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Rheumatology Advance Access originally published online on February 4, 2008
Rheumatology 2008 47(3):362-367; doi:10.1093/rheumatology/kem371
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Associated factors and impact of myocarditis in patients with SLE from LUMINA, a multiethnic US cohort

M. Apte1,2, G. McGwin, Jr1,3, L. M. Vilá4, R. A. Kaslow1, G. S. Alarcón2, J. D. Reveille5 and for the LUMINA Study Group

1Department of Epidemiology, 2Department of Medicine, Division of Clinical Immunology and Rheumatology, 3Department of Surgery, Section of Trauma, Burns and Critical Care, The University of Alabama at Birmingham, Birmingham, AL, 4Department of Medicine, Division of Rheumatology, The University of Puerto Rico Medical Sciences Campus, San Juan, PR and 5Department of Medicine, Division of Rheumatology, The University of Texas Health Science Center at Houston, TX, USA.

Correspondence to: G. S. Alarcón, 830 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35294-3408, USA. E-mail: graciela.alarcon{at}ccc.uab.edu


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. To examine the factors associated with myocarditis and its impact on disease outcomes in SLE patients.

Methods. SLE patients aged ≥16 yrs, disease duration ≤5 yrs from LUMINA (LUpus in Minorities: NAture vs nurture), a multiethnic US cohort, were studied. Myocarditis was defined as per the category 3 of the pericarditis/myocarditis item of the SLAM-Revised (SLAM-R). Patients with concurrent pericardial involvement were excluded. Patients with myocarditis were compared with those without myocarditis or its sequelae in the preceding year. The association between myocarditis and baseline variables (T0) was first examined. The impact of myocarditis on disease activity over time (SLAM-R), damage accrual [SLICC Damage Index (SDI)] at last visit (TL) and mortality was evaluated.

Results. Fifty-three of the 496 patients studied had myocarditis. African American ethnicity [Odds ratio (OR) = 12.6; 95% CI 1.6, 97.8] and SLAM-R at diagnosis (OR = 1.1, 95% CI 1.0, 1.1) were significantly and independently associated with myocarditis. Myocarditis did not predict disease activity over time, but approached significance as a predictor of SDI at TL in multivariable analyses P = 0.051. Kaplan–Meier curves indicated that myocarditis was associated with shorter survival (log-rank = 4.87, P = 0.02), particularly in patients with ≥5 yrs disease; however, myocarditis was not retained in the Cox proportional hazards regression model.

Conclusions. Ethnicity and disease activity at diagnosis were associated with the occurrence of myocarditis in SLE. Myocarditis did not significantly impact on disease activity over time, but impacts some on damage accrual and survival, reflecting overall the more severe disease those patients experience.

KEY WORDS: Myocarditis, Lupus, Damage, Survival


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
SLE is a multi-system chronic and recurrent inflammatory disease of unknown aetiology that can affect all major organ systems including all components of the cardiovascular system [1, 2]. Twenty-five per cent of patients with SLE have cardiovascular involvement at some point in the course of their disease, and cardiovascular disease is the third major cause of death in these patients, albeit not all cardiovascular disease or cardiovascular deaths are inflammatory in nature; in fact, a significant proportion are due to atherosclerosis [3, 4]. Myocarditis is a rare but potentially fatal manifestation of SLE [5]. It is often subclinical in nature, but 5–10% of all SLE patients develop symptomatic myocarditis [6, 7]. Myocarditis may present as fever, dyspnoea, palpitations, non-exertional chest pain with resting tachycardia, jugular venous distension, gallop rhythms, new cardiac murmurs and peripheral oedema; cardiomegaly may be present and echocardiographic manifestations are variable and include non-specific ST-T wave changes, conduction abnormalities, premature atrial and ventricular complexes and ventricular and supraventricular tachycardia [8]. Patients with myocarditis may develop congestive heart failure [9]. Simultaneous involvement of other cardiac structures, particularly the pericardium, occurs in ~50% of patients [4].

Case reports and series have described the short-term outcomes of clinically detectable myocarditis [6, 10]; however, the contribution of myocarditis to long-term outcomes in SLE has not been adequately described. Here we have explored the factors associated with the occurrence of clinically defined myocarditis and its impact on intermediate and long-term outcomes in patients with SLE from the LUMINA (LUpus in Minorities: NAture vs nurture) cohort. Based on prior published reports, we hypothesized that myocarditis will occur more frequently in patients of Hispanic and African American ethnicity [11, 12] and in those positive for either anti-Ro or anti-phospholipid (aPL) antibodies [8, 13] and that patients with myocarditis will have poorer outcomes including diminished survival [5].


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
LUMINA is a longitudinal cohort for the study of outcomes in SLE patients. Patients enrolled in the study have defined Hispanic, African American or Caucasian ethnicity (all four grandparents of the same ethnicity), have met at least four revised and updated American College of Rheumatology (ACR) criteria at diagnosis [14, 15], have a disease duration of ≤5 yrs and reside in the catchment areas of the three participating institutions: The University of Alabama at Birmingham, AL, The University of Texas Health Science Center at Houston, TX and The University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA. The LUMINA study has been approved by the institutional review board for engaging human subjects in research at each participating institution and informed patient consent was obtained according to the Declaration of Helsinki.

The LUMINA cohort is currently in its 13th year [11, 16].

Visits and data collection
Study visits are conducted every 6 months for the first year and annually thereafter. At each visit, patients undergo a physical examination, an interview and laboratory testing. All available medical records are reviewed for the study period to complement and complete clinical data.

Variables
LUMINA is a comprehensive database, which includes variables from the socioeconomic–demographic, clinical, immunological, genetic and psychological and behavioural domains. Only variables included in the analyses for the present study are described here.

From the socioeconomic–demographic domain the following variables as assessed at baseline or enrolment visit (T0) were included: age, gender, ethnicity, number of years of education, poverty (as defined by the US Federal government and adjusted for the number of members in the household) [17], presence of health insurance, marital status (married or living together) and self-reported smoking or alcohol intake.

From the clinical domain we included: (i) disease activity as ascertained by the SLAM-Revised (SLAM-R) [18] (without the myocarditis/pericarditis component) at TD (diagnosis), T0 and averaged over time; (ii) damage accrual as ascertained with the SLICC Damage Index (SDI) (without the heart failure, valvular disease and pericarditis components) [19]; (iii) disease duration (TD–T0), total duration (T0–last visit or TL); (iv) number of ACR criteria at diagnosis and disease onset type (acute if criteria were accrued within 4 weeks or insidious if otherwise); (v) organ system involvement by categories (integument, musculoskeletal, renal, haematological, neuropsychiatric, pulmonary, arterial or venous thrombosis and hypertension); (vi) patients’ and physicians’ global assessments of disease activity as measured on 10 cm visual analogue scales (VAS); (vii) thyroid dysfunction (hypo- or hyperthyroidism); (viii) acute-phase reactants (ESR) concomitant with the clinical event and by categories of the SLAM-R; and (ix) medication usage (hydroxychloroquine used ever and average weighted glucocorticoid dose, taking into account the interval between study visits).

The genetic domain included selected HLA-DRB1, HLA-DQB1 and HLA-DQA1 alleles assessed using standard laboratory techniques as previously described [16]. Autoantibodies tested for were ANA, anti-dsDNA, anti-Sm, anti-Ro, anti-La and IgM and IgG aPL antibodies and the lupus anti-coagulant. ANA testing was performed on Hep-2 cells by indirect immunoflourescence and anti-dsDNA testing was performed using the Crithidia luciliae method (Antibodies Inc., Davis, CA, USA) [20]. Anti-Smith, anti-Ro and anti-La antibodies were assessed by immunodiffusion (Inova Diagnostics, San Diego, CA, USA) [21], whereas IgG and IgM aPL antibodies were determined by ELISA (Louisville Diagnostics, Louisville, KY, USA) [22]. The lupus anti-coagulant was assessed by the Staclot method [Diagnostic Stago 92 600, Asnieres-Sur-Seine (France)] [23].

From the psychological and behavioural domain the following variables were included: learned helplessness score derived from the Rheumatology Attitude Index [24] and abnormal illness-related behaviours assessed with the Illness Behavior Questionnaire (IBQ) [25] in which higher scores indicate higher levels of helplessness and of abnormal illness-related behaviours, respectively. Social support was assessed with the Interpersonal Support Evaluation List (ISEL) in which higher scores indicate higher levels of social support [26].

For this study, clinical myocarditis was defined as the presence of clinically detectable inflammation of the myocardium with haemodynamic compromise and/or arrhythmia within the 4 weeks preceding study visits, using category 3 of the ‘myocarditis or pericarditis’ item of the SLAM-R [18]. In order to avoid including patients with pericarditis alone, clinical information gathered during the same visit was used to exclude patients with pleuro-pericarditis in the 4 months preceding or following study visits. Recognizing that myocarditis may be subclinical, patients with congestive heart failure, conduction defects, cardiomyopathy or endocarditis/valvular heart disease that could be indicative of undetected myocarditis or of its consequences were excluded from the analyses.

Statistical analyses
We examined the associations of clinical myocarditis with T0 variables and the impact of myocarditis on disease activity over time, damage accrual at TL and survival. Descriptive and univariable analyses of baseline variables related to myocarditis were done using chi-square tests for categorical variables and ANOVA (analysis of variance) for continuous variables; Fisher's exact test was used when indicated. The associations between myocarditis and T0 variables for the different domains were further examined with a series of univariable logistic regressions. Variables found to be significant at the 0.05 level and those deemed to be clinically relevant or declared to be of interest a priori were entered into a logistic regression model with myocarditis as the dependent variable.

In the analysis of the impact of clinical myocarditis on disease activity, the average-weighted SLAM-R (without the myocarditis/pericarditis component) was set as the dependent variable. The relationship between variables from the different domains and the weighted SLAM-R average was examined by linear regression for the continuous variables and by ANOVA for categorical variables. Variables significant in these analyses (P < 0.05) were then examined with a multivariable linear regression model. The impact of clinical myocarditis on damage (SDI) at TL was examined using Poisson univariable regressions for each predictor variable with adjustment for total disease duration. Except for highly correlated variables, each of those significant at the 0.05 level in the univariable analyses was entered into a backward stepwise Poisson multivariable regression. Survival was examined using Kaplan–Meier (K–M) curves for clinical myocarditis and known predictors of mortality (SLAM-R, SDI and poverty at T0). Cox proportional hazards regression was performed on variables for which the proportionality assumption could be verified [27]. Adjusted survival estimates obtained from this Cox model were then plotted as survival curves for clinical myocarditis [28].

All analyses were performed using SAS version 9.1, SAS Institute Inc., Cary, NC, USA.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Of the 636 patients in the LUMINA cohort, 71 developed myocarditis during the course of the disease; 18 of them were excluded due to concurrent pericarditis. There were 565 patients without myocarditis; 122 of them were excluded due to the presence of manifestations suggestive of either subclinical myocarditis or of myocarditis sequelae (conduction defects, congestive heart failure, cardiomyopathy or endocarditis/valvular disease) within 4 months of study visits.

Thus, 496 patients, 53 cases (10.7%) of clinical myocarditis and 443 non-cases (89.3%) were included in these analyses. These included 98 (19.8%) Hispanics from Texas, 93 (18.8%) Hispanics from Puerto Rico, 172 (34.7%) African Americans and 133 (26.8%) Caucasians. The study population was predominantly female (90.5%), with a mean age of 35.9 yrs (S.D. 12.2), a mean disease duration of 17.1 months (S.D. 16.1) and a mean total disease duration of 63.1 months (S.D. 42.7).

Clinical myocarditis was an early disease manifestation with 45 of the 53 patients (84.9%) having clinically detectable myocarditis before T0.

Association of clinical myocarditis with baseline variables
Univariable analyses
The association of clinical myocarditis with selected baseline sociodemographic variables is shown in Table 1. Age, smoking, drinking, number of years of education, poverty and health insurance were not associated with myocarditis. There were significant differences in the ethnic distribution between the two groups, with the myocarditis group having a higher proportion of African Americans (60.9%) and lower proportion of Hispanics from Puerto Rico (1.9%) than the non-myocarditis group (31.6 and 20.8%, respectively).


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  		TABLE 1. Selected sociodemographic baseline characteristics of patients with SLE from LUMINA as a function of the presence of myocarditis

 
Acute onset type, renal involvement, haematological involvement and the proportion of deceased patients were more frequent among patients with myocarditis than among patients without it; likewise, diabetes mellitus was more frequent among them. Disease activity as assessed by the SLAM-R at diagnosis (without the myocarditis/pericarditis components) and the physician VAS were higher among patients with myocarditis than in those without it. Disease activity as assessed by the patient was numerically higher in the myocarditis patients, but the difference was only of borderline statistical significance. The number of ACR criteria at diagnosis and damage accrued at T0 were higher among those patients with myocarditis than among those without it. The frequencies of hypo- or hyperthyroidism were comparable in both treatment groups; however, the proportion of patients in the myocarditis group who had higher levels of ESR (>50 mm/h) was greater than in the non-myocarditis group. Myocarditis patients were also more likely to be treated with glucocorticoids (and with higher maximum doses), or mycophenolate mofetil and less likely to be treated with hydroxychloroquine. These data are shown in Table 2. There were no differences in the frequency distribution of the autoantibodies examined or of the selected HLA-DRB1, HLA-DQB1 and HLA-DQA1 alleles examined (data not shown). Univariable logistic regressions yielded similar results (data not shown).


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  		TABLE 2. Selected baseline clinical characteristics of SLE patients from LUMINA with and without myocarditis

 
Multivariable analysis
Data from this analysis are shown in Table 3. The only variables which were significantly associated with clinical myocarditis were African American ethnicity [odds ratio (OR) = 12.6, 95% CI 1.6, 97.8, P = 0.015] and SLAM-R at diagnosis (OR = 1.1, 95% CI 1.0, 1.1, P = 0.006). In an alternative model, ESR and the highest dose of glucocorticoids used were included. Although ~25% of the patients could not be included because of missing data, this model was consistent with the one presented. In addition, ESR was also significant (OR = 3.1; 95% CI 4, 7.1). None of the medications was retained in this model.


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  		TABLE 3. Factors associated with the occurrence of myocarditis by univariable and multivariable analyses in LUMINA patients

 
Impact of clinical myocarditis on disease activity
Factors previously shown to influence SLAM-R in the LUMINA cohort were significantly associated with the average weighted SLAM-R [12] in the univariable analyses, but clinical myocarditis was not among those associated (data not shown); thus, no multivariable analyses were performed.

Impact of clinical myocarditis on damage
Univariable analyses
Clinical myocarditis predicted damage at TL (parameter estimate = 0.61, P ≤ 0.001) in univariable Poisson regressions adjusted for total duration. African Americans and Hispanics (Texas) accrued more damage at TL as compared with Caucasians and Hispanics (Puerto Rico). Other variables significant in the univariable analyses were older age, being below the poverty line, lacking health insurance, being a smoker, having higher disease activity, greater number of ACR criteria at diagnosis, higher physician global assessment at T0, higher SDI at T0, having more abnormal illness-related behaviours, having a higher average glucocorticoid dose and having never taken hydroxychloroquine.

Multivariable analysis
In the reduced Poisson multivariable regression analyses, clinical myocarditis predicted damage at TL with borderline statistical significance (parameter estimate = 0.48, P = 0.051). In addition, Hispanic (Texas) and African American ethnicities and damage at baseline (SDI at T0) were strong independent predictors of damage at TL. Older age, higher disease activity over time and higher score on the illness behaviour questionnaire were also significant, albeit less important than the other variables. These data are depicted in Table 4.


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  		TABLE 4. Poisson multivariable regression analyses of damage accruala in LUMINA patients

 
Impact on survival
As noted before (Table 2), there was a higher proportion of deceased patients (10 of 53, 18.6%) among the clinical myocarditis group than among those without myocarditis (37 of 443, 8.4%). In survival curves for the myocarditis and the non-myocarditis groups (Fig. 1), prognosis was comparable for the first 4 yrs of disease after which survival in the myocarditis group dropped drastically, resulting in overall shorter survival time (log rank = 4.87, P = 0.02). Factors previously shown to affect mortality in the LUMINA cohort, disease activity, damage and poverty at baseline were assessed in this group of patients [29]. Survival probability progressively declined with increasing levels of disease activity, presence of any damage at T0, and poverty. Survival curves for clinical myocarditis adjusted for these variables (Fig. 2) suggest that myocarditis shortens survival after 5 yrs of disease duration. However, clinical myocarditis was not retained in a Cox proportional hazards regression. Baseline SDI [hazards ratio (HR) = 1.37, P = 0.005] and SLAM-R scores (HR = 1.08, P = 0.008) were significant predictors of mortality whereas poverty (HR = 1.84, P = 0.069) was a borderline significant predictor (data not shown).


Figure 1
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  		FIG. 1. Kaplan–Meier survival curve in LUMINA patients as function of presence of myocarditis: Present Figure 1 Absent ––––––––– (Log rank = 4.87; P = 0.02).

 

Figure 2
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  		FIG. 2. Survival curves derived from Cox proportional regression analysis adjusted for SDI at baseline, disease activity (SLAM-R) at baseline and poverty as a function of the presence of myocarditis: Present Figure 2 Absent –––––––––.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
We have examined the baseline variables associated with clinical myocarditis and its impact on intermediate (damage) and long-term (survival) outcomes in SLE using a large multiethnic US cohort. Previous studies of myocarditis in SLE have been limited to case reports and series; our systematic study offers clear advantages.

The proportion of patients in our cohort who developed clinically detectable myocarditis was similar to the 5–10% in published reports [7, 8, 30]. The strong association of African American ethnicity with the development of clinical myocarditis in SLE reflects the worse overall disease experience in terms of disease activity, damage and other clinical manifestations in this group of patients. Although the association between African American ethnicity and clinical myocarditis is not surprising, it has nevertheless, not been described before. This association is unlikely to be due to confounding sociodemographic variables like poverty, education and access to healthcare through availability of health insurance because patients with and without clinical myocarditis did not differ significantly in these variables (data not shown).

Interestingly, Hispanics from Texas have been previously shown to develop cardiovascular involvement almost as frequently as the African Americans early in SLE [11], yet clinical myocarditis does not seem to be one of these manifestations. It is conceivable, however, that clinical myocarditis may have been missed if these patients had not been very symptomatic and thus they might not have sought medical care. This is indeed a possibility given the relatively high proportion of uninsured among them (51%) as compared with patients in the other groups (2–16%). The proportion of Hispanics from Puerto Rico who developed clinical myocarditis was much lower than for any other ethnic group; although this group was included in the cohort later than the others, this is unlikely to explain the lower incidence because nearly all clinical myocarditis in our population developed relatively early. We have previously shown that Puerto Rican Hispanic SLE patients have a milder course with much lower disease activity and damage at baseline than Hispanics from Texas [31], and their lower frequency of clinical myocarditis is consistent with this finding.

Clinical myocarditis was associated with disease activity at TD, perhaps because most patients developed myocarditis early in the disease and before their inclusion into the LUMINA cohort; in contrast, we found no association between clinical myocarditis and disease activity over the duration of the disease, most likely because myocarditis was an early event in our patients. Several findings suggest that their overall disease was more serious: they had a significantly higher number of ACR criteria at diagnosis, higher damage accrual, higher physician and patient global assessments of disease activity at T0, and developed renal and haematological involvement more frequently. They also had higher ESR levels and were more likely to be treated with glucocorticoids (and at higher dose) and mycophenolate mofetil.

The likely explanation for myocarditis is acute and chronic inflammation, with accompanying auto-antibody formation, as part of the underlying pathogenesis of SLE. The presence of anti-Ro antibodies has been variably associated with the development of myocarditis in SLE [4, 13, 32]. One report of this association [33] led to our hypothesis that the presence of anti-Ro and aPL antibodies at T0 would be associated with myocarditis. Our failure to corroborate these relationships may be due to the time when these antibodies were measured (T0) relative to the time when myocarditis actually occurred (close to TD).

Clinical myocarditis was significantly associated with higher damage (SDI) at TL in the univariable analysis adjusted for total duration of disease. Since we excluded potential markers of myocarditis (the heart failure, valvular disease and pericarditis components of SDI from the damage index), the higher SDI in the myocarditis group indicates accrual of overall damage rather than only cardiac damage as a consequence of myocarditis. Our finding in multivariable analysis of a borderline statistically significant association of myocarditis with damage indicate that this is not a strong predictor of damage accrual, but rather a relatively minor one as compared with others that have been constantly found in this and other analyses of our cohort. For example, SDI at T0, Hispanic (Texas) and African American ethnicities had the strongest relationship with damage at TL, while older age, higher levels of abnormal illness-related behaviours and disease activity had smaller effects on damage [34–37]. The backward elimination method for reducing the multivariable model allowed easier examination of a large number of variables, but it may not have identified the ‘best’ predictive combination of variables. Furthermore, our alternative multivariable analyses suggest that clinical myocarditis is also highly associated with an elevated ESR, which is not surprising given the inflammatory nature of this clinical event; in this alternative analyses, medications were not found to be positively or negatively associated with clinical myocarditis.

Mortality was higher in the clinical myocarditis than the non-myocarditis group (18.9% vs 8.4%), particularly after 5 yrs of disease. Survival as a function of the presence or absence of clinical myocarditis was almost parallel for the first 5 yrs, after which a steep drop occurred for those patients who had had myocarditis. Myocarditis was significant in a univariable Cox regression but not in the multivariable Cox proportional hazards regression. SDI at T0, SLAM-R at T0 were highly significant and poverty was of borderline significance. However, the elimination of myocarditis may be an ‘artefact’ of modelling because clinical myocarditis had higher SDI at T0, and SDI in turn showed a highly significant association with mortality. In other words, myocarditis may exert its effect on mortality in these patients indirectly through higher damage accrual as measured by SDI. Taken all together, our data suggest that SLE patients who develop myocarditis tend to have more serious disease manifestations than those who do not develop it.

Our study was not without limitations. First and foremost, we recognize that our definition of clinical myocarditis has some inherent problems; the subclinical nature of myocarditis and the fact that SLAM-R measures manifestations occurring in the 4 weeks prior to visits may have obscured its recognition in some patients. Further, by excluding patients with other cardiac manifestations suggestive of undetected myocarditis, we could not examine conduction defects, congestive heart failure and valvular heart disease and their impact on mortality. Second, since myocarditis was an early manifestation in our patients, limited clinical data were available prior to the event, and often only data from the baseline visit could be used to examine associations; for example, data on troponin or brain natriuretic peptide or other ‘marker’ of myocardial injury were not available to corroborate our clinical definition of myocarditis; however, we know that the proportion of patients with high ESR as per the categories of the SLAM-R was greater in the myocarditis than in the non-myocarditis group of patients indicating the acuteness of the event. Third, detailed data as to how patients were managed for their myocarditis per se were not available although we know that they were more likely to be treated with glucocorticoids (and a higher dose) and mycophenolate mofetil. Finally, the near absence of myocarditis in Hispanics from Puerto Rico precluded any inferences about the condition in this ethnic subgroup.

In summary, myocarditis developed early in the course of disease in our SLE patients of African American ethnicity and with higher SLAM-R at diagnosis. We believe this is the first report of an association between African American ethnicity and myocarditis. Myocarditis was not associated with higher disease activity over time but probably had some impact on damage accrual. Patients who developed myocarditis experienced higher mortality, especially after 5 yrs of disease duration, probably due to the higher damage accrued. Our study thus suggests that the occurrence of myocarditis in lupus patients has intermediate and long-term consequences.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors acknowledge all LUMINA patients, without whom this study would not have been possible, the supporting staff (Martha L. Sanchez, MD, MPH and Ellen Sowell at the University of Alabama at Birmingham, AL, Carmine Pinilla-Diaz, MT, at the University of Puerto Rico Medical Sciences Campus, PR and Robert Sandoval, BA, at the University of Texas Health Science Center at Houston, TX, USA) for their efforts in securing patient follow-up and performing other LUMINA-related tasks and Maria Tyson, AA, for her expert assistance in the preparation of the manuscript.

Funding: Supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases R01-AR42503 (UAB, UPR, UTH), General Clinical Research Centers M01-RR02558 (UTH) and M01-RR00032 (UAB) and from the National Center for Research Resources (NCRR/NIH) RCMI Clinical Research Infrastructure Initiative (RCRII) award 1P20RR11126 (UPR).

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 13 June 2007; revised version accepted 13 December 2007.
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