Mizoribine therapy for patients with lupus nephritis: the association between peak mizoribine concentration and clinical efficacy

The clinical efficacy of mizoribine (MZR; 4-carbamoyl-1-b-d-ribofuranosylimidazolium) in patients with lupus nephritis was investigated. Thirteen Japanese patients with biopsy-proved lupus nephritis were enrolled in this study. A change in global assessments score, total protein (TP) of serum, serum creatinine, creatinine clearance (Ccr), proteinuria, titers of serum anti-ds DNA antibody, C3, C4, and hemolytic complement activity (CH50) were examined. Following MZR treatment, the level of urinary protein decreased (P < 0.05), whereas the level of Ccr increased (P < 0.05). Moreover, the level of TP significantly increased from 5.5 g/dl to 6.3 g/dl (P < 0.01) and the level of C3 increased significantly (P < 0.01). However, there was no change in the levels of both C4 and CH50. The titer of anti-ds DNA antibody significantly decreased (P < 0.05). The dosage of prednisolone could be tapered from 24.8 mg to 14.9 mg daily during the period. The clinical effects associated with MZR concentration in the blood revealed that there was a significant correlation between the peak MZR blood concentration of more than 0.66 μg/ml and clinical improvement (P = 0.021). Our results suggest that an optimal MZR blood concentration was important for the treatment of lupus nephritis. The first two authors contributed equally to this work.     

Mizoribine therapy for patients with lupus nephritis: the association between peak mizoribine concentration and clinical efficacy

Abstract

The clinical efficacy of mizoribine (MZR; 4-carbamoyl-1-b-d-ribofuranosylimidazolium) in patients with lupus nephritis was investigated. Thirteen Japanese patients with biopsy-proved lupus nephritis were enrolled in this study. A change in global assessments score, total protein (TP) of serum, serum creatinine, creatinine clearance (Ccr), proteinuria, titers of serum anti-ds DNA antibody, C3, C4, and hemolytic complement activity (CH50) were examined. Following MZR treatment, the level of urinary protein decreased (P < 0.05), whereas the level of Ccr increased (P < 0.05). Moreover, the level of TP significantly increased from 5.5?g/dl to 6.3?g/dl (P < 0.01) and the level of C3 increased significantly (P < 0.01). However, there was no change in the levels of both C4 and CH50. The titer of anti-ds DNA antibody significantly decreased (P < 0.05). The dosage of prednisolone could be tapered from 24.8?mg to 14.9?mg daily during the period. The clinical effects associated with MZR concentration in the blood revealed that there was a significant correlation between the peak MZR blood concentration of more than 0.66?µg/ml and clinical improvement (P = 0.021). Our results suggest that an optimal MZR blood concentration was important for the treatment of lupus nephritis.     

Evaluation of visfatin in patients with systemic lupus erythematosus: Correlation with disease activity and lupus nephritis

IntroductionRenal involvement affects about 50% of SLE patients accounting for significant morbidity and mortality in these patients. The adipokine “visfatin” acting as a growth factor for B-lymphocyte-precursors, exerts several proinflammatory functions. It was demonstrated as a marker of endothelial dysfunction (ED) in chronic kidney disease (CKD) thus could be a factor linking inflammation in SLE and kidney disease.Aim of the workTo assess serum visfatin level in SLE patients and its correlation to disease activity and lupus nephritis (LN) in these patients.Patients and methodsSerum level of visfatin using enzyme-linked immunosorbent assay (ELISA), chemical and immunological markers of SLE and LN were measured in 40 SLE patients and 40 age and sex matched healthy controls. Disease activity and renal involvement were assessed using SLE Disease Activity Index (SLEDAI) and Renal SLEDAI respectively further dividing patients into active versus inactive and LN versus non-LN respectively. Renal biopsies were taken from LN subgroup and were classified according to the modified WHO classification.ResultsA significantly higher serum visfatin level was found on comparing SLE patients (mean 109 ± 180 ng/ml, median18) with controls (mean 9.4 ± 11 ng/ml, median2.5) with statistically highly significant difference (z = 5.2, P < 0.001). Also there was a statistically significant difference as regards serum visfatin level between active SLE patients (mean 173 ± 111 ng/ml, median 14) and inactive patients (mean 139 ± 88 ng/ml, median 5) (z = 2.1, P < 0.05) as well as between patients with LN (mean 226 ± 180 ng/ml, median18) and patients with no LN (mean 101 ± 140 ng/ml, median 8(2-229)) (z = 2.1, P < 0.05). Visfatin had a highly significant positive correlation with disease duration (r = 0.48, P < 0.001), SLEDAI (r = 0.62, P < 0.001) as well as ESR, CRP and, renal score (r = 0.45, 0.35, and 0.65, respectively) while inverse correlation with estimated GFR (r = ?0.614) and C3 and C4 titre (r = ?0.26, r = ?0.35, respectively) was recorded. Visfatin showed high sensitivity in detecting active SLE and LN 83% and 85%, respectively.ConclusionSerum visfatin is strongly associated with LN in SLE patients and is a promising biomarker for prediction of renal involvement in these patients. It reflects SLE activity specially LN activity namely renal score and GFR decline. Further prospective studies are required to confirm visfatin as a destructive mediator of predictive and prognostic value in active lupus nephritis.     

Serum interleukin-18 levels in patients with systemic lupus erythematosus: Relation with disease activity and lupus nephritis

Aim of the workTo further investigate the possible role of IL-18 in the pathogenesis of systemic lupus erythematosus (SLE) and development of lupus nephritis (LN), and to explore its relationship with pathological classes of LN, degree of acute renal activity and chronic damage.Patients and methodsForty-one SLE patients with LN, thirty-one lupus non-nephritis patients and fifteen age and sex matched healthy controls were enrolled in this study. SLE patients were subjected to disease activity assessment by SLEDAI, renal disease activity assessment by the Systemic Lupus International Collaborating Clinics (SLICC) Renal Activity Score, laboratory investigations including measurement of serum interleukin-18 using Enzyme Linked Immunosorbent Assay. Renal biopsy was obtained from LN patients and pathological classification was made according to World Health Organization (WHO) criteria. Analysis of activity and chronicity indices was done on these biopsy specimens.ResultsSerum levels of IL-18 were significantly higher in patients with LN than lupus non-nephritis patients and healthy controls (p < 0.001). There were significant correlations between IL-18 and SLEDAI (p = 0.002), proteinuria (p = 0.027), renal activity score (p = 0.003) and activity index (p = 0.039) in patients with LN. There was no significant difference in the serum levels of IL-18 between WHO classes of LN.ConclusionIL-18 appears to have a pathogenic role in the development of SLE and plays a crucial role in triggering inflammation in LN. Serum IL-18 levels could be a useful biomarker to assess the activity of renal disease in SLE.     

IgG therapy in systemic lupus erythematosus

Summary Two paediatric patients with systemic lupus erythematosus were treated with immunoglobulin G (IgG). In the first case treatment resulted in regression of the most acute symptoms and a long remission was achieved. In the second patient, who was treated during the chronic stage of the disease, there was no significant effect on the course of the SLE.Abbreviations ESR Erythrocyte sedimentation rate - T Thoracic vertebra - DNA Deoxyribonucleic acid - HLA HLA system (of histocompatibility loci) - IgG Immunoglobulin G - RES Reticuloendothelial system - SLE Systemic lupus erythematosus - CNS Central nervous system     

Efficacy and safety of tacrolimus for induction therapy in patients with active lupus nephritis

Abstract

After the completion of a double-blind placebo-controlled trial, tacrolimus (TAC) was approved for the treatment of lupus nephritis (LN) in Japan. However, the approved maximal dose, 3 mg/day, is almost half the dose used for induction therapy outside Japan. In this study, we retrospectively evaluated the efficacy and safety of low-dose TAC (≤3 mg/day) for induction therapy in 13 adult patients (2 men and 11 women) with active LN. Eight patients were treated for LN flares. Twelve patients underwent renal biopsies: 8 with class IV, 2 with class III + V, 1 with class IV + V, and 1 with class V renal histology, according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification. The mean initial doses of prednisone and TAC were 34.6 ± 14.5 and 2.7 ± 0.6 mg/day, respectively. All the patients achieved a complete remission (CR) at 7.7 ± 6.7 months (mean ± SD) after the last administration of TAC, except for 2 patients who discontinued TAC treatment; 1 because of worsening systemic lupus erythematosus and 1 because of hypertension. Two patients experienced a flare-up after achieving CR. The mean blood TAC concentration 12 h after the last administration (C12) was significantly lower among the patients with flare-ups than among those with a sustained CR (1.5 ± 1.5 vs. 5.1 ± 1.9 ng/mL, P = 0.034). These data showed that low-dose TAC was effective for induction therapy in patients with active LN, although a lower TAC concentration may be associated with a poor outcome.     

Kidney disease in systemic lupus erythematosus

Summary Glomerulonephritis is a major determinant of outcome in patients with systemic lupus erythematosus. Persistently active lupus nephritis imposes serious threats of end-stage renal failure and cardiovascular morbidity. Sustained corticosteroid treatment has been characterized as having an uncertain net benefit on the control of lupus nephritis, mainly because these drugs have relatively weak efficacy and they have been shown to confer their own set of cardiovascular risk factors. Controlled trials of corticosteroids, azathioprine and cyclophosphamide have demonstrated that the best control of clinical activity of proliferative lupus nephritis is attained with cyclophosphamide. To date, intermittent pulse cyclophosphamide treatment has produced the most facorable balance of efficacy and toxicity in patients with lupus nephritis.     

Serum level of galectin-9 in systemic lupus erythematosus patients with lupus nephritis: Relation to clinical characteristics and disease activity

Aim of the workTo assess galectin-9 (Gal-9) level in the serum of systemic lupus erythematosus (SLE) patients with and without renal involvement and clarify its relation with disease activity.Patients and methods50 SLE patients; 25 with lupus nephritis (LN) and 25 without as well as 25 controls were studied. Systemic Lupus International Collaborating Clinics (SLICC) renal activity score and SLE disease activity index 2000 (SLEDAI-2 K) were determined. Serum Gal-9 was measured in all participants.ResultsGal-9 level was significantly elevated in SLE patients with (16.7; 11.6–33.7 ng/ml) and without (15.9; 11.8–25 ng/ml) compared to controls (3.9; 2.8–5.4 ng/ml) (p < 0.001) but was comparable between the patients groups (p = 0.83). In LN patients, serum Gal-9 and SLICC renal activity score significantly correlated (r = 0.48, p = 0.016). Serum Gal-9 significantly correlated with SLEDAI-2 K in patients with (r = 0.71, p < 0.001) and without (r = 0.95, p < 0.001) LN, with anti-double stranded deoxyribonucleic acid (anti-ds-DNA) titers (with r = 0.57, p < 0.001 and without r = 0.79, p < 0.001) and inversely with C3 (with r = -0.44, p = 0.027 and without r = -0.63, p < 0.001) and C4 (with r = -0.47, p = 0.018 and without r = -0.43, p = 0.03). Gal-9 had an area under the curve (AUC) of 0.96 to distinguish SLE cases from control. However, AUC between LN group and non-nephritic SLE was 0.48. On regression, SLEDAI-2 K was the only significant factor associated with serum Gal-9 (p < 0.001).ConclusionIn SLE patients, significantly raised Gal-9 levels and relation with disease activity were detected indicating its clinical relevance as biomarker of disease activity and its potential value in the disease diagnosis. Its value in discriminating LN from non-nephritic SLE is limited.     

Antinucleosome antibodies in systemic lupus erythematosus patients: Relation to disease activity and lupus nephritis

Aim of the work

To evaluate the level of anti-nucleosome (anti-NCS) antibodies in systemic lupus erythematosus (SLE) patients and study their association with disease activity and lupus nephritis.

Serum beta2-microglobulin level in systemic lupus erythematosus patients: Relation to disease activity

Aim of the workTo assess the level of β2-microglubulin (β2M) in systemic lupus erythematosus (SLE) patients and its association with disease activity and other disease parameters.Patients and methods40 SLE patients and 22 matched controls were studied. Serum β2M was assessed using enzyme-linked immunosorbent assay (ELISA). SLE Disease Activity Index (SLEDAI) and the damage index were assessed.ResultsThe patients were 36 females and 4 males (F:M 9:1) with a mean age of 28.5 ± 7.9 years and disease duration of 6.7 ± 3.3 years. The SLEDAI was 9.3 ± 5.2 and the damage index 1.83 ± 1.84. The mean level of serum β2M was significantly higher in SLE patients (6.42 ± 2.46 mg/L) than control (2.47 ± 0.4 mg/L) (p < 0.01).The serum level of β2M was significantly higher in patients with nephritis (n = 22) (7.45 ± 2.47 mg/L) compared to those without (n = 18) (5.17 ± 1.82 mg/L)(p = 0.002), And it was similar in those with and without arthritis (7.24 ± 2.3 mg/L vs 5.88 ± 2.4 mg/L (p0.07).The β2M significantly correlated with disease activity (r = 0.86, p 0.001), serum creatinine (r = 0.52, p > 0.001), urea (r = 0.63, p < 0.001), 24 h urinary protein (r = 0.56, p < 0.001), hematuria (r = 0.4, p < 0.01) and pyuria (r = 0.41; p < 0.01), ESR (r = 0.48; p < 0.01) and inversely with hemoglobin level (r = ?0.34; p = 0.03). No significant correlation was found with C-reactive protein or with disease damage. Serum (β2M) significantly predicted nephritis and disease activity (sensitivity 63.6 %, specificity 77.8 %; p < 0.001 and 95 %CI: 0.25–0.41; p < 0.001 respectively).ConclusionSerum β2M is significantly associated with disease activity and lupus nephritis, suggesting that serum β2M may serve as a potential biomarker to monitor the disease activity and predicting lupus nephritis. However its association to disease severity needs further longitudinal studies.     

Sequential evaluation of clinical and laboratory changes amongst children suffering from lupus nephritis during intermittent intravenous cyclophosphamide therapy

We prospectively evaluated the efficacy and safety of a 24-month course of intermittent intravenous cyclophosphamide (IC) therapy for children suffering from lupus nephritis soon after the diagnosis of systemic lupus erythematosus (SLE) was made. Eight children with severe lupus nephritis were treated with IC monthly for 6 months and then every 3 months, totaling 24 months. The repeated measurements of sequential serological parameters of lupus nephritis, monitored over the course of the study, were analyzed statistically. The urine creatinine clearance rate (Ccr), the 24-h urine protein excretion, and the serum creatinine level significantly improved (p<0.05) after 6, 9 and 12 months of treatment, respectively. The serum C3, C4, albumin, and triglyceride level, the hemoglobin level, and the erythrocyte sedimentation rate significantly improved (p<0.05) 1 month after treatment. The IC appeared to elicit a significant effect (p<0.05) upon the mean leukocyte and neutrophil counts but had no effect (p>0.05) on the platelet count. The lymphocyte count decreased (p<0.05) during the first six monthly IC, whereas the lymphocyte count returned to the baseline level during the quarterly IC events. From a total of 96 IC doses given to those SLE patients, severe myelotoxicity occurred in one patient when lymphocyte count declined to 98 mm^-3; however, no sign of clinical infection was observed. The daily steroid dosage can be tapered rapidly, and the SLE-associated hyperlipidemia resolved parallel to the resolution of the acute lupus nephritis. We concluded that the efficacy of a 24-month IC course for a child suffering from lupus nephritis is significant.     

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a typical autoimmune disease that leads to multiple organ damage. For over half a century, SLE has been treated mainly with nonspecific glucocorticoids and immunosuppressants, and the development of molecular target drugs with few adverse reactions is awaited. The treatment goal is remission without systemic symptoms or organ damage. An anti-B-cell activating factor antibody belimumab and an anti-type I interferon receptor antibody anifrolumab are used for patients with active SLE who respond poorly to standard of cares. Additionally, as many susceptibility genes for SLE are associated with signal transduction of dendritic and B cells, cytokines and signaling molecules that bridge the innate and adaptive immune systems are the current focus of attention. Promising approaches include the development of a Janus kinase inhibitors targeting tyrosine kinase deucravacitinib, plasmacytoid dendritic cell-targeted drugs, proteasome inhibitors (e.g., iberdomide), type II anti-CD20 antibody, and obinutuzumab.     

Early achievement of complete renal response predicts good long-term renal outcome and low systemic damage in newly diagnosed lupus nephritis class III or IV

Abstract

Objective. To identify predictors of long-term renal prognosis after induction therapy in patients with newly diagnosed lupus nephritis class III or IV.

Methods. We retrospectively studied patients with newly diagnosed lupus nephritis class III or IV. We divided them into two groups according to the complete renal response (CR) status at 3 years after induction therapy. We compared baseline clinical characteristics, renal pathological findings, and time to achieve CR, and identified predictors. Patients were followed up for to 10 years to assess long-term systemic damage.

Results. Eighteen patients with CR and 9 with non-CR were included. There were no significant differences in baseline characteristics. Early CR, which was defined as achieving CR at 3 months after induction therapy, was significantly associated with maintaining CR at 3 years (p = 0.012). Patients with early CR less frequently had flare in systemic manifestation compared with those without over 10 years (p = 0.026). Deterioration of systemic damage was observed more often in non-early CR patients than early CR patients at 10 years (p = 0.029).

Conclusion. Achieving CR at 3 months after induction therapy may predict CR at 3 years, reduced organ damage, and a low incidence of disease flare for 10 years.     

Endothelial cell-binding antibodies in patients with systemic lupus erythematosus

 The implications of endothelial cell-binding IgG antibodies (EC IgG) in systemic lupus erythematosus (SLE) was evaluated by determining level of EC IgG in sera from 112 SLE patients. The serum EC IgG level was determined by the cyto-ELISA method using human umbilical vein endothelial cells (HUVEC), human microvascular endothelial cells (HMVEC), and aortic endothelial cells (HAEC) as antigens. The levels of EC IgG were significantly higher among patients with SLE than among healthy control subjects (P < 0.001), and 68% (76/112) of SLE patients were shown to be EC IgG-positive. In patients with active lupus nephritis, the level of EC IgG was statistically and significantly elevated compared with those without lupus nephritis (P < 0.05). Negative correlations between EC IgG level and levels of CH50, C3, and lymphocyte count were revealed (P < 0.05, P < 0.005, and P < 0.05, respectively). When clinical course was evaluated, the levels of EC IgG correlated with disease activity. Definitive correlations in antibody levels between HUVEC and HMVEC, and between HUVEC and HAEC were revealed (both P < 0.0001). The results of this study revealed that the EC IgG in patients with SLE was involved in the onset of clinical manifestation, especially in patients with active lupus nephritis. Received: January 28, 2002 / Accepted: July 12, 2002 Acknowledgments This investigation was supported by grants from the Research Committee on Intractable Vasculitides, and the Ministry of Health and Welfare of Japan, from 1996 to 2000. Correspondence to:H. Bando     

Antiphospholipid antibodies in children with systemic lupus erythematosus: a prospective study in northern India

Twenty-seven children with systemic lupus erythematosus (SLE) were tested for antiphospholipid antibodies (APLA), i.e. lupus anticoagulant and immunoglobulin (Ig)G or IgM anticardiolipin antibodies (ACLA), with beta-2 glycoprotein I as cofactor, in a single-centre, prospective study over 2 years. Eighteen patients (67%) tested positively for one or the other APLA during the course of the study. Twelve children (44%) tested positively for IgG ACLA and ten (37%) for IgM ACLA, whereas eight (30%) were positive for lupus anticoagulant. In two patients with thrombosis, IgG anticardiolipin positivity was seen to be variable. Unlike the results of most other reports in the literature, lupus anticoagulant positivity was not consistently associated with thrombosis. A majority of the children (83%) tested positively for ACLA during disease activity. Immunoglobulin G and IgM ACLA positivity did not correlate significantly with disease status. The results of this prospective study would indicate that, though frequently present, APLA may be unable to be predictive of disease behaviour in children with SLE.     

Soluble and membranous endothelial protein C receptor in systemic lupus erythematosus patients: Relation to nephritis

Aim of the work

To investigate the role of endothelial protein C receptor (EPCR) (membrane and soluble forms) as a biomarker of lupus nephritis (LN) in systemic lupus erythematosus (SLE) patients and to study its relation to the prognosis and response to treatment.

Maternal and fetal outcomes of 72 pregnancies in Argentine patients with systemic lupus erythematosus (SLE)

The purpose of the following study was to analyze maternal and fetal outcomes in pregnant patients with systemic lupus erythematosus (SLE) and the influence of SLE exacerbations on those pregnancies. Seventy-two pregnancies in 61 SLE patients treated between January 1986 and February 2004 in Hospital de Clínicas “José de San Martin” were reviewed retrospectively. Patient age was 28.1 ± 6.2 years (mean±standard deviation [SD]). Mean SLE duration was 4.5 ± 3.2 years (range 6 months–10 years). No patient acquired the disorder during gestation. Four (5.5%) patients had signs of active disease at the beginning of her pregnancy. Sixteen patients, accounting for 20 pregnancies, had a history of lupus nephritis. Nine patients met secondary antiphospholipid syndrome criteria and had 13 pregnancies. There were 14 exacerbations of the disease during pregnancy (19.4%), with most flares being mild. The most common obstetric complications were gestational hypertension in 15 pregnancies (20.8%) and preeclampsia in 8 pregnancies (11%). Forty-six percent of pregnancies ended in preterm deliveries. There were 62 live births (1 twin birth; 85%), 6 stillbirths (8%), and 5 spontaneous abortions (7%). Thirty-nine percent of newborns had low birth weight. Adequate pregnancy follow-up and delivery care by an interdisciplinary team in Argentine SLE patients with no pre-gestational preparation resulted in maternal and fetal outcomes similar to those seen in world reference centers.     

Disease flare patterns and predictors of systemic lupus erythematosus in a monocentric cohort of 423 Japanese patients during a long-term follow-up: The JUDE study

Objective: To clarify the clinical features of systemic lupus erythematosus (SLE) patients, factors associated with flares, and changes over time.

Methods: Patients having SLE with a visiting history were entered into the Juntendo University Database of Erythematosus. We included 423 cases in the long-term follow-up analysis, and 383 cases were followed for 10 years after the initiation of any therapeutic intervention (comparative analysis: 1973–1982, 82 cases; 1983–1992, 141, and 1993–2002, 160). We assessed changes in the patients’ background characteristics, disease symptoms, flare rates, etc.

Results: Among the 423 cases, the mean follow-up period was 25.9 years, and mean number of flares was 0.51. Of those, 31.9% had ≥1 flares. Thrombocytopenia at onset contributed to the flares. For disease symptoms at onset, a recent trend in increasing thrombocytopenia was observed. The combination rate of immunosuppressive agents for diseases other than lupus nephritis was slightly increased, and there was no improvement until the first flare or in the flare rate.

Conclusions: Thrombocytopenia at onset is predictive factor for flares. Since SLE is a diverse disease with varying symptoms at recurrence, the treatment guidelines should be improved for thrombocytopenia from a long-term perspective.     

Serum L-ficolin levels in patients with systemic lupus erythematosus

Abstract

Objective L-ficolin plays an important role in innate immunity and is involved in apoptosis. The objective of this study was to investigate the relationship between serum L-ficolin levels and clinical manifestations in patients with systemic lupus erythematosus (SLE).

Methods Serum L-ficolin levels were determined by enzyme-linked immunosorbent assay in 66 SLE patients and 50 healthy controls.

Results Median serum L-ficolin levels were 5.0 and 8.7 μg/ml in SLE patients and controls, respectively (p = 0.0001). There were no significant differences in serum L-ficolin levels between the active disease group [SLE Disease Activity Index (SLEDAI) > 6] and the inactive disease group (SLEDAI < 5). Decreased serum L-ficolin levels were associated with thrombocytopenia (median of with vs. without thrombocytopenia 3.4 vs. 5.3 μg/ml, p = 0.008). There were no correlations between serum L-ficolin levels and SLEDAI, serum C3, or serum C4 levels.

Conclusion The association between L-ficolin and thrombocytopenia suggests a pathogenic role for L-ficolin in thrombocytopenia in SLE.