A phase II,randomized, double‐blind,placebo‐controlled,dose‐ranging study of belimumab in patients with active systemic lupus erythematosus

Objective

To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE).

Methods

Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score ≥4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52‐week study. Coprimary end points were the percent change in the SELENA–SLEDAI score at week 24 and the time to first SLE flare.

Results

Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA–SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24–52 was significantly longer with belimumab treatment (154 versus 108 days; P = 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer ≥1:80 and/or anti–double‐stranded DNA [anti‐dsDNA] ≥30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA–SLEDAI score (?28.8% versus ?14.2%; P = 0.0435), physician's global assessment (?32.7% versus ?10.7%; P = 0.0011), and Short Form 36 physical component score (+3.0 versus +1.2 points; P = 0.0410). Treatment with belimumab resulted in a 63–71% reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4% reduction in anti‐dsDNA titers (P = 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups.

Conclusion

Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.

     

Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus

Objective

Disease activity in systemic lupus erythematosus (SLE) is typically monitored by measuring serum C3 and C4. However, these proteins have limited utility as lupus biomarkers, because they are substrates rather than products of complement activation. The aim of this study was to evaluate the utility of measuring the erythrocyte‐bound complement activation products, erythrocyte‐bound C3d (E‐C3d) and E‐C4d, compared with that of serum C3 and C4 for monitoring disease activity in patients with SLE.

Methods

The levels of E‐C3d and E‐C4d were measured by flow cytometry in 157 patients with SLE, 290 patients with other diseases, and 256 healthy individuals. The patients with SLE were followed up longitudinally. Disease activity was measured at each visit, using the validated Systemic Lupus Activity Measure (SLAM) and the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).

Results

At baseline, patients with SLE had higher median levels of E‐C3d and E‐C4d (P < 0.0001) in addition to higher within‐patient and between‐patient variability in both E‐C3d and E‐C4d when compared with the 2 non‐SLE groups. In a longitudinal analysis of patients with SLE, E‐C3d, E‐C4d, serum C3, and anti–double‐stranded DNA (anti‐dsDNA) antibodies were each significantly associated with the SLAM and SELENA–SLEDAI. In a multivariable analysis, E‐C4d remained significantly associated with these SLE activity measures after adjusting for serum C3, C4, and anti‐dsDNA antibodies; however, E‐C3d was associated with the SLAM but not with the SELENA–SLEDAI.

Conclusion

Determining the levels of the erythrocyte‐bound complement activation products, especially E‐C4d, is an informative measure of SLE disease activity as compared with assessing serum C4 levels and should be considered for monitoring disease activity in patients with SLE.

     

Dysregulated expression of CXCR4/CXCL12 in subsets of patients with systemic lupus erythematosus

Objective

CXCR4 is a chemokine with multiple effects on the immune system. In murine lupus models, we demonstrated that monocytes, neutrophils, and B cells overexpressed CXCR4 and that its ligand, CXCL12, was up‐regulated in diseased kidneys. We undertook this study to determine whether CXCR4 expression was increased in peripheral blood leukocytes from patients with systemic lupus erythematosus (SLE) and whether CXCL12 expression was increased in kidneys from patients with SLE.

Methods

Peripheral blood leukocytes from 31 SLE patients, 8 normal controls, and 9 patients with rheumatoid arthritis were prospectively analyzed by flow cytometry for CXCR4 expression. Biopsy samples (n = 14) from patients with lupus nephritis (LN) were immunostained with anti‐CXCL12 antibody.

Results

CD19+ B cells and CD4+ T cells from SLE patients displayed a >2‐fold increase (P = 0.0001) and >3‐fold increase (P < 0.0001), respectively, in median CXCR4 expression compared with that in controls (n = 7–8). Moreover, CXCR4 expression on B cells was 1.61‐fold higher in patients with SLE Disease Activity Index (SLEDAI) scores >10 (n = 8) than in patients with SLEDAI scores ≤10 (n = 16) (P = 0.0008), 1.71‐fold higher in patients with class IV LN (n = 5) than in patients with other classes of LN (n = 7) (P = 0.02), and 1.40‐fold higher in patients with active neuropsychiatric SLE (NPSLE) (n = 6) than in patients with inactive NPSLE (n = 18) (P = 0.01). CXCL12 was significantly up‐regulated in the tubules and glomeruli of kidneys in patients with LN (n = 14), with the percentage of positive cells correlating positively with the severity of LN.

Conclusion

CXCR4 appears to be up‐regulated in multiple leukocyte subsets in SLE patients. The heightened expression of CXCR4 on B cells in active NPSLE and of CXCL12 in nephritic kidneys suggests that the CXCR4/CXCL12 axis might be a potential therapeutic target for SLE patients with kidney and/or central nervous system involvement.

     

A phase III,randomized, placebo‐controlled study of belimumab,a monoclonal antibody that inhibits B lymphocyte stimulator,in patients with systemic lupus erythematosus

Objective

To assess the efficacy/safety of the B lymphocyte stimulator inhibitor belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE).

Methods

In a phase III, multicenter, randomized, placebo‐controlled trial, 819 antinuclear antibody–positive or anti–double‐stranded DNA–positive SLE patients with scores ≥6 on the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) were randomized in a 1:1:1 ratio to receive 1 mg/kg belimumab, 10 mg/kg belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days for 72 weeks. The primary efficacy end point was the SLE Responder Index (SRI) response rate at week 52 (an SRI response was defined as a ≥4‐point reduction in SELENA–SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, and no worsening in physician's global assessment score versus baseline).

Results

Belimumab at 10 mg/kg plus standard therapy met the primary efficacy end point, generating a significantly greater SRI response at week 52 compared with placebo (43.2% versus 33.5%; P = 0.017). The rate with 1 mg/kg belimumab was 40.6% (P = 0.089). Response rates at week 76 were 32.4%, 39.1%, and 38.5% with placebo, 1 mg/kg belimumab, and 10 mg/kg belimumab, respectively. In post hoc sensitivity analyses evaluating higher SELENA–SLEDAI score thresholds, 10 mg/kg belimumab achieved better discrimination at weeks 52 and 76. Risk of severe flares over 76 weeks (based on the modified SLE Flare Index) was reduced with 1 mg/kg belimumab (34%) (P = 0.023) and 10 mg/kg belimumab (23%) (P = 0.13). Serious and severe adverse events, including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups.

Conclusion

Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE.

     

Urinary lipocalin‐2 is associated with renal disease activity in human lupus nephritis

Objective

Pathogenic monoclonal anti–double‐stranded DNA (anti‐dsDNA) antibodies up‐regulate the expression of lipocalin‐2 in glomerular mesangial cells. This study was undertaken to investigate whether polyclonal anti‐dsDNA antibodies promote the local secretion of lipocalin‐2 in the kidneys of patients with systemic lupus erythematosus (SLE), and whether urinary lipocalin‐2 represents a marker of kidney involvement in SLE.

Methods

Hispanic, African American, and white patients with SLE and normal healthy control subjects from affiliated hospitals of the Albert Einstein College of Medicine were recruited for this cross‐sectional study. Patients were classified based on the presence of active renal disease according to the SLE Disease Activity Index (SLEDAI). Correlations of clinical and laboratory data with urinary and serum levels of lipocalin‐2 were assessed.

Results

Among SLE patients, urinary lipocalin‐2 levels were significantly higher in those with lupus nephritis (LN) (median 17.1 ng/mg creatinine, interquartile range [IQR] 10.3–45.4; n = 32) than in those without LN (median 11.2 ng/mg creatinine, IQR 3.1–20.3; n = 38) (P = 0.023). Compared with the values in normal controls (median 4 ng/ml, IQR 0–11.1; n = 14), urinary levels of lipocalin‐2 in SLE patients were significantly higher (non‐normalized median 19.3 ng/ml, IQR 8–34.2) (P = 0.004). The presence of lipocalin‐2 in the urine of patients with LN correlated significantly with the renal SLEDAI score (r = 0.452, P = 0.009), but not with extrarenal disease activity.

Conclusion

The high prevalence of LN in SLE patients and the prognostic significance of kidney disease support the need for identifying early biomarkers to assess the risk of nephritis development and for following up patients with established disease. These findings indicate that urinary lipocalin‐2 is a potential marker of the presence and severity of renal involvement in adult patients with SLE.

     

Anti‐C1q antibodies are associated with systemic lupus erythematosus global activity but not specifically with nephritis: A controlled study of 126 consecutive patients

Objective

Several studies have shown that anti‐C1q antibodies correlate with the occurrence and activity of nephritis in systemic lupus erythematosus (SLE). However, the significance of anti‐C1q antibodies in SLE has not been fully characterized. The aim of this study was to investigate associations between anti‐C1q antibodies and clinical and serologic parameters of SLE.

Methods

An enzyme‐linked immunosorbent assay kit was used to measure anti‐C1q antibodies in the sera of 126 consecutive patients with active SLE who were admitted to our university hospital from 2007 through 2009. Sera obtained from patients with high titers of anti‐C1q antibodies at the initial evaluation (n = 20) were reevaluated following treatment. Control sera were obtained from patients with other autoimmune diseases and from normal healthy control subjects (n = 20 in each group). Associations between anti‐C1q antibodies and clinical and serologic parameters of SLE were statistically analyzed.

Results

Anti‐C1q antibodies were detected in the sera of 79 of 126 patients with SLE. The prevalence and titers of anti‐C1q antibodies were significantly (P < 0.0001) higher in SLE patients than in patients with rheumatoid arthritis, patients with systemic sclerosis, and normal healthy control subjects. The prevalence and titers of anti‐C1q antibodies were not significantly associated with active lupus nephritis (P = 0.462 and P = 0.366, respectively). Anti‐C1q antibody titers were significantly correlated with SLE Disease Activity Index 2000 scores and the levels of anti–double‐stranded DNA antibodies, C3, C4, CH50, and C1q (P < 0.0001 for all comparisons). Moreover, anti‐C1q antibody titers significantly decreased as clinical disease was ameliorated following treatment (P = 0.00097).

Conclusion

These findings indicate that anti‐C1q antibodies are associated with SLE global activity but not specifically with active lupus nephritis.

     

Expression of CD44 variant isoforms CD44v3 and CD44v6 is increased on T cells from patients with systemic lupus erythematosus and is correlated with disease activity

Objective

To quantify the expression of CD44 and variant isoforms CD44v3 and CD44v6 on T cells from patients with systemic lupus erythematosus (SLE), and to assess correlations of the level of expression of these molecules with disease manifestations.

Methods

Information on clinical and demographic characteristics was collected, and blood samples were obtained from 72 patients with SLE and 32 healthy control subjects matched to the patients by sex, race, and age. Expression of CD44 and variants CD44v3 and v6 on T cell subsets was determined by flow cytometry, and Pearson's correlations of their expression levels with clinical variables, SLE Disease Activity Index (SLEDAI) scores, and presence of lupus nephritis were determined. Wilcoxon's rank sum tests and conditional multivariable regression analyses were applied to identify differences in the expression of CD44 between patients with SLE and healthy controls.

Results

Expression of CD44 was higher on CD4+ and CD8+ T cells from SLE patients compared with controls (P ≤ 0.03). Expression of CD44v3 and CD44v6 was also higher on total T cells and CD4+ and CD8+ T cells from SLE patients compared with controls (P ≤ 0.03). Cell surface levels of CD44v3 on total T cells, CD4+ T cells, and CD8+ T cells as well as cell surface expression of CD44v6 on total T cells and CD4+ T cells were correlated with the SLEDAI score (P < 0.05). The presence of lupus nephritis was associated with the expression of CD44v6 on total T cells, CD4+ T cells, and CD4−CD8− T cells (P < 0.05). Positivity for anti–double‐stranded DNA antibodies was associated with the expression levels of CD44v6 on T cells (P < 0.05).

Conclusion

These results indicate that expression levels of CD44v3 and CD44v6 on T cells may represent useful biomarkers of SLE activity.

     

Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide‐resistant proliferative lupus nephritis

Objective

Rituximab is a monoclonal antibody directed against the CD20 marker of B cells. Because of its ability to deplete B lymphocytes, it has been suggested that the drug could be of benefit in B cell–dependent diseases, including systemic lupus erythematosus (SLE). The purpose of this study was to investigate the histopathologic and clinical effects of combination treatment with rituximab and cyclophosphamide (CYC) in patients with CYC‐resistant proliferative lupus nephritis.

Methods

Seven female patients with proliferative lupus nephritis were treated with rituximab in combination with CYC. Renal biopsies were performed before treatment and during followup. SLE activity was evaluated by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group index. In 6 of the 7 patients, immunostaining of lymphocyte subpopulations in the renal tissue was performed before treatment and during followup.

Results

At 6 months of followup, significant clinical improvement was noted, with a reduction in SLEDAI scores (from a mean of 15 to 3), anti–double‐stranded DNA antibody levels (from a mean of 174 IU/ml to 56 IU/ml), and anti‐C1q antibody levels (from a mean of 35 units/ml to 22 units/ml). On repeat renal biopsy, improvement in the histopathologic class of nephritis occurred in a majority of patients, and a decrease in the renal activity index was noted (from 6 to 3). A reduction in the number of CD3, CD4, and CD20 cells in the renal interstitium was noted in 50% of the patients on repeat biopsy.

Conclusion

At 6 months of followup, all patients had responded both clinically and histopathologically to combination therapy. For patients with proliferative lupus nephritis who fail to respond to conventional immunosuppressive therapy including CYC, combined treatment with rituximab and CYC may constitute a new treatment option.

     

Interferon‐regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: A validation study

Objective

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by unpredictable flares of disease activity and irreversible damage to multiple organ systems. An earlier study showed that SLE patients carrying an interferon (IFN) gene expression signature in blood have elevated serum levels of IFN‐regulated chemokines. These chemokines were associated with more‐severe and active disease and showed promise as SLE disease activity biomarkers. This study was designed to validate IFN‐regulated chemokines as biomarkers of SLE disease activity in 267 SLE patients followed up longitudinally.

Methods

To validate the potential utility of serum chemokine levels as biomarkers of disease activity, we measured serum levels of CXCL10 (IFNγ‐inducible 10‐kd protein), CCL2 (monocyte chemotactic protein 1), and CCL19 (macrophage inflammatory protein 3β) in an independent cohort of 267 SLE patients followed up longitudinally over 1 year (1,166 total clinic visits).

Results

Serum chemokine levels correlated with lupus activity at the current visit (P = 2 × 10⁻¹⁰), rising at the time of SLE flare (P = 2 × 10⁻³) and decreasing as disease remitted (P = 1 × 10⁻³); they also performed better than the currently available laboratory tests. Chemokine levels measured at a single baseline visit in patients with a Systemic Lupus Erythematosus Disease Activity Index of ≤4 were predictive of lupus flare over the ensuing year (P = 1 × 10⁻⁴).

Conclusion

Monitoring serum chemokine levels in SLE may improve the assessment of current disease activity, the prediction of future disease flares, and the overall clinical decision‐making.

     

Markers of oxidative and nitrosative stress in systemic lupus erythematosus: Correlation with disease activity

Objective

Free radical–mediated reactions have been implicated as contributors in a number of autoimmune diseases, including systemic lupus erythematosus (SLE). However, the potential for oxidative/nitrosative stress to elicit an autoimmune response or to contribute to disease pathogenesis, and thus be useful when determining a prognosis, remains largely unexplored in humans. This study was undertaken to investigate the status and contribution of oxidative/nitrosative stress in patients with SLE.

Methods

Sera from 72 SLE patients with varying levels of disease activity according to the SLE Disease Activity Index (SLEDAI) and 36 age‐ and sex‐matched healthy controls were evaluated for serum levels of oxidative/nitrosative stress markers, including antibodies to malondialdehyde (anti‐MDA) protein adducts and to 4‐hydroxynonenal (anti‐HNE) protein adducts, MDA/HNE protein adducts, superoxide dismutase (SOD), nitrotyrosine (NT), and inducible nitric oxide synthase (iNOS).

Results

Serum analysis showed significantly higher levels of both anti–MDA/anti–HNE protein adduct antibodies and MDA/HNE protein adducts in SLE patients compared with healthy controls. Interestingly, not only was there an increased number of subjects positive for anti‐MDA or anti‐HNE antibodies, but also the levels of both of these antibodies were statistically significantly higher among SLE patients whose SLEDAI scores were ≥6 as compared with SLE patients with lower SLEDAI scores (SLEDAI score <6). In addition, a significant correlation was observed between the levels of anti‐MDA or anti‐HNE antibodies and the SLEDAI score (r = 0.734 and r = 0.647, respectively), suggesting a possible causal relationship between these antibodies and SLE. Furthermore, sera from SLE patients had lower levels of SOD and higher levels of iNOS and NT compared with healthy control sera.

Conclusion

These findings support an association between oxidative/nitrosative stress and SLE. The stronger response observed in serum samples from patients with higher SLEDAI scores suggests that markers of oxidative/nitrosative stress may be useful in evaluating the progression of SLE and in elucidating the mechanisms of disease pathogenesis.

     

Safety and efficacy of rituximab in systemic lupus erythematosus: Results from 136 patients from the French autoimmunity and rituximab registry

Objective

A number of open‐label studies have suggested the potential benefit of rituximab (RTX) in systemic lupus erythematosus (SLE). However, in 2 recent randomized controlled trials (RCTs) of RTX, the primary end points were not met. We undertook this study to evaluate the safety and efficacy of RTX in off‐trial patients with SLE seen in regular clinical practice.

Methods

We analyzed prospective data from the French AutoImmunity and Rituximab (AIR) registry, which includes data on patients with autoimmune disorders treated with RTX.

Results

One hundred thirty‐six patients received treatment for SLE. The mean ± SD score on the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) was 11.3 ± 8.9 at baseline. Severe infections were noted in 12 patients (9%), corresponding to a rate of 6.6/100 patient‐years. Most severe infections occurred within the first 3 months after the last RTX infusion. Five patients died, due to severe infection (n = 3) or refractory autoimmune disease (n = 2). Overall response was observed in 80 of 113 patients (71%) by the SELENA–SLEDAI assessment. Efficacy did not differ significantly between patients receiving RTX monotherapy and those receiving concomitant immunosuppressive agents (who had higher baseline disease activity). Articular, cutaneous, renal, and hematologic improvements were noted in 72%, 70%, 74%, and 88% of patients, respectively. Among responders, 41% experienced a relapse of disease, with a response in 91% after retreatment with RTX.

Conclusion

Data from the AIR registry show a satisfactory tolerance profile and clinical efficacy of RTX in patients with SLE. The contrasting results with those from recent RCTs leave open the question of the therapeutic use of RTX in SLE. Additional controlled studies with new designs are needed to define the place of RTX in the therapeutic arsenal for SLE.

     

Decreases in anti–double‐stranded DNA levels are associated with concurrent flares in patients with systemic lupus erythematosus

Objective

To determine the degree to which changes in anti–double‐stranded DNA (anti‐dsDNA), as determined by Crithidia and enzyme‐linked immunosorbent assays (ELISAs), precede or coincide with changes in systemic lupus erythematosus (SLE) activity, as measured by 5 clinical indices, the physician's global assessment (PGA), modified SLE Disease Activity Index (M‐SLEDAI), modified Lupus Activity Index (M‐LAI), Systemic Lupus Activity Measure (SLAM), and the modified British Isles Lupus Assessment Group (M‐BILAG).

Methods

Disease activity and anti‐dsDNA were measured monthly in 53 SLE patients who were followed up for 1 year. Lupus flare was defined as an increase in PGA of ≥1.0, M‐SLEDAI ≥3, M‐LAI ≥0.1, SLAM ≥3, and M‐BILAG ≥4 within a 1‐month period. Flare rates were calculated for groups, which were defined by “previous” (1 month prior to the flare) or “concurrent” (at the time of the flare) changes in anti‐dsDNA. Logistic regression models were used to determine the significance of the association between recent changes in anti‐dsDNA and flare, controlling for the prednisone dosage.

Results

Flares occurred at 12% of visits, based on the PGA measure of disease activity. Using the other indices, flare rates were 19% (M‐SLEDAI), 25% (M‐LAI), 13% (SLAM), and 12% (M‐BILAG). A concurrent decrease in anti‐dsDNA (ELISA) was associated with significantly higher flare rates based on PGA (18 of 84, 21%; P = 0.0014), M‐SLEDAI (27 of 89, 30%; P = 0.0019), M‐LAI (37 of 89, 42%; P = 0.0001), and M‐BILAG (19 of 89, 21%; P = 0.0264) scores. Flare rates were also significantly higher after a previous increase in anti‐dsDNA (ELISA) based on M‐SLEDAI (26 of 93, 30%; P = 0.0022) and M‐LAI (34 of 93, 37%; P = 0.0117) scores. Flare rates tended to be lowest when there was a concurrent increase in anti‐dsDNA (ELISA). Analysis of specific organ systems showed that a concurrent decrease in anti‐dsDNA (ELISA) was significantly associated with increases in renal disease activity. Similar results were obtained using the Crithidia assay.

Conclusion

A previous increase in anti‐dsDNA levels occurred before SLE flares, as measured by the M‐SLEDAI and M‐LAI only. However, during lupus flares, including the subset of renal flares, anti‐dsDNA levels frequently decreased. We hypothesize that this decrease in anti‐dsDNA represents deposition in tissue at the time of flare.

     

Nonrenal disease activity following mycophenolate mofetil or intravenous cyclophosphamide as induction treatment for lupus nephritis: Findings in a multicenter,prospective, randomized,open‐label,parallel‐group clinical trial

Objective

To assess the effect of mycophenolate mofetil compared with intravenous pulses of cyclophosphamide on the nonrenal manifestations of lupus nephritis.

Methods

Patients with active lupus nephritis (renal biopsy class III, IV, or V) were recruited for the study (n = 370) and treated with mycophenolate mofetil (target dosage 3 gm/day) or intravenous cyclophosphamide (0.5–1.0 gm/m²/month), plus tapered prednisone, for 24 weeks. Nonrenal outcomes were determined using measures of whole body disease activity, including the British Isles Lupus Assessment Group (BILAG) disease activity index, the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and immunologic variables.

Results

Both treatments were effective on whole body disease activity in the systems examined, as indicated by changes in the classic BILAG index. With either treatment, remission was induced, notably in the mucocutaneous, musculoskeletal, cardiovascular/respiratory, and vasculitis systems, and flares were rare, as measured by the SELENA–SLEDAI. Levels of complement C3, C4, and CH50 and titers of anti–double‐stranded DNA antibodies were normalized after treatment with either mycophenolate mofetil or intravenous cyclophosphamide.

Conclusion

In addition to the efficacy of both treatments on the renal system, this analysis showed that remission could also be induced in other systems. There was no clear difference in efficacy between mycophenolate mofetil and intravenous cyclophosphamide in ameliorating either the renal or nonrenal manifestations. Mycophenolate mofetil is, therefore, a suitable alternative to cyclophosphamide for the treatment of renal and nonrenal disease manifestations in patients with biopsy‐proven lupus nephritis.

     

Coordinate overexpression of interferon‐α–induced genes in systemic lupus erythematosus

Objective

To study the contribution of interferon‐α (IFNα) and IFNγ to the IFN gene expression signature that has been observed in microarray screens of peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE).

Methods

Quantitative real‐time polymerase chain reaction analysis of healthy control PBMCs was used to determine the relative induction of a panel of IFN‐inducible genes (IFIGs) by IFNα and IFNγ. PBMCs from 77 SLE patients were compared with those from 22 disease controls and 28 healthy donors for expression of IFIGs.

Results

Expression of IFNα‐inducible genes was significantly higher in SLE PBMCs than in those from disease controls or healthy donors. The level of expression of all IFIGs in PBMCs from SLE patients with IFNα pathway activation correlated highly with the inherent responsiveness of those genes to IFNα, suggesting coordinate activation of that cytokine pathway. Expression of genes preferentially induced by IFNγ was not significantly increased in SLE PBMCs compared with control PBMCs. IFNα‐regulated gene‐inducing activity was detected in some SLE plasma samples.

Conclusion

The coordinate activation of IFNα‐induced genes is a characteristic of PBMCs from many SLE patients, supporting the hypothesis that IFNα is the predominant stimulus for IFIG expression in lupus.

     

The sense of smell in systemic lupus erythematosus

Objective

To assess the olfactory functions in systemic lupus erythematosus (SLE) patients compared with age‐ and sex‐matched healthy controls, and to examine the association between the sense of smell and disease activity and central nervous system (CNS) involvement.

Methods

Olfactory functions in 50 SLE patients and 50 age‐ and sex‐matched controls were evaluated using the Sniffin' Sticks test, the 3 stages of which are threshold, discrimination, and identification (TDI) of different odors. TDI scores were analyzed according to SLE disease activity and CNS involvement.

Results

In both the SLE and control groups, smell deficit correlated with male sex and older age. A decrease in the sense of smell was observed in SLE patients (46%) and controls (25%) (P ≤ 0.02), while loss of smell (anosmia) was documented only in SLE patients (10%). Total TDI scores and individual stages of smell correlated with SLE Disease Activity Index (P < 0.001) and CNS manifestations (P < 0.03).

Conclusion

Our findings suggest that there is a decrease in the sense of smell in SLE patients compared with healthy subjects and that the decrease in the sense of smell among SLE patients correlates with disease activity and CNS involvement.

     

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.

     

Role of the Fcγ receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: A meta‐analysis

Objective

To assess the impact of the Fcγ receptor type IIa (FcγRIIa)–R/H131 polymorphism on the risk for systemic lupus erythematosus (SLE) and development of lupus nephritis.

Methods

A meta‐analysis was performed based on the Medline and Embase databases (last retrieval August 2001), assessment of bibliographies of pertinent articles, and additional data gathered after contact with primary investigators.

Results

A total of 25 comparisons from 17 studies involving R/H131 genotyping of 1,405 patients with lupus nephritis, 1,709 SLE patients without nephritis, and 2,580 non‐SLE controls were included. No association between RR genotype and risk of lupus nephritis relative to both other genotypes (odds ratio [OR] 1.05, 95% confidence interval [95% CI] 0.88–1.27) was demonstrated in the total meta‐analysis or in any racial subgroup. The RR genotype was more frequent in SLE patients as a whole (OR 1.30, 95% CI 1.10–1.52) and in SLE patients without nephritis (OR 1.27, 95% CI 1.04–1.55) compared with disease‐free controls. A potential dose–response relation between the R131 allele and the risk of SLE was also identified, with an OR of 1.23 for RR versus RH (95% CI 1.03–1.46). The OR was 1.55 for RR versus HH (95% CI 1.21–1.98). There was no significant heterogeneity between racial subgroups. The population‐attributable fractions of SLE cases due to the FcγRIIa‐R131 allele were 13%, 40%, and 24% in subjects of European, African, and Asian descent, respectively.

Conclusion

The FcγRIIa‐R/H131 polymorphism represents a significant risk factor for SLE but has no clear effect on susceptibility for lupus nephritis.

     

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.

     

Risk factors and impact of recurrent lupus nephritis in patients with systemic lupus erythematosus undergoing renal transplantation: Data from a single US institution

Objective

To determine the risk factors for recurrent lupus nephritis, allograft loss, and survival among patients with systemic lupus erythematosus (SLE) undergoing kidney transplantation.

Methods

The archival records of all kidney transplant recipients with a prior diagnosis of SLE (according to the American College of Rheumatology criteria) from June 1977 to June 2007 were reviewed. Patients who had died or lost the allograft within 90 days of engraftment were excluded. Time‐to‐event data were examined by univariable and multivariable Cox proportional hazards regression analyses.

Results

Two hundred twenty of nearly 7,000 renal transplantations were performed in 202 SLE patients during the 30‐year interval. Of the 177 patients who met the criteria for study entry, the majority were women (80%) and African American (65%), the mean age was 35.6 years, and the mean disease duration was 11.2 years. Recurrent lupus nephritis was noted in 20 patients (11%), allograft loss in 69 patients (39%), and death in 36 patients (20%). African American ethnicity was found to be associated with a shorter time‐to‐event for recurrent lupus nephritis (hazard ratio [HR] 4.63, 95% confidence interval [95% CI] 1.29–16.65) and death (HR 2.47, 95% CI 0.91–6.71), although, with the latter, the association was not statistically significant. Recurrent lupus nephritis and chronic rejection of the kidney transplant were found to be risk factors for allograft loss (HR 2.48, 95% CI 1.09–5.60 and HR 2.72, 95% CI 1.55–4.78, respectively). In patients with recurrent lupus nephritis, the lesion in the engrafted kidney was predominantly mesangial, compared with a predominance of proliferative or membranous lesions in the native kidneys.

Conclusion

African American ethnicity was independently associated with recurrent lupus nephritis. Allograft loss was associated with chronic transplant rejection and recurrence of lupus nephritis. Recurrent lupus nephritis is infrequent and relatively benign, without influence on a patient's survival.