Clinical Chemistry 48: 1681-1688, 2002;
(Clinical Chemistry. 2002;48:1681-1688.)
© 2002 American Association for Clinical Chemistry, Inc.
Neopterin and Quinolinic Acid Are Surrogate Measures of Disease Activity in the Juvenile Idiopathic Inflammatory Myopathies
Lisa G. Rider1,2,1a,
Adam S. Schiffenbauer2,1,
Mark Zito3,
Ken L. Lim4,5,
Alaa Ahmed6,
Lawrence S. Zemel7,
Robert M. Rennebohm8,
Murray H. Passo9,
Ronald M. Summers10,
Jeanne E. Hicks11,
Peter A. Lachenbruch12,
Melvyn P. Heyes3,13 and
Frederick W. Miller1,2 in cooperation with the Juvenile Dermatomyositis Disease Activity Collaborative Study Group
1 Laboratory of Molecular and Developmental Immunology, Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, MD 20892, and Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892.
2 Environmental Autoimmunity Group, National Institute of Environmental Health Sciences (NIEHS), NIH, Bethesda, MD 20892.
3 Laboratory of Neurotoxicology, National Institute of Mental Health (NIMH), NIH, Bethesda, MD 20892.
4 Department of Medicine and Rheumatology, University of Glasgow, Glasgow Royal Infirmary, Glasgow G31 2ER, Scotland.
5 Sherwood Forest Hospitals NHS Trust, Kings Mill Centre, Notts NG17 4JL, England.
6 Specialty Laboratories, Santa Monica, CA 90404.
7 Connecticut Children’s Medical Center, University of Connecticut, Hartford, CT 06106.
8 Columbus Children’s Hospital, Ohio State University, Columbus, OH 43205.
9 Children’s Hospital, University of Cincinnati, Cincinnati, OH 45229.
Departments of
10
Radiology and
11
Rehabilitation Medicine, Clinical Center (CC), NIH, Bethesda, MD 20892.
12 Division of Biostatistics, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, MD 20852.
13 Curagen Inc., Branford, CT 06405.
aAddress correspondence to this author at: Environmental Autoimmunity Group, NIEHS, NIH, 9 Memorial Dr., Room 1W101, MSC 0958, Bethesda, MD 20892. Fax 301-480-4127; e-mail RIDER{at}niehs.nih.gov.
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Abstract
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Objective: We evaluated the utility of neopterin and quinolinic acid (QUIN) as surrogate measures of disease activity in juvenile idiopathic inflammatory myopathies (IIMs).
Methods: Plasma and first morning void urine samples were measured for neopterin and QUIN using commercial ELISA, HPLC, or gas chromatography–mass spectrometry in 45 juvenile IIM patients and 79 healthy controls. Myositis disease activity assessments were obtained.
Results: Plasma and urine neopterin and QUIN concentrations were increased in juvenile IIM patients compared with healthy controls (P <0.017). Urine neopterin and QUIN highly correlated with each other (rs = 0.73; P <0.0001). Urine neopterin and QUIN correlated moderately with myositis disease activity assessments, including physician and parent global activity assessments, muscle strength testing, functional assessments (Childhood Myositis Assessment Scale, Childhood Health Assessment Questionnaire), skin global activity, and edema on magnetic resonance imaging (rs = 0.42–0.62; P <0.05), but generally not with muscle-associated enzymes in serum. Urine neopterin or QUIN, in combination with either serum lactate dehydrogenase (LD) or aspartate aminotransferase (AST), significantly predicted global disease activity (R2 =0.40–0.56; P <0.002), and both were more sensitive to change than these serum enzymes (standardized response means, -0.41 to -0.48).
Conclusions: Urinary neopterin and QUIN are candidate measures of disease activity in juvenile IIM patients and add significantly to the prediction of global disease activity in combination with serum LD or AST values. Measurement of these markers in first morning void urine specimens appears to be as good as, or possibly better than, measurements of their concentrations in plasma.
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Introduction
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The juvenile idiopathic inflammatory myopathies (IIMs)
2
are chronic inflammatory diseases that affect primarily muscle, skin, and less commonly, other organ systems. Dermatomyositis (DM), the most common of these disorders in children, involves chronic infiltration of B and T lymphocytes, as well as monocytes/macrophages, around the capillaries and arterioles of muscle and other affected organs (1). Recent immunopathologic studies also support a role for monocyte and endothelial cell-derived cytokines, particularly interleukin-1-
(IL-1) and tumor necrosis factor- (TNF-), in the pathogenesis of the IIM (2)(3). Although several measures have recently been validated to assess disease activity in juvenile IIM, few are objective and few discriminate between active disease and disease-related damage (4)(5). Muscle enzyme activities in serum are used to serially monitor disease activity in IIM patients; however, in juvenile patients, concentrations of these enzymes are sometimes within reference values even in the presence of active disease (6).
Neopterin, an aromatic pteridine derived from intracellular guanosine triphosphate, is released primarily by human macrophages and monocytes on stimulation by T-lymphocyte-derived interferon-
(IFN-). Serum and urine neopterin concentrations are increased in numerous infectious and malignant and inflammatory disorders, and correlate with disease activity in rheumatic diseases, including systemic lupus erythematosus, rheumatoid arthritis, and Wegener granulomatosis (7)(8)(9). Although IFN- is the most potent inducer of neopterin synthesis, neopterin production may also be triggered by other immune activators, including other interferons, IL-1, TNF-, and lipopolysaccharide (10). Endothelial cells may also produce neopterin in vitro, and this production is augmented in the presence of IFN- in combination with TNF- (11). Serum concentrations of neopterin are increased in juvenile and adult patients with DM and polymyositis and correlate with muscle strength and function in juvenile DM (12)(13).
Quinolinic acid (QUIN) is generated through the metabolism of L-tryptophan in the kynurenine pathway and is produced by macrophages and brain tissue (14)(15)(16). Similar to neopterin, IFN- is the primary inducer of QUIN production, although IFN-, TNF-, IL-6, and lipopolysaccharide are alternative activators (15)(17). QUIN is increased in the cerebrospinal fluid and peripheral blood of patients with central nervous system inflammatory diseases, including those with neuropsychiatric systemic lupus erythematosus, and is increased in the peripheral blood of patients with L-tryptophan-associated eosinophilia-myalgia syndrome (18)(19).
Because of the limitations of current measures in assessing disease activity in juvenile IIM, we further investigated the role of neopterin and also examined QUIN, a related marker of cellular immunity, as surrogate measures of disease activity. We examined peripheral blood concentrations and first morning void urine samples, considering that urine neopterin concentrations are generally 300-fold more concentrated in morning urine samples compared with serum and may thus be potentially more sensitive disease markers (20).
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Patients and Methods
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patients and controls
Approval from the Institutional Review Boards of all participating centers was obtained, and all participants or their parents/legal guardians provided informed assent or consent to participate. Forty-five patients with probable or definite juvenile IIM (39 with juvenile DM, 3 with juvenile polymyositis, and 3 with juvenile DM overlapping with another connective tissue disease), enrolled from four participating centers from 1994 to 1997, were evaluated at a baseline assessment, and 23 patients had a follow-up evaluation at 7–9 months (21). The mean (SD) age of the juvenile IIM patients was 9.8 ± 4.1 years (range, 3.7–17.7 years), and duration of active disease averaged 23 ± 24 months (range, 1–110 months; Table 1
). Eighty-four percent of patients were receiving prednisone, at a mean dose of 0.4 ± 0.6 mg · kg-1 · day-1 (range, 0–2.2 mg · kg-1 · day-1), but the morning dose of prednisone was held before sample collection. Thirty-eight patients had evidence of active disease at initial assessment. None of the patients had a neuropathy, central nervous system vasculitis, or infection.
Using standardized assessments, a pediatric rheumatologist assessed Physician Global Disease Activity, Skin Global Activity, and the Childhood Myositis Assessment Scale (CMAS) at each visit, as described previously (22)(23) (Table 1
). Pediatric physical therapists assessed muscle strength on the Kendall 10-point scale in 21 patients seen at a single center, using 26 proximal, distal, and axial muscle groups (score range, 0–120) (24). All parents completed a global activity assessment and the Childhood Health Assessment Questionnaire (CHAQ) (22). Serum concentrations of skeletal muscle-associated enzyme activities, including creatine kinase, aldolase, lactate dehydrogenase (LD), aspartate aminotransferase (AST), and alanine aminotransferase, were also obtained at each assessment and converted to a standardized reference interval, because of the varying upper limits of normal at the four participating centers. All clinical evaluations were performed blinded to the neopterin and QUIN results. Short-tau inversion recovery or fat-suppressed T2-weighted magnetic resonance imaging of the proximal thighs was obtained from 22 patients and read by a single radiologist blinded to the clinical findings. Both subcutaneous edema and muscle activity were scored on a Likert scale [0 (inactive) to 4 (extremely severe edema)], as described previously (24).
Seventy-nine healthy volunteers, enrolled from 1995 to 1997, were used as controls to establish childhood reference intervals for urine creatinine, as well as urine and plasma neopterin and QUIN (Table 1
). Controls were free of infectious illnesses and received no immunizations within 4 weeks of enrollment. Subgroups of controls did not differ in age, gender, or ethnic background.
neopterin
Plasma neopterin (nmol/L) was measured by ELISA (American Laboratory Products Company) performed by Specialty Laboratories (Santa Monica, CA) in 13 juvenile IIM patients and 35 controls, with samples diluted 1:200 (5 µL in 995 µL of sample diluent). A first morning void sample from 45 patients and 79 controls was measured for neopterin in the laboratory of one coauthor (K. Lim) by reversed-phase HPLC as described previously and expressed as the µmol/L neopterin relative to the age-adjusted urine creatinine concentration (9). Urine creatinine was determined by a kinetic alkaline picrate (Jaffe) method (9). Because of the presence of an age-dependent variation in urine creatinine (25), a regression model for urine creatinine was developed using the healthy controls (mean urine creatinine in controls = 6.3016 +0.40295 x age; adjusted R2 =0.13; P = 0.0007). Each patient’s actual urine creatinine concentration (nmol/L) was divided by the mean age-adjusted creatinine concentration determined by the regression model. After this adjustment in urine creatinine, no age-dependent variation in urine creatinine, neopterin, or QUIN was present. Although this was a highly significant linear relationship, the coefficient of multiple determination (R2) was low, and the regression equation did not capture all of the variation in the urine creatinine/age relationship. All samples were collected in containers wrapped in aluminum foil to avoid exposure to sunlight, were stored at -80 °C, and were analyzed without knowledge of the participant’s clinical status or clinical findings. Samples were shipped between enrollment sites and laboratories on dry ice.
quin
QUIN was measured in the plasma from 24 juvenile IIM patients and 74 controls and in first morning void urine samples from 36 patients and 68 controls by a modified gas chromatographic–mass spectrometric assay performed in the Laboratory of Neurotoxicology, National Institute of Mental Health (NIMH), NIH (26). All specimens were assayed without knowledge of the individual’s clinical status or clinical findings. Plasma (20 µL) or urine (100 µL) and QUIN calibrators were mixed with 200 µL of deionized water containing 30 pmol of [2H3]QUIN as an internal standard. Samples were freeze-dried overnight. QUIN and [2H3]QUIN were derivatized to dihexafluoroisopropanol esters (hexaflouroisopropanol and trifluoroacetylimidazole; 50 µL each), heated to 80 °C for 1 h, washed with 500 µL of water, and extracted into 300 µL of heptane. Extracts were injected directly (1 or 2 µL) onto a 1-m deactivated silica precolumn attached to a 15-m BD5 analytical column (J&W Scientific; 110 °C isothermal). QUIN was quantified using a Hewlett-Packard Model 5988 quadrupole mass spectrometer operated in the electron capture negative chemical ionization mode with methane reagent gas. The molecular anions of QUIN (m/z 467) and [2H3]QUIN (m/z 470) were monitored, and each peak was quantified at the appropriate retention time. Plasma QUIN was expressed as nmol/L and urine QUIN as µmol/L per age-adjusted urine creatinine concentration, as described above.
statistics
Differences between patients and controls were examined by the Wilcoxon signed-rank test. Spearman rank correlations were used to examine the correlation between activity measures and neopterin or QUIN. Linear regression modeling was used to estimate the contribution of neopterin and QUIN to global disease activity. Standardized response mean (SRM) was used to examine responsiveness between baseline and 7- to 9-month follow-up assessments (22). Because this is an exploratory study, any cited P values should be considered descriptive. P values were deemed significant based on an of 0.05 and were adjusted for multiple comparisons using the Holm procedure (27). Only significant adjusted P values are reported.
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Results
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Median plasma (3.8 nmol/L) and urine (5.1 µmol/L) neopterin were higher in juvenile IIM patients (Fig. 1A
) than in healthy controls [1.5 nmol/L (P =0.017) and 1.7 µmol/L (P <0.0001), respectively]. Median plasma (582 nmol/L) and urine (84 µmol/L) QUIN concentrations were also increased in juvenile IIM patients (Fig. 1B
) compared with healthy childhood controls [424 nmol/L (P = 0.002) and 41 µmol/L (P <0.0001), respectively]. The sample size of inactive patients was inadequate to separately compare active and inactive patients.
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Figure 1. Plasma (A) and urine (B) neopterin and plasma (C) and urine (D) QUIN concentrations in IIM patients and controls.
Plasma (A) and urine (B) neopterin concentrations are significantly higher in juvenile IIM patients than in healthy controls (P = 0.017 and P <0.0001, respectively). Plasma (C) and urine (D) QUIN concentrations are also significantly higher in juvenile IIM patients compared with healthy controls (P = 0.002 and P <0.0001, respectively). Horizontal lines denote median values.
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There was no significant correlation between any of the neopterin or QUIN concentrations and either prednisone dose (rs = 0.06–0.15; P 
0.29) or duration of active disease (rs =0.35–0.36; P 0.11), nor was a relationship observed between the presence of calcinosis and these markers (P = 0.12–0.7). Urine QUIN was higher in juvenile IIM patients with a history of cutaneous or gastrointestinal ulcerations (median, 129 µmol/L) than in those without ulcerative disease (median, 70.5 µmol/L; P = 0.01). None of the other markers showed a significant relationship with a history of cutaneous or gastrointestinal ulcerations (P 0.31).
Regarding the relationship of these markers to each other on initial assessment, plasma and urine QUIN correlated with each other (rs = 0.60; P <0.01). Urine neopterin and QUIN showed a strong correlation (rs = 0.73; P <0.0001;Fig. 2
). Plasma QUIN did not correlate with plasma or urine neopterin, and plasma neopterin was not significantly correlated with urine neopterin or QUIN (rs = 0.02–0.56;P >0.06), although this may reflect a small sample size for the number of plasma neopterin samples tested (n = 13).
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Figure 2. Correlation of urine QUIN and neopterin (A), physician global assessment of disease activity (B), CMAS (C), and CHAQ (D) in juvenile IIM patients.
MD, physician; VAS, Visual Analog Scale.
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Urine neopterin and QUIN were significantly correlated with various clinical measures of myositis disease activity, including physician and parent global assessments of disease activity (rs = 0.42–0.55, respectively;P <0.01), manual muscle testing total score (rs = -0.62 and -0.61; P <0.05), CMAS score (rs = -0.50 and -0.57; P <0.01), CHAQ (rs = 0.54 and 0.58; P <0.01), and skin global activity (rs = 0.49 for urine neopterin;P <0.01; Fig. 2
). Urine neopterin and QUIN were also significantly correlated with muscle edema present on magnetic resonance imaging (rs = 0.55 and 0.57;P <0.01). Neither measure correlated with any of the muscle-associated enzymes in serum, including the activities of creatine kinase, aldolase, LD, or AST (rs = 0.02–0.35; P >0.05). Plasma neopterin and QUIN did not correlate with myositis disease activity measures, although this analysis was limited by the small sample size (n = 9–13) for plasma neopterin.
Using linear regression analysis, we assessed how well neopterin and QUIN predicted Physician Global Disease Activity relative to LD and AST in 28 patients with all four measures available, with particular interest in modeling physician global activity because we had previously demonstrated this to be a valid and comprehensive measure of disease activity in juvenile IIM (23). LD and AST were particularly examined, as these two muscle-associated enzymes were previously reported to be good indicators of disease activity in juvenile DM (28)(29). Urine neopterin and QUIN concentrations were individually better predictors of global disease activity than either LD or AST alone, although all significantly predicted global disease activity in univariate models (Table 2
). In multiple regression modeling, a model consisting of either one of the urine markers combined with LD or AST improved the prediction of global disease activity substantially above the univariate models (Table 2
). Urine neopterin and urine QUIN highly correlated with each other; therefore, adding one to a model containing the other led to neither significantly predicting global activity (data not shown). The best model of global disease activity combined urine neopterin, LD, and AST, which explained 63% of the variance in total global disease activity as assessed by the physician. Insufficient data existed to examine plasma neopterin and plasma QUIN in predicting global disease activity.
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Table 2. Prediction of physician global disease activity from urine neopterin and QUIN concentrations and selected serum muscle-associated enzyme activities, using linear regression modeling.
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Although relatively little follow-up data were available, the responsiveness of urine neopterin and QUIN was examined and compared with Physician Global Disease Activity as well as LD and AST (Table 3
). Physician Global Disease Activity was sensitive to change (SRM = -1.1), whereas neopterin and QUIN were moderately responsive over the 8-month period of observation (SRM = -0.48 and -0.41, respectively). Both measures, however, were more sensitive to change than either LD or AST alone (SRM = -0.07 to -0.37).
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Table 3. Sensitivity to changes in urine neopterin and QUIN concentrations over 7–9 months compared with serum muscle-associated enzyme activities and Physician Global Activity.
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Discussion
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This is the first study to demonstrate that plasma and urine neopterin, as well as plasma and urine QUIN, is increased in juvenile IIM patients compared with healthy controls. Because both QUIN and neopterin are produced and secreted by activated macrophages, these data support a role for macrophages in the pathogenesis of juvenile myositis. Nonetheless, these mediators may also be derived from other tissue sources in juvenile DM, and current evidence suggests that under certain circumstances endothelial cells may produce neopterin and skeletal muscle may produce QUIN (15)(16). QUIN may also be produced in the brain (16), but none of these patients had evidence of central nervous system vasculitis or other neurologic pathology. The strong correlation between urine neopterin and QUIN, however, supports the concept that macrophages are their primary source in juvenile IIM rather than other tissues. Pachman et al. (30) also found a strong correlation between serum neopterin and macrophage expression in juvenile DM muscle biopsies. Although IFN- is an important activator of the production of both neopterin and QUIN, interestingly, both may be activated by TNF- and QUIN may also be activated by IL-1; both cytokines are present in the affected muscle tissue of IIM patients (2)(3). In adult IIM, in fact, serum neopterin correlates with soluble TNF receptors (13).
Urine neopterin and QUIN both correlated moderately to strongly with several different clinical measures of myositis disease activity, including global activity assessments, measures of muscle strength and function, and with muscle edema present on magnetic resonance imaging examination. The correlations of these urine measures with myositis disease activity measures were stronger than with plasma neopterin or QUIN. The poor correlation between circulating neopterin and muscle strength and functional measures, in contrast to a previous study of juvenile DM patients (12), may be attributable in part to the small sample size available in the current study for plasma measurements, but it is also consistent with data from a study of adult DM/polymyositis (13).
In the present study, urine neopterin and QUIN concentrations, in combination with LD and AST activities, also were good predictors of Physician Global Disease Activity. In fact, each correlated better with physician global assessments than either LD or AST alone (29), two serum muscle enzymes that have previously been found to be valuable in the assessment of juvenile DM disease activity (28). Both urine neopterin and QUIN were also moderately sensitive to change, and in this regard, again they were more responsive than either serum LD or AST activity. Therefore, either marker may improve the assessment of disease activity in juvenile IIM over the serum muscle enzymes that are routinely used in the clinical assessment of patients, although in combination with these enzymes, disease activity assessment may be even further enhanced.
Urine neopterin and QUIN concentrations were 2- to 3-fold increased over control values compared with only a 1.4- to 2.5-fold increase in the plasma measures over reference values, and first morning void urine values were 100- to 1000-fold more concentrated than their corresponding plasma measurements. Urine and plasma measurements of QUIN did correlate moderately. The higher concentrations and stronger correlation of urine markers with myositis disease activity measures suggest that first morning void urine measurements of neopterin and QUIN are potentially more useful than the corresponding plasma values as surrogate measures of disease activity. Urine samples are also easier to collect than blood samples from children, giving them a practical advantage over other tests. Additionally, the neopterin test is commercially available for clinical evaluation of patients. Neopterin is stable in frozen serum or urine for long periods of time, so it can be shipped, but because of its sensitivity to light, it should be kept in a container with no light access (7)(8).
In summary, urine neopterin and QUIN concentrations appear to be useful surrogate measures of disease activity in juvenile IIM and to significantly predict global activity. Adding information regarding the activity of a single muscle enzyme, either LD or AST, to these measures appears to further enhance the prediction of global activity. Thus, measuring urine neopterin and QUIN may have particular value in clinically assessing patients when serum concentrations of muscle enzymes are within the reference intervals and when it is not clear from the clinical assessment of strength and function whether myositis disease activity is contributing to the patient’s disabilities.
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Acknowledgments
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We thank Drs. Patience White, Ildy Katona, Stephen George, Stephen Ray Mitchell, Carol Lindsley, and Balu Athreya for patient referrals. We thank Drs. Gyorgy Csako and Rafaela Goldbach-Mansky for critical reading of the manuscript. This study was supported by funding from the intramural research programs of the Center for Biologics Evaluation and Research, Food and Drug Administration (L.G. Rider, P.A. Lachenbruch, and F.W. Miller); the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH (L.G. Rider and F.W. Miller);the National Institute of Mental Health, NIH (M. Zito and J.E. Heyes);the Clinical Center, NIH (R.M. Summers and J.E. Hicks); and by Specialty Laboratories. Dr. Lim was the recipient of the Davidson Lecturer in Medicine and Rheumatology at the University of Glasgow.
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Footnotes
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1 These authors contributed equally. 
2 Nonstandard abbreviations: IIM, idiopathic inflammatory myopathy; DM, dermatomyositis; IL-1, interleukin-1; TNF-, tumor necrosis factor-; IFN-, interferon-; QUIN, quinolinic acid; CMAS, Childhood Myositis Assessment Scale; CHAQ, Childhood Health Assessment Questionnaire; CK, creatine kinase; LD, lactate dehydrogenase; AST, aspartate aminotransferase; and SRM, standardized response mean.
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Abstract
Introduction
