ≥30 kg/m2 from the study. Although there was no significant difference in the prevalence of metabolic syndrome in the PV patients compared to controls, the components of metabolic syndrome including elevated blood sugar, hyperlipidaemia, BMI and waist circumference were still more numerous in our patients (P <0.05). These components can contribute to increased CVD and are reported to be important triggers in AF pathogenesis.[27] It has been reported that metabolic syndrome and obesity can increase PWD as a marker for AF. A study revealed that even impaired fasting glucose is associated with increased atrial conduction time and can be regarded as an etiological factor for the development of AF.[28]

Major limitations of the present study were cross-sectional design, lack of long-term clinical follow up of the patients and small sample size.

In conclusion, we evaluated the P-wave variables and metabolic syndrome components in PV patients and found that PWD, P-max values and metabolic syndrome components were significantly higher than controls. Our result has revealed that PV patients are at risk of developing AF.

Acknowledgements

This study was supported by the Skin Research Center, ShahidBeheshti University of Medical Sciences, Tehran, Iran.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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