High‐sensitivity C‐reactive protein,disease activity,and cardiovascular risk factors in systemic lupus erythematosus

Objective

To study the level of high‐sensitivity C‐reactive protein (hsCRP) and its relationship with disease activity, damage, and cardiovascular risk factors in patients with systemic lupus erythematosus (SLE).

Methods

Consecutive patients who fulfilled ≥4 American College of Rheumatology criteria for SLE who did not have a concurrent infection were recruited. Blood was assayed for hsCRP level, and disease activity, organ damage of SLE, and cardiovascular risk factors were assessed. Linear regression analyses were performed for the relationship between hsCRP levels, SLE activity, damage, and cardiovascular risk factors.

Results

In total, 289 patients were studied (94% women, mean ± SD age 39.0 ± 13.1 years, and mean ± SD SLE duration 7.8 ± 6.7 years). The mean ± SD Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was 4.9 ± 5.6 and clinically active SLE was present in 122 patients (42%). The mean ± SD hsCRP level was 4.87 ± 12.7 mg/liter, and 28 patients with active SLE (23%) had an undetectable hsCRP level (<0.3 mg/liter). The linear regression analyses revealed a significant correlation between hsCRP level and musculoskeletal disease (β = 0.21), hematologic disease (β = 0.19), active serositis (β = 0.46), and clinical SLEDAI score (β = 0.24) after adjusting for age, sex, body mass index, serum creatinine, and the use of various medications (P < 0.005 for all). hsCRP levels correlated significantly with anti–double‐stranded DNA titer (β = 0.33, P < 0.001) but did not correlate with complement C3 (β = ?0.07, P = 0.26). An hsCRP level >3 mg/liter was significantly associated with male sex, long‐term smoking, diabetes mellitus, a higher atherogenic index, and a history of arterial thrombosis. hsCRP levels correlated significantly with pulmonary and endocrine damage scores.

Conclusion

hsCRP was detectable in 77% of SLE patients with clinically active disease and correlated with SLEDAI scores, particularly in serositis and in the musculoskeletal and hematologic systems. Elevated hsCRP levels in SLE were associated with certain cardiovascular risk factors and a history of arterial thromboembolism.

     

Dehydroepiandrosterone treatment of women with mild‐to‐moderate systemic lupus erythematosus: A multicenter randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the efficacy and tolerability of dehydroepiandrosterone (DHEA) at a dosage of 200 mg/day in adult women with active systemic lupus erythematosus (SLE).

Methods

In a multicenter randomized, double‐blind, placebo‐controlled trial, 120 adult women with active SLE received oral DHEA (200 mg/day; n = 61) or placebo (n = 59) for 24 weeks. The primary end point was the mean change from baseline in the Systemic Lupus Activity Measure (SLAM) score at 24 weeks of therapy. Secondary end points included time to first flare, change in SLE Disease Activity Index (SLEDAI) score, and physician's and patient's global assessment scores at week 24.

Results

The two groups were well balanced for baseline characteristics. Mean reductions in SLAM scores from baseline were similar and were not statistically significantly different between treatment groups (DHEA −2.6 ± 3.4 versus placebo −2.0 ± 3.8, mean ± SD). The number of patients with flares was decreased by 16% in the DHEA group (18.3% of DHEA‐treated patients versus 33.9% of placebo‐treated patients; P = 0.044, based on time to first flare). The mean change in the patient's global assessment was statistically significant between the two groups (DHEA −5.5 versus placebo 5.4; P = 0.005). The number of patients with serious adverse events, most of which were related to SLE flare, was significantly lower in DHEA‐treated patients compared with placebo‐treated patients (P = 0.010). Expected hormonal effects, including increased testosterone levels and increased incidence of acne, were observed. No life‐threatening reactions or serious safety issues were identified during this study.

Conclusion

The overall results confirm that DHEA treatment was well‐tolerated, significantly reduced the number of SLE flares, and improved patient's global assessment of disease activity.

     

Antibodies to high‐density lipoprotein and β2‐glycoprotein I are inversely correlated with paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome

Objective

To determine the prevalence of anti–high‐density lipoprotein (anti‐HDL) antibodies and to establish a possible relationship between anti‐HDL, anticardiolipin antibodies (aCL), anti–β₂‐glycoprotein I (anti‐β₂GPI), and paraoxonase (PON) activity in patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS).

Methods

Thirty‐two patients with SLE and 36 with primary APS were enrolled in a cross‐sectional study. Twenty age‐ and sex‐matched healthy subjects were used as controls. Serum levels of IgG and IgM aCL, anti‐β₂GPI, and antiprothrombin antibodies and IgG anti‐HDL were measured by enzyme‐linked immunosorbent assay. Total cholesterol, HDL cholesterol, HDL₂, and HDL₃ were determined by standard enzymatic techniques. PON activity was assessed by quantification of nitrophenol formation, and total antioxidant capacity (TAC) by chemiluminescence.

Results

Levels of total HDL, HDL₂, and HDL₃ were reduced in patients with SLE compared with controls (mean ± SD 0.51 ± 0.3, 0.37 ± 0.3, and 0.14 ± 0.1 mmoles/liter, respectively, versus 1.42 ± 0.9, 1.01 ± 0.7, and 0.40 ± 0.2). Patients with SLE and primary APS had higher titers of anti‐HDL antibodies and lower PON activity than controls. In the SLE population, PON activity was inversely correlated with IgG anti‐HDL titers (r = −0.48, P = 0.005) whereas in the primary APS population, IgG anti‐β₂GPI was the only independent predictor of PON activity (r = −0.483, P = 0.003). In the SLE group, anti‐HDL was inversely correlated with TAC (r = −0.40, P < 0.02), and PON activity was positively correlated with TAC (r = 0.43, P < 0.02).

Conclusion

IgG anti‐HDL and IgG anti‐β₂GPI antibodies are associated with reduced PON activity in patients with SLE and primary APS. Since the physiologic role of PON is to prevent low‐density lipoprotein oxidation with its attendant atherogenic effects, the reported interactions may be relevant to the development of atherosclerosis in SLE and primary APS.

     

Assessing utility values in rheumatoid arthritis: A comparison between time trade‐off and the EuroQol

Objective

To compare the utility values and quality‐adjusted life years (QALYs) obtained by the Time Trade‐Off instrument (TTO) and the EuroQol‐5D (EQ‐5D) in patients with rheumatoid arthritis (RA); to analyze the association between utility values and Disease Activity Score 28 (DAS28) and Health Assessment Questionnaire (HAQ).

Methods

We conducted a longitudinal, prospective, 1‐year study of RA patients selected randomly from 10 rheumatology clinics. TTO and EQ‐5D were administered at 4 scheduled visits.

Results

The study sample comprised 300 RA patients (82% women, mean age 59 years, mean disease duration 10.3 years). A total of 260 patients completed both the TTO and the EQ‐5D at baseline, and the mean ± SD TTO scores were significantly higher than the EQ‐5D scores (0.81 ± 0.22 versus 0.53 ± 0.35, P < 0.0001). The intraclass correlation coefficient (ICC) for the utility methods was 0.19. Data about changes in both TTO and EQ‐5D scores during the study year were available in 163 patients. These changes tended to be larger in the TTO scores than the EQ‐5D scores (mean ± SD 0.05 ± 0.25 versus ?0.005 ± 0.35, P = 0.054). The ICC for the mean changes in the utility scores was 0.24. Patients obtained a mean ± SD of 0.04 ± 0.20 QALYs based on TTO scores and 0.004 ± 0.27 based on EQ‐5D scores (P = 0.12). At baseline, the EQ‐5D scores were highly correlated with the HAQ (r = ?0.74) and moderately correlated with the DAS28 (r = ?0.47), whereas the TTO correlated poorly with both the HAQ and DAS28. Correlation between the mean change in the EQ‐5D and in the HAQ was moderate (r = ?0.55).

Conclusion

TTO and EQ‐5D do not yield the same utility values. The results suggest that the EQ‐5D is more representative of RA status than the TTO, a valuable conclusion when addressing economic evaluations in RA.

     

Expansion of toll‐like receptor 9–expressing B cells in active systemic lupus erythematosus: Implications for the induction and maintenance of the autoimmune process

Objective

Toll‐like receptors (TLRs) are pattern‐associated receptors in innate immunity that may be involved in the recognition of self antigens and the production of pathogenic autoantibodies. This study was undertaken to examine the expression and function of various TLRs in subpopulations of peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE).

Methods

The expression of TLRs in PBMCs from 50 SLE patients with active disease (SLE Disease Activity Index [SLEDAI] score ≥8; n = 26) or inactive disease (SLEDAI score <8; n = 24) and 20 healthy controls was studied by flow cytometry. TLR expression was assessed on various subpopulations of PBMCs (TLR‐2 and TLR‐4 by membrane staining; TLR‐3 and TLR‐9 by intracellular staining). TLR function was accessed by stimulating PBMCs with specific ligands.

Results

The proportion of B cells and monocytes expressing TLR‐9 was higher among patients with active SLE (mean ± SD 49.5 ± 24.4% and 30.7 ± 24.1%, respectively) than among patients with inactive disease (22.8 ± 19.6% and 14.3 ± 8.4%, respectively; P = 0.02 and P = 0.03). Among B cells, the proportion of plasma cells and memory B cells expressing TLR‐9 was increased in patients with active SLE. Increased percentages of TLR‐9–expressing B cells correlated with the presence of anti–double‐stranded DNA antibodies (P = 0.007). Treatment with serum from patients with active disease increased the percentage of TLR‐9–expressing plasma cells in serum from healthy controls. Enhanced induction of HLA–DR after TLR‐9 stimulation was documented in B cells from patients with active disease.

Conclusion

In patients with active SLE, the proportion of peripheral blood memory B cells and plasma cells expressing TLR‐9 is increased. Endogenous nucleic acids released during apoptotic cell death may stimulate B cells via TLR‐9 and contribute to SLE pathogenesis.

     

AC13, a C‐terminal fragment of apolipoprotein A‐I,is a candidate biomarker for microscopic polyangiitis

Objective

Microscopic polyangiitis (MPA) is necrotizing vasculitis of unknown etiology. We analyzed the serum peptide profile of MPA to find a biomarker for this disease.

Methods

Serum peptides from 33 patients with MPA, 7 with granulomatosis with polyangiitis (Wegener's), 7 with Churg‐Strauss syndrome, 6 with giant cell arteritis, and 25 with systemic lupus erythematosus (SLE) were comprehensively analyzed by mass spectrometry. Peptide function on human microvascular endothelial cells (HMVECs) was examined by enzyme‐linked immunosorbent assay and real‐time polymerase chain reaction.

Results

A total of 102 serum peptides were detected from the 78 patients. One of the peptides, peptide 1,523, showed significantly higher ion intensity in MPA (mean ± SD 46.8 ± 39.3 arbitrary units [AU]) than in the other systemic vasculitides (14.1 ± 12.2 AU) (P < 0.05) or in SLE (17.0 ± 12.1 AU) (P < 0.05). In MPA, peptide 1,523 showed significantly higher ion intensity before treatment than 1 week (P < 0.05) and 6 weeks (P < 0.05) after the initiation of treatment. Peptide 1,523 was identified as 13 C‐terminal amino acid residues of apolipoprotein A‐I (Apo A‐I) and was designated “AC13.” Validation of AC13 ion intensity using another MPA cohort (n = 14) similarly showed significantly higher ion intensity (90.1 ± 167.9 AU) compared to 14 patients with rheumatoid arthritis (8.6 ± 5.4 AU) (P < 0.01) and 14 healthy subjects (11.8 ± 6.1 AU) (P < 0.01). Serum concentrations of Apo A‐I and high‐density lipoprotein cholesterol were down‐regulated in MPA before treatment and returned to their normal ranges 6 weeks after the initiation of treatment (both P < 0.01). Stimulation of HMVECs with AC13 significantly up‐regulated secretion of interleukin‐6 (IL‐6) (P < 0.05) and IL‐8 (P < 0.01).

Conclusion

AC13, a candidate biomarker for MPA, may be useful for monitoring disease activity and may exacerbate vascular inflammation through up‐regulation of proinflammatory cytokines.

     

Assessment of atherosclerotic risk factors and endothelial function in children and young adults with pediatric‐onset systemic lupus erythematosus

Objective

To characterize atherosclerotic risk factors and endothelial function in pediatric‐onset systemic lupus erythematosus (SLE).

Methods

Lipoproteins, oxidized state, and autoantibodies to oxidized low‐density lipoprotein (Ox‐LDL) were assessed. Endothelial function was evaluated using brachial artery reactivity.

Results

Thirty‐three SLE patients and 30 controls were studied. SLE subjects had significantly decreased mean high‐density lipoprotein (HDL) cholesterol (41 mg/dl versus 51 mg/dl; P = 0.002) and apolipoprotein A‐I (97 mg/dl versus 199 mg/dl; P = 0.0004). There was no difference between groups in markers of oxidized state (including nitric oxide metabolites, isoprostanes, and Ox‐LDL) or in endothelial function. However, SLE subjects had increased median anti‐Ox‐LDL IgG (2,480 relative light units [RLU] versus 1,567 RLU; P = 0.0007) and IgG immune complexes with LDL (4,222 RLU versus 2,868 RLU; P = 0.002).

Conclusion

Pediatric SLE patients had significantly decreased levels of HDL cholesterol and apolipoprotein A‐I and elevated titers of autoantibodies to Ox‐LDL. Despite these atherosclerotic risk factors, SLE patients had normal measures of oxidized state and endothelial function.

     

Anaerobic exercise capacity in patients with juvenile‐onset idiopathic inflammatory myopathies

Objective

To 1) report the feasibility of an “all‐out” 30‐second cycling exercise test (Wingate Anaerobic Exercise Test [WAnT]) in juvenile‐onset idiopathic inflammatory myopathy (JIIM) patients, 2) describe the anaerobic exercise capacity in juvenile dermatomyositis patients, and 3) determine if the anaerobic exercise capacity could be related to disease duration or disease phase.

Methods

Twenty patients (age 14.13 ± 5.4 years) with JIIM participated in this study. All patients were able to perform the WAnT without adverse events.

Results

Comparison with healthy controls revealed a ?29.3 ± 26.58% (P = 0.001) and ?27.6 ± 25.7% (P = 0.002) impairment in mean power and peak power on the WAnT, respectively. The WAnT correlated with disease phase and with knee extensor muscle strength.

Conclusion

The WAnT might be a valuable adjunct next to other assessment tools in the followup of JIIM patients.

     

Health‐related quality of life in juvenile‐onset systemic lupus erythematosus and its relationship to disease activity and damage

Objective

To assess the health‐related quality of life (HRQL) of patients with juvenile‐onset systemic lupus erythematosus (JSLE) and its relationship with disease activity and accumulated damage.

Methods

In this cross‐sectional study, HRQL was assessed using the Child Health Questionnaire (CHQ), disease activity using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and accumulated damage using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).

Results

A total of 297 patients were included. The mean ± SD physical and psychosocial summary scores of the CHQ were 40.2 ± 15.0 and 44.8 ± 10.7, respectively. The most impaired CHQ subscales were global health, general health perceptions, and parent impact–emotional. The SLEDAI score was significantly correlated with both the physical summary score (r = ?0.29, P < 0.0001) and psychosocial summary score (r = ?0.25, P < 0.0001), whereas the SDI score was significantly correlated only with the physical summary score (r = ?0.23, P = 0.0001).

Conclusion

We found that patients with JSLE have significant impairment of their HRQL, particularly in the physical domain. HRQL may be affected by both disease activity and accumulated damage, particularly in the renal, central nervous, and musculoskeletal systems.

     

Cognitive–behavioral therapy attenuates nociceptive responding in patients with fibromyalgia: A pilot study

Objective

To explore the possibility that cognitive–behavioral therapy (CBT) influences fibromyalgia symptoms via descending inhibition of nociception, we evaluated the effects of CBT on the nociceptive flexion reflex (NFR) threshold, an objective measure of spinal nociceptive transmission.

Methods

Female fibromyalgia patients (n = 32) were randomized to 6 weekly sessions of telephone‐delivered CBT or usual care (UC). Assessments of the NFR threshold and clinical outcomes were conducted at baseline, week 6 (post‐CBT), and week 12.

Results

From baseline to week 6, the NFR threshold increased in the CBT group and decreased in the UC group (mean ± SD 4.4 ± 13.7 mA versus ?10.2 ± 9.9 mA; P = 0.005). This difference was also apparent at week 12 (mean ± SD 7.3 ± 9.2 mA for CBT versus ?5.4 ± 13.5 mA for UC; P = 0.01). The groups reported similar reductions in NFR pain ratings at week 6 (mean ± SD ?20.2 ± 23.9 for CBT versus ?14.9 ± 16.4 for UC; P = 0.8) and week 12 (mean ± SD ?8.9 ± 25.3 for CBT versus ?10.8 ± 24.1 for UC; P = 0.4).

Conclusion

Compared with UC, CBT reduced nociceptive responding in fibromyalgia patients. Moreover, while the UC group exhibited longitudinal decreases in both the stimulation level and pain associated with the NFR threshold, those receiving CBT required more intense stimulation to elicit the NFR as well as rated that stimulation as less painful than at baseline. These data indicate the need for a larger study to confirm that changes in nociceptive responsivity may underlie the benefits of CBT in fibromyalgia patients.

     

Increased thickness of the arterial intima‐media detected by ultrasonography in patients with rheumatoid arthritis

Objective

To determine whether arterial wall thickening is advanced in rheumatoid arthritis (RA) patients compared with healthy controls by measuring the intima‐media thickness (IMT) of the common carotid and femoral arteries, and to evaluate the factors associated with arterial IMT in patients with RA.

Methods

We studied 138 RA patients and 94 healthy controls (matched for age, sex, and other major risk factors for atherosclerosis). IMT was measured on digitized still images of the common carotid and femoral arteries obtained by high‐resolution ultrasonography (10‐MHz in‐line Sectascanner). Laboratory variables relevant to RA activity were measured by routine methods. The degree of RA progression was assessed by scoring (Larsen method) metacarpophalangeal (MCP) joints on hand radiographs. Activities of daily living were determined by a modified Health Assessment Questionnaire (M‐HAQ) score, and physical activity levels were assessed by ultrasound measurement of the calcaneus (expressed as the osteo‐sono assessment index [OSI] Z score).

Results

Common carotid and femoral artery IMTs were significantly higher (P < 0.05) in RA patients (mean ± SD 0.641 ± 0.127 and 0.632 ± 0.125 mm, respectively) compared with controls (0.576 ± 0.115 and 0.593 ± 0.141 mm, respectively). Multiple regression analysis revealed a significant association between RA and the common carotid artery IMT. Moreover, the common carotid artery IMT in RA patients was positively associated with disease duration, the MCP joint Larsen score, and the M‐HAQ score, and was negatively associated with the calcaneus OSI Z score. No significant association was found between corticosteroid treatment and common carotid artery IMT.

Conclusion

RA patients exhibited greater thickness of the common carotid and femoral arteries than healthy controls. The duration and severity of RA and decreased activities of daily living, but not corticosteroid treatment, were independently associated with the increased arterial wall thickness.

     

sE‐selectin for stratifying outcome in rheumatoid arthritis

Objectives

To determine the usefulness of sE‐selectin as a marker for early diagnosis and stratification of rheumatoid arthritis.

Methods

We investigated several markers of disease activity, including circulating adhesion molecules and other standard laboratory tests, in a 2–3 year followup analysis of patients with rheumatoid arthritis.

Results

The mean ± SD levels of sE‐selectin (91.68 ± 31.8 ng/ml versus 49.83 ± 14.76 ng/ml) and rheumatoid factor (375.7 ± 394.4 U versus 44.66 ± 37.63 U) were strongly elevated in severe (n = 15) versus mild (n = 7) courses of disease. Statistical calculation of mean and standard deviation revealed that sE‐selectin represents a highly significant marker for the presence of persistent and aggressive disease over time, regardless of therapeutic intervention and observation time points (P = 0.0004). Notably, regression analysis identified constant values for all parameters analyzed and, therefore, a stable course of the disease could be predicted from the beginning.

Conclusion

sE‐selectin appears to be a powerful marker to predict the severity of rheumatoid arthritis.

     

Proinflammatory high‐density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis

Objective

Women with systemic lupus erythematosus (SLE) have a 7–50‐fold increased risk of coronary artery disease (CAD). In the general population, oxidized low‐density lipoprotein (ox‐LDL) increases the risk for CAD. Normal high‐density lipoproteins (HDLs) protect LDL from oxidation; proinflammatory HDLs do not. This study was undertaken to determine whether patients with SLE, who have chronic inflammation that causes oxidative damage, have more proinflammatory HDL and higher levels of ox‐LDL, thus predisposing them to atherosclerosis.

Methods

One hundred fifty‐four women with SLE, 48 women with rheumatoid arthritis (RA), and 72 healthy controls were studied. The ability of the patients' HDL to prevent oxidation of normal LDL was measured. Values >1.0 (the value assigned for LDL oxidation in the absence of HDL) after the addition of HDL indicated proinflammatory HDL. Plasma ox‐LDL levels were measured as the amount of oxidation produced by the patient's LDL after the removal of HDL.

Results

SLE patients had more proinflammatory HDL (mean ± SD score 1.02 ± 0.57, versus 0.68 ± 0.28 in controls [P < 0.0001] and 0.81 ± 0.22 in RA patients [P = 0.001 versus SLE patients]). A higher proportion of SLE patients had proinflammatory HDL: 44.7% of SLE patients versus 4.1% of controls and 20.1% of RA patients had scores >1.0 (P < 0.006 between all groups). Levels of ox‐LDL correlated with levels of proinflammatory HDL (r = 0.37, P < 0.001). SLE patients with CAD had significantly higher proinflammatory HDL scores than patients without CAD (P < 0.001).

Conclusion

HDLs are proinflammatory in a significant proportion of SLE patients and are associated with elevated levels of ox‐LDL. Abnormal HDLs impair the ability to prevent LDL oxidation and may predispose to atherosclerosis.

     

Familiality and co‐occurrence of clinical features of systemic lupus erythematosus

Objective

To evaluate familiality of 15 clinical and laboratory features in systemic lupus erythematosus (SLE)–affected sibpairs, and to estimate correlations with the age at SLE diagnosis in affected sibpairs and parent–offspring pairs.

Methods

Concordance rates and sibling risk ratios were used as indicators of familiality for 15 manifestations of SLE. Pearson's correlations and paired t‐tests were used to compare the age at SLE diagnosis in affected sibpairs and in parent–offspring pairs.

Results

Increased sibling risk ratios (1.9–3.9) for thrombocytopenia, discoid rash, neurologic disorder (defined as seizure or psychosis), and hemolytic anemia were observed in 159 SLE‐affected sibpairs. Among these clinical features, paired expression of hemolytic anemia plus thrombocytopenia and hemolytic anemia plus neurologic disorder appeared to be more frequent in 709 SLE patients than would be expected by chance (P < 0.00001 and P < 0.007, respectively). The ratio of the presence of both hemolytic anemia and neurologic disorder was ∼13 times higher in the younger affected sib than in the older affected sib (P < 0.02). Familiality of patient age at SLE diagnosis, as observed by relative correlations, was greater in 125 affected sibpairs (r = 0.67, P < 0.0001) than in 37 affected parent–offspring pairs (r = 0.47, P = 0.003). The median ± SD age at SLE diagnosis was significantly lower in offspring (21.5 ± 10.1 years) than in their parents (41.6 ± 15.8 years) (P < 0.0001) but was not different in sibpairs. The combined non‐Caucasian sibpairs had a younger mean age at SLE diagnosis compared with Caucasian sibpairs (P = 0.014).

Conclusion

Evidence for familiality of thrombocytopenia, discoid rash, neurologic disorder, hemolytic anemia, and co‐occurring neurologic disorder plus hemolytic anemia in SLE was observed in 159 affected sibpairs. Familiality of the age at SLE diagnosis in relative pairs suggests that shared genes and/or shared environmental exposures impact disease susceptibility. Shared immediate environmental triggers appear less compelling, because the average time between dates of diagnosis was 11 years in parent–offspring pairs and 7.5 years in affected sibpairs. The significantly earlier age at disease diagnosis in offspring compared with their parents suggests that some forms of anticipation might play a role in susceptibility to SLE. Stratifying families by subphenotypes that are familial may reduce heterogeneity and facilitate identification of genetic risk factors for SLE.

     

Expression of the markers BDCA‐2 and BDCA‐4 and production of interferon‐α by plasmacytoid dendritic cells in systemic lupus erythematosus

Objective

To study the expression of blood dendritic cell antigen 2 (BDCA‐2) and BDCA‐4 molecules by plasmacytoid dendritic cells (PDCs) in the blood of patients with systemic lupus erythematosus (SLE), and to study PDC production of interferon‐α (IFNα) and its inhibition by anti–BDCA‐2 and anti–BDCA‐4 antibodies.

Methods

Peripheral blood mononuclear cells (PBMCs) from SLE patients (SLE PBMCs) and from healthy controls were induced to produce IFNα in vitro by SLE serum containing an endogenous IFNα‐inducing factor (SLE‐IIF) or by herpes simplex virus type 1 (HSV‐1). The frequencies and numbers of BDCA‐2–, BDCA‐3–, and BDCA‐4–expressing cells were analyzed by flow cytometry, and the effects of anti–BDCA‐2 and anti–BDCA‐4 monoclonal antibodies (mAb) on IFNα production were investigated.

Results

IFNα production by SLE PBMCs induced by SLE‐IIF or HSV‐1 was decreased compared with that of healthy control PBMCs (P = 0.002 and P = 0.0007, respectively). The proportions of BDCA‐2– and BDCA‐3–expressing cells in SLE PBMCs were reduced compared with those in PBMCs from healthy controls (P = 0.01 and P = 0.004, respectively). IFNα producers in culture, especially among SLE PBMCs, displayed reduced BDCA‐2 expression and constituted only a minority of the BDCA‐2–positive cells, at least in healthy control PBMCs (median 18%). IFNα production by both SLE and healthy control PBMCs stimulated by SLE‐IIF or HSV‐1 was markedly reduced by anti–BDCA‐2 mAb (median 81–98% inhibition). Anti–BDCA‐4 mAb only partially inhibited SLE‐IIF–induced IFNα production.

Conclusion

SLE patients had a reduced number of BDCA‐2–expressing PDCs, also termed natural IFNα‐producing cells, and their IFNα production could be inhibited by anti–BDCA‐2/4 mAb. Such mAb may be a therapeutic option for inhibiting the ongoing IFNα production in SLE patients.

     

Systemic lupus erythematosus in a multiethnic lupus cohort (LUMINA). XVII. Predictors of self‐reported health‐related quality of life early in the disease course

Objective

To determine the baseline factors predictive of self‐reported health‐related quality of life (HRQOL) early in the course of systemic lupus erythematosus patients (SLE) from a multiethnic LUMINA (Lupus in Minorities: Nature versus nurture) cohort.

Methods

LUMINA patients with ≥2 visits were studied. Self‐reported HRQOL was examined with the 8 subscales and 2 summary measures (the Physical Component Summary [PCS], and the Mental Component Summary [MCS]) of the Short Form 36 (SF‐36). Bivariable and multivariable analyses were done with the PCS, MCS and 8 subscales as the dependent variables. The analyses were performed including and excluding the corresponding SF‐36 measure from the independent variables. Age, sex, and ethnicity were included in all models. Time was modeled in all regressions.

Results

A total of 1,351 visits (346 patients [80 Hispanics‐Texas, 34 Hispanics‐Puerto Rico, 126 African Americans, and 106 Caucasians]) were included in these analyses. Mean ± SD PCS and MCS scores were 36.7 ± 12.0 and 46.6 ± 11.5, respectively. The scores for the eight subscales of the SF‐36 were also lower than those for the general population. Baseline SF‐36 measures were highly predictive of subsequent HRQOL. In the same set of regressions, older age was found to consistently predict poor self‐reported HRQOL whereas fibromyalgia, helplessness, fatigue, and abnormal illness‐related behaviors were also predictive, but less consistently. Estimated adjusted variances in these regressions ranged from 23% (Role‐Emotional [RE]) to 43% (Physical Functioning [PF]).

Conclusion

In patients with SLE, poor baseline HRQOL was highly predictive of subsequent poor HRQOL. Other predictive variables of poor functioning were primarily psychological/behavioral and socioeconomic‐demographic.

     

Reduced insular γ‐aminobutyric acid in fibromyalgia

Objective

Recent scientific findings have reinvigorated interest in examining the role of γ‐aminobutyric acid (GABA), the major inhibitory central nervous system neurotransmitter, in chronic pain conditions. Decreased inhibitory neurotransmission is a proposed mechanism in the pathophysiology of chronic pain syndromes such as fibromyalgia (FM). The purpose of this study was to test the hypothesis that decreased levels of insular and anterior cingulate GABA would be present in FM patients, and that the concentration of this neurotransmitter would be correlated with pressure–pain thresholds.

Methods

Sixteen FM patients and 17 age‐ and sex‐matched healthy controls underwent pressure–pain testing and a 3T proton magnetic resonance spectroscopy session in which the right anterior insula, right posterior insula, anterior cingulate, and occipital cortex were examined in subjects at rest.

Results

GABA levels in the right anterior insula were significantly lower in FM patients compared with healthy controls (mean ± SD 1.17 ± 0.24 arbitrary institutional units versus 1.42 ± 0.32 arbitrary institutional units; P = 0.016). There was a trend toward increased GABA levels in the anterior cingulate of FM patients compared with healthy controls (P = 0.06). No significant differences between groups were detected in the posterior insula or occipital cortex (P > 0.05 for all comparisons). Within the right posterior insula, higher levels of GABA were positively correlated with pressure–pain thresholds in the FM patients (Spearman's rho = 0.63; P = 0.02).

Conclusion

Diminished inhibitory neurotransmission resulting from lower concentrations of GABA within the right anterior insula may play a role in the pathophysiology of FM and other central pain syndromes.

     

Frequency of osteopenia in children and young adults with childhood‐onset systemic lupus erythematosus

Objective

To determine the frequency of osteopenia in patients with childhood‐onset systemic lupus erythematosus (SLE) compared with that in healthy matched controls, and to evaluate the relationship between disease‐related variables and bone mineral mass.

Methods

Bone mineral density (BMD) and bone mineral content (BMC) were measured in a cohort of 70 patients with childhood‐onset SLE (mean ± SD disease duration 10.8 ± 8.3 years, mean ± SD age 26.4 ± 9.9 years) and 70 age‐ and sex‐matched healthy controls. BMD and BMC of the femoral neck, lumbar spine, total body, and distal one‐third of the radius were measured by dual x‐ray absorptiometry. We investigated the relationship between BMC and the following disease variables: cumulative dose of corticosteroids, organ damage, current use of corticosteroids, use of cyclophosphamide, age at disease onset, and disease activity at the time of diagnosis. Biochemical markers of bone metabolism were also measured.

Results

BMD values for the lumbar spine and femoral neck were significantly lower in patients than in healthy controls. The reduction in BMD of the lumbar spine was significantly greater than that of the total body. In multiple linear regression analyses, a higher cumulative corticosteroid dose was significantly associated with lower BMC of the lumbar spine and femoral neck. Decreased lumbar spine BMC was also related to male sex.

Conclusion

The frequency of osteopenia was higher in patients with childhood‐onset SLE than in matched controls. The lumbar spine was the most seriously affected skeletal site, followed by the femoral neck. The cumulative dose of corticosteroids was shown to be an important explanatory variable for BMC values in the lumbar spine and femoral neck.

     

Anti–müllerian hormone and ovarian reserve in systemic lupus erythematosus

Objective

To study the level of anti–müllerian hormone (AMH) and its relationship to age and previous exposure to cyclophosphamide (CYC) in patients with systemic lupus erythematosus (SLE).

Methods

Consecutive female patients ages 18–52 years who had menses at least once during the preceding 12 months and fulfilled ≥4 American College of Rheumatology criteria for SLE were recruited. AMH was determined using an enzyme‐linked immunosorbent assay (ELISA) kit. Serum AMH levels were compared in patients with and without previous use of immunosuppressive agents. The relationship of the AMH level to the patient's age and CYC exposure was studied by linear regression and receiver operating characteristic (ROC) curve analysis.

Results

A total of 216 patients were studied (mean ± SD age 35.1 ± 10.1 years, mean ± SD SLE duration 7.6 ± 5.9 years). The mean ± SD AMH level was significantly lower in patients previously exposed to CYC therapy than in those who had not been exposed after adjustment for age (1.58 ± 2.92 versus 1.73 ± 2.11 ng/ml; P = 0.04). The median time interval between the AMH assay and the last dose of CYC administered was 6.7 years (interquartile range 3.4–8.5). AMH levels in users versus nonusers of other immunosuppressive agents, including mycophenolate mofetil, azathioprine, and the calcineurin inhibitors, were not statistically different. Linear regression revealed increasing age (beta −0.32, P = 0.02) and each 5 gm of CYC exposure (beta −0.28, P = 0.047) were independently associated with a lower AMH level. In patients ages 30 years and younger, a cumulative CYC dose cutoff of 5.9 gm yielded a sensitivity of 0.75 and a specificity of 0.80 for the prediction of undetectable AMH level on ROC curve analysis.

Conclusion

AMH is a sensitive marker for ovarian damage due to previous CYC exposure in women with SLE.

     

N‐terminal pro–brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium‐channel blockers

Objective

To evaluate N‐terminal pro–brain natriuretic peptide (NT‐proBNP) as a marker of early pulmonary artery hypertension (PAH) and to study changes in the levels of this marker following treatment with dihydropyridine‐type calcium‐channel blocker (DTCCB) in patients with systemic sclerosis (SSc).

Methods

We evaluated 40 consecutive SSc patients who had been hospitalized for followup care (mean ± SD age 56 ± 11 years and mean ± SD duration of cutaneous disease 9 ± 9 years; 27 with limited cutaneous and 13 with diffuse cutaneous disease) but who had no clinical symptoms of heart failure and had a normal left ventricular ejection fraction. At baseline, 10 patients had PAH, defined as a systolic pulmonary artery pressure (sPAP) >40 mm Hg, as measured by echocardiography. Levels of NT‐proBNP were determined at baseline (after discontinuation of DTCCB treatment for 72 hours), after taking 3 doses of DTCCB following treatment reinitiation (assessment 1), and after 6–9 months of continuous DTCCB treatment (assessment 2) in the 20 patients who attended regular appointments (including the 10 patients with PAH at baseline).

Results

At baseline, 13 patients had high NT‐proBNP values for their ages. High NT‐proBNP levels identified patients with PAH with a sensitivity of 90%, a specificity of 90.3%, a positive predictive value of 69.2%, and a negative predictive value of 96%. The NT‐proBNP level correlated with the sPAP (r = 0.44; P = 0.006). By assessment 1, the number of patients with PAH and high levels of NT‐proBNP had decreased from 9 of 10 to 2 of 10 (P = 0.02). This decrease was partially sustained at assessment 2 (4 of 10 patients; P = 0.06).

Conclusion

NT‐proBNP is a useful biologic marker that can be used to diagnose early PAH in SSc patients without clinical heart failure. Measurement of NT‐proBNP may be valuable for the evaluation of treatment with DTCCB and vasodilators in patients with PAH.