Neurally mediated hypotension in systemic lupus erythematosus patients with fibromyalgia

S. Tang, H. Calkins1 and M. Petri1

Department of Medicine & Geriatrics, Princess Margaret Hospital, Hong Kong and 1Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.

Correspondence to: M. Petri, Johns Hopkins University, School of Medicine, Baltimore, Maryland. E-mail: mpetri{at}jhmi.edu


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Objective. Fibromyalgia (FM) is a major determinant of poor health status in systemic lupus erythematosus (SLE). FM has been shown to be associated with neurally mediated hypotension (NMH) in the general population, in which effective treatments exist. We explored whether NMH was more common in SLE patients with FM than those without.

Methods. Seventy-six SLE patients (4 male, 72 female; 1 ethnic Indian, 28 African American, 47 Caucasian; mean age 40.2 ± 9.4 yr) were recruited and their FM status ascertained using American College of Rheumatology (ACR) classification criteria. Patients who were pregnant or deconditioned were excluded. A two-stage tilt-table test was used to detect NMH. All patients completed the SF-36 Heath Status Inventory (SF-36) and the Krupp Fatigue Severity Scale (KFSS) to evaluate their quality of life. Serological markers and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were recorded. Medications that might interfere with testing were temporarily withheld before the tilt-table test.

Results. The prevalence of NMH (first stage) in SLE patients was 47.9%. Seven patients had both NMH and postural orthostatic tachycardia syndrome. Two patients had borderline results with symptoms reproduced but an inadequate drop in systolic blood pressure by definition (a drop of at least 25 mmHg defines an abnormal response). Eighteen (23.7%) SLE patients had FM and 51 (67.1%) had at least one tender point (TP). The frequency of NMH (first or second stage) in SLE with FM was 58.3% compared with 69.4% in SLE without FM (odds ratio 0.62, 95% CI 0.16–2.37). SF-36 and KFSS scores were not significantly different in SLE patients with and without NMH. However, both scores were found to be associated with FM status (P<0.001 and P = 0.014), reflecting poor health status in the FM group. No confounding variable was found to be significantly associated with both NMH and FM.

Conclusion. NMH is common in SLE patients with a high prevalence rate. The large increase in NMH, a form of autonomic neuropathy, in SLE, has not been explained. However, NMH has no impact on quality of life above that determined by FM, and has no statistically significant association with FM status. Identification of NMH may be important in selected patients with SLE who have chronic fatigue, but NMH cannot explain the increased prevalence of FM in SLE.

KEY WORDS: Neurally mediated hypotension, SLE, Fibromyalgia.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Fibromyalgia (FM) is a chronic pain disorder characterized by widespread pain, chronic fatigue, muscle tenderness, sleep disorder, paraesthesia, anxiety, irritable bowel syndrome, irritable bladder syndrome (idiopathic interstitial cystitis) and migraine headache [1]. In the United States, the prevalence of FM is 2.0% for both sexes, 3.4% for women and 0.5% for men [2, 3]. The number of persons aged 18 and older in the United States who have FM is about 3.7 million [2]. The prevalence of FM is much higher in patients with systemic lupus erythematosus (SLE), in the range of 21 to 61% [411]. Multiple studies have shown that FM in SLE patients is highly associated with poor health status [8, 9, 1219]. Patients with FM were much more likely to be unable to perform daily activities, less likely to be employed, and more likely to receive welfare or medical disability benefits than those without [3, 5, 2023]. We hypothesized that this large increase in the frequency of FM in SLE might be due to an SLE-specific mechanism.

Various studies have shown the lack of association between FM and SLE activity [5, 7, 8, 14, 18, 24, 25]. FM is believed to result from central nervous system dysfunction with altered pain perception and abnormal pain processing [142]. Studies have suggested the involvement of the autonomic nervous system in this syndrome [4349]. In previous studies at Johns Hopkins Hospital, FM and chronic fatigue syndrome (CFS) have both been shown to be strongly associated with neurally mediated hypotension (NMH), a form of autonomic neuropathy, in the general population [45, 50, 51]. In our previous study, we found that 74% (17 out of 23) of SLE patients with FM or CFS have NMH [11]. These results suggest that NMH (or a closely associated abnormality in autonomic function) may play a role in the pathogenesis of FM symptoms.

This study was designed to determine the prevalence of NMH in SLE patients and to explore whether NMH is more common in SLE patients with FM than those without. The hypothesis, if proved correct, would have profound implications as effective treatments exist for NMH, which could then be introduced and tested in patients with SLE.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Subjects
Ninety-seven SLE out-patients were randomly enrolled from the Hopkins Lupus Cohort from July 2001 to August 2002. They all fulfilled the 1982 revised American College of Rheumatology (ACR) classification criteria for SLE. Patients with and without FM during prospective follow-up were both recruited. Fibromyalgia had been diagnosed using 1990 ACR classification criteria, i.e. with widespread body pain for at least 6 months’ duration and tenderness at 11 or more of the 18 specific tender point (TP) sites [1]. Patients who were pregnant or obviously deconditioned (recent surgery, prolonged bed rest) were excluded. Three patients were lost to follow-up, 16 patients withdrew from the study due to time conflicts, one patient withdrew after undergoing orthopaedic surgery and one patient withdrew due to poor compliance with the test schedule. Therefore, 76 participants completed the study.

Tender point assessment
Following the recommendation of the Multicenter Criteria Committee of the ACR, our trained assessors examined all patients for FM TP by applying uniform pressure of about 4 kg with a thumb over 18 pre-defined TP sites (bilateral occiput, low cervical, trapezius, supraspinatus, second ribs, lateral epicondyles, gluteal, greater trochanters and medial fat pad of the knees) [1]. A TP was considered ‘positive’ if the patient stated that the palpation was painful, involuntary verbal or facial expression of pain occurred, or a wince or withdrawal was observed [1, 46].

Disease activity assessment
SLE disease activity was measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Lupus Activity Index (LAI) [52]. SLEDAI contains 24 descriptors (clinical, biochemical and serological parameters) with pre-assigned severity weights. The score ranges from 0 (no disease activity) to 105 (maximum disease activity). A score of 6 is considered clinically important [53]. LAI was recorded by the same rheumatologist at the study visit with a score ranging from 0 to 3, a higher score indicating more active disease. Urine sodium level was measured to assess average salt intake, as salt intake is one of the treatment modalities of NMH.

Quality-of-life (QOL) assessment
All patients completed the Medical Outcome Study SF-36 Short Form Health Status (SF-36) and the Krupp Fatigue Severity Score (KFSS) during the same visit. SF-36 is a health status questionnaire designed to assess eight health domains with limitation in physical (dpf) or social function (dsf) due to health problems; role limitation because of physical (dpr) or emotional (dre) problems; bodily pain (dbp); mental health (dmh); vitality (dvt)—a balance of energy vs fatigue; and general health perceptions (dgh). SF-36 has been validated as a measure for perceived health status in SLE [54]. Its score ranges from 0–100 for each domain (a lower score indicating a greater level of disability). KFSS is a nine-item questionnaire that assesses the effect of fatigue on daily activities. Each item on the scale is scored from 1–7 with the KFSS score calculated by taking the mean of the nine items, a higher score signifying a greater severity of fatigue [8]. Patients also completed a 100 mm visual analogue fatigue scale (VAS) which was scored from 0 (no fatigue) to 1.00 (worst fatigue imaginable) [24].

Tilt-table testing
After written informed consent, patients underwent two-stage 70° upright tilt-table testing at Johns Hopkins Cardiovascular Laboratory to detect NMH. Medications that might affect the test result (including diuretics, anti-hypertensives like beta-blockers and calcium channel blockers, anti-depressants like tricyclic anti-depressants and selective serotonin receptor antagonists, proton pump inhibitors, pyridostigmine, beta-adrenergic agonists and anti-cholinergic agents for asthma) were recorded and temporarily withheld (from 1 to 3 days dependent on the half-life of the individual medication) prior to the test. Investigators and staff at the tilt-table laboratory were blinded as to the FM status of patients. Throughout the test, the blood pressure and heart rate of patients were monitored non-invasively at least every 5 min. After 10 min in supine position, the table was tilted to 70° for 45 min (stage 1). An abnormal response was defined by syncope or pre-syncope (severe light-headedness with a sensation of imminent loss of consciousness) with a drop in systolic blood pressure of at least 25 mmHg and no associated increase in heart rate. If an abnormal response was not observed in stage 1, sublingual nitroglycerine spray was given to patients before continuing the test in the upright position for another 10 min (stage 2). This drug was used to assess the body’s response to vasodilatation. We defined an abnormal response in stage 2 using the same criteria as in stage 1. Other abnormal responses, including postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension, were also recorded.

Sample size and power
With 76 SLE patients and given the prevalence of NMH of 0.74 in SLE with FM (from our preliminary data), we have 80% power (or more) to detect differences of 30% (or more) between patients with and without FM based on our study design.

Statistical analysis
We assessed the association of FM with demographical characteristics, lupus activity, serological markers and quality-of-life assessment scores by unpaired Student’s t-test, {chi}2 and Fisher exact tests, whichever was appropriate. We attempted to identify confounding variable(s) associated with both FM and NMH by analysis of variance (ANOVA). Continuous variables were expressed as mean ± standard deviation unless otherwise specified. A P value of 0.05 and confidence interval of 95% defined statistical significance.

Ethical approval and informed consent
This study was approved by the Joint Committee of Clinical Investigation of Johns Hopkins Hospital. Informed written consent was obtained for all participants according to the declaration of Helsinki.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Seventy-six patients completed the study. Their baseline characteristics are abstracted in Table 1. The mean duration of disease was 11.3 ± 8.6 yr (range 1–34). Their mean Physician Disease Activity Index was 0.63 ± 0.61 (range 0–3) and their mean SLEDAI score was 1.99 ± 2.22 at the study visit. Their mean FSS, VAS and SF-36 scores were 5.23 ± 1.60, 0.47 ± 0.26 and 50.52 ± 21.32 respectively.


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TABLE 1. Baseline characteristics of participants under study

 
Forty-eight patients had the tilt-table test performed. The prevalence of NMH in this cohort of SLE patients was 47.9%, defined as showing abnormal response in either stage 1 or 2 of the test. Seven out of 48 (14.6%) patients had both NMH and POTS. Two out of 48 (4.2%) patients had borderline results with symptoms reproduced during the tilt-table test but an inadequate drop in systolic blood pressure by definition (a drop of at least 25 mmHg defined an abnormal response). Those SLE patients with NMH reported symptoms reminiscent of FM during the tilt-table test, as shown in Fig. 1. We found no significant association between NMH and demographic characteristics, disease activity or serological markers.



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FIG. 1. Symptoms of participants with NMH during the tilt-table test.

 
As depicted in Fig. 2, 67.1% of participants had at least one TP on assessment, and 23.7% of participants fulfilled the diagnostic criteria of FM with widespread pain and >=11 TPs for at least 6 months. The mean number of TPs was 5.16 ± 5.84 (range 0–18). Fibromyalgia was associated significantly with lower educational level and higher levels of C3 and C4; the results are summar-ized in Table 2. The male sex had fewer tender points (0.8 ± 1.0 vs 5.4 ± 5.9, P<0.001), non-Caucasian ethnicity (3.29 ± 5.28 vs 6.13 ± 5.93) and those with positive anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody (3.21 ± 4.63 vs 5.81 ± 6.09) tended to have fewer TPs, though the association did not reach statistical significance. When NMH was defined to be an abnormal response present in either stage 1 or 2, the frequency of NMH in SLE patients with FM was 58.3%, compared with 69.4% in those without FM (odds ratio 0.62, 95% CI 0.16–2.37] (Fig. 3). We did not find any confounding variable that was significantly associated with both NMH and FM.



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FIG. 2. Number of tender points in our cohort of SLE patients.

 

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TABLE 2. Association of fSibromyalgia with other variables (values in brackets are percentages)

 


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FIG. 3. NMH in SLE patients with and without FM.

 
SF-36 (including all its eight domains), VAS and KFSS scores were not significantly different between those with and without NMH. However, the SF-36 score was significantly lower and KFSS was significantly higher in participants with FM (P<0.001 and P = 0.014 respectively) than those without FM, both reflecting a greater degree of disability and a poor health status with FM.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
FM is a common frustrating problem in the community with no definite effective treatment. It affects 2% of the general population and adds a significant economic burden to society. Our study showed a high prevalence rate of FM of 26.3% in the SLE population. This prevalence rate is consistent with other studies and demonstrates the burden of FM in SLE patients. The mean Fatigue Severity Scale (FSS) of our study patients was 5.23, indicating a higher degree of fatigue severity when compared with healthy adults in the general population (FSS 2.3), patients with multiple sclerosis (FSS 4.8) and another lupus population (FSS 4.7) [24, 55, 56].

We were able to show that FM was significantly associated with lower educational level. This result agreed with our previous findings [13], although another study failed to show this association [12]. This phenomenon might be explained by poorer coping skills in those with lower education [13]. Keeping in line with other studies, we found that males and non-Caucasians tended to have fewer tender points than females and Caucasians [5, 10]. Serological markers of disease activity had been shown to poorly correlate with FM status. Our results showed that higher C3 and C4 levels were associated with FM status. As we evaluated our participants at a single point of time, we could not determine if fatigue would co-vary over time with serological markers of disease in this study.

NMH had been shown to associate with chronic fatigue and FM in the general population [45, 50, 51]. Our study failed to identify the same association in the SLE population. However, we demonstrated a high prevalence rate of NMH in SLE patients, compared with the 12% prevalence reported in the general population [45, 51]. We hypothesized that this high prevalence of NMH, as well as the high prevalence of FM, in the SLE population was due to SLE-specific mechanisms. Although we were not able to show an association of FM and NMH in SLE, our patients with NMH did have FM symptoms reproduced during the tilt-table test [45].

Surprisingly, we failed to identify any association of NMH with quality of life. This may be because most of our SLE patients with NMH were asymptomatic and did not have a previous history of syncope or pre-syncope.

One limitation of our study was the predominance of females in the SLE group. NMH has been found to be more common in the female population [57, 58]. The gender difference might have contributed to a higher prevalence rate of NMH in our study. However, this would be unlikely to explain the dramatic difference in prevalence between the two groups. Further studies are needed to explore the underlying mechanisms.


    Conclusion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Fibromyalgia is a common but poorly understood problem in SLE. NMH, which associates with FM in the general population, is more prevalent in SLE patients than in the general population. The large increase in NMH in SLE has not been explained. However, in SLE, NMH has no impact on quality of life above that determined by FM, and has no statistically significant association with FM status. Identification of NMH may be important in selected patients with SLE who have chronic fatigue and/or pain, but NMH cannot explain the increased prevalence of FM in SLE.

The authors have declared no conflicts of interest.


    Acknowledgments
 
This work was supported by an Arthritis Foundation Chapter Research Grant Award, AR43737 and MOIRR00052.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 

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Submitted 5 September 2003; revised version accepted 9 December 2003.



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