Geneviève Depresseux

The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide

Objective: To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomised prospective trial comparing low-dose (LD) and high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis. Patients and methods: Data for survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomised in the ELNT, except in 6 lost to follow-up. Results: Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (5/44 (11%) vs 2/46 (4%), 6/44 (14%) vs 5/46 (11%) and 2/44 (5%) vs 4/46 (9%), respectively) nor did mean serum creatinine, 24 h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. After 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy was confirmed. Conclusion: The data confirm that a LD IVCY regimen followed by AZA—the “Euro-Lupus regimen”—achieves good clinical results in the very long term.

Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial

Background Long-term immunosuppressive treatment does not efficiently prevent relapses of lupus nephritis (LN). This investigator-initiated randomised trial tested whether mycophenolate mofetil (MMF) was superior to azathioprine (AZA) as maintenance treatment. Methods A total of 105 patients with lupus with proliferative LN were included. All received three daily intravenous pulses of 750 mg methylprednisolone, followed by oral glucocorticoids and six fortnightly cyclophosphamide intravenous pulses of 500 mg. Based on randomisation performed at baseline, AZA (target dose: 2 mg/kg/day) or MMF (target dose: 2 g/day) was given at week 12. Analyses were by intent to treat. Time to renal flare was the primary end point. Mean (SD) follow-up of the intent-to-treat population was 48 (14) months. Results The baseline clinical, biological and pathological characteristics of patients allocated to AZA or MMF did not differ. Renal flares were observed in 13 (25%) AZA-treated and 10 (19%) MMF-treated patients. Time to renal flare, to severe systemic flare, to benign flare and to renal remission did not statistically differ. Over a 3-year period, 24 h proteinuria, serum creatinine, serum albumin, serum C3, haemoglobin and global disease activity scores improved similarly in both groups. Doubling of serum creatinine occurred in four AZA-treated and three MMF-treated patients. Adverse events did not differ between the groups except for haematological cytopenias, which were statistically more frequent in the AZA group (p=0.03) but led only one patient to drop out. Conclusions Fewer renal flares were observed in patients receiving MMF but the difference did not reach statistical significance.

Relapses of lupus nephritis: incidence, risk factors, serology and impact on outcome.

We prospectivelyfollowed a cohort of 46 newly diagnosed cases of lupus nephritis (LN) over a mean period of five years in order to determine the renal relapse rate, to identify potential risk factors for relapses, to assess the value of serological tests during flares and to analyse their impact on global outcome. Of the patients 37% experienced at least one renal flare, the first episode occurring after a mean follow-up of 40 months, when most patients were still treated with low-dose glucocorticoidsand azathioprine. Baseline biochemical and pathological data did not differ between relapsing and nonrelapsing patients. Serological findings (low complement and high anti-DNA antibody) were less pronounced at relapse. Moreover, neither a decline in complement nor a rise in anti-DNA antibody titres were observed by the time of renal relapse, compared to immediate pre-flare values. Poor outcomes were observed only in relapsing patients. Taken together, renal relapses in LN patients are common, have a negative impact on outcome, but cannot be readily predicted. These results stress the importance of regular blood and urine examinations in LN patients, even years after the initial episode.

Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis

Objective To report the 10-year follow-up of the MAINTAIN Nephritis Trial comparing azathioprine (AZA) and mycophenolate mofetil (MMF) as maintenance therapy of proliferative lupus nephritis, and to test different definitions of early response as predictors of long-term renal outcome. Methods In 2014, data on survival, kidney function, 24 h proteinuria, renal flares and other outcomes were collected for the 105 patients randomised between 2002 and 2006, except in 13 lost to follow-up. Results Death (2 and 3 in the AZA and MMF groups, respectively) and end-stage renal disease (1 and 3, respectively) were rare events. Time to renal flare (22 and 19 flares in AZA and MMF groups, respectively) did not differ between AZA and MMF patients. Patients with good long-term renal outcome had a much more stringent early decrease of 24 h proteinuria compared with patients with poor outcome. The positive predictive value of a 24 h proteinuria <0.5 g/day at 3 months, 6 months and 12 months for a good long-term renal outcome was excellent (between 89% and 92%). Inclusion of renal function and urinalysis in the early response criteria did not impact the value of early proteinuria decrease as long-term prognostic marker. Conclusions The long-term follow-up data of the MAINTAIN Nephritis Trial do not indicate that MMF is superior to AZA as maintenance therapy in a Caucasian population suffering from proliferative lupus nephritis. Moreover, we confirm the excellent positive predictive value of an early proteinuria decrease for long-term renal outcome. Trial registration number NCT00204022.

Osteoporosis after organ transplantation

Sir—Gudrun Leidig-Bruckner and colleagues (Feb 3, p 342) report a high frequency of osteoporotic fractures in cardiac or liver allograft recipients. Age and lumbar mineral-density decrease were the only independent predictors at multivariate analysis. They saw no dose-dependent effect of glucocorticoids, but most events occurred in the first year after transplantation, when glucocorticoids are given at higher doses. However, differences between patients given glucocorticoids might be difficult to identify, since most transplant patients received standard doses. The best way to assess the role of glucocorticoids would be to compare patients assigned glucocorticoids with those who receive none. We prospectively measured, every 6 months, bone-mineral density (with dual-energy X-ray absorptiometry) of lumbar vertebrae in 53 renal-transplant recipients randomly assigned cyclosporine alone (13 patients), cyclosporine plus steroids (20), or cyclosporine plus steroids plus azathioprine (20). In patients given steroid-free immunosuppression, the bone-mineral density increased significantly from transplant to 18 months post-transplant, which suggests that cyclosporine does not interfere with bone mineralisation. In the two glucocorticoid-treated groups, bonemineral density decreased significantly by 18 months. In a multicentre study, our intention-to-treat analysis showed the cumulative risk of bone complications was significantly lower at 4 years in patients given steroid-free immunosuppression than in those given steroids. The causes of osteoporotic fractures in organ-transplant recipients is multifactorial, but glucocorticoids might play a major part. Since there is now evidence that, at least in kidney transplantation, steroid-free immunosuppression with cyclosporine, tacrolimus, or rapamune is feasible and does not affect graft survival, patients at higher risk of osteoporosis, such as malnourished or immobilised patients, should be considered for such a treatment.

Hand Radiological Damage in Systemic Sclerosis: Comparison with a Control Group and Clinical and Functional Correlations

OBJECTIVE To define the burden of hand radiological damage in systemic sclerosis (SSc) patients, compared with a control group. METHODS Both hands of 167 SSc patients and 168 hands (82 right and 86 left) of age- and gender-matched controls were imaged by conventional radiograph. Two musculoskeletal radiologists semiquantitatively scored the following lesions: tuft acro-osteolysis, tuft calcinosis, joint space narrowings, marginal erosions, surface erosions, collapse arthropathies, periarticular calcifications, and juxta-articular osteoporosis, at the following areas: tufts, distal interphalangeal, proximal interphalangeal, metacarpophalangeal, carpal, and first carpometacarpal joints. Clinical and functional characteristics of the 167 SSc patients were obtained from the Belgian Systemic Sclerosis Cohort database. RESULTS Tuft acro-osteolysis and calcinosis were the most common findings observed in SSc patients and were almost absent in controls. SSc patients displaying tuft acro-osteolysis/calcinosis suffered from more severe disease. Arthropathies were infrequently detected and mainly consisted of a mixture of osteoarthritis-related changes (joint space narrowing and surface erosions)-also observed in controls-and of 2 types of rare SSc-associated arthropathies: a rheumatoid arthritis-like pattern, characterized by marginal erosions (n = 7 patients), and a collapse arthropathy (n = 6 patients), characterized by pressure erosions and joint subluxation. CONCLUSIONS Although a rheumatoid arthritis-like or a collapse arthropathy can be observed in SSc patients, arthropathies are less common than previously reported.

Repeat kidney biopsies fail to detect differences between azathioprine and mycophenolate mofetil maintenance therapy for lupus nephritis: data from the MAINTAIN Nephritis Trial

BACKGROUND In the MAINTAIN Nephritis Trial, azathioprine (AZA) and mycophenolate mofetil (MMF) were compared as maintenance immunosuppressive treatment of proliferative lupus nephritis (LN) after a short-course of intravenous cyclophosphamide. Here, we compare the pathological findings on repeat kidney biopsies between the two groups. METHODS Per protocol, repeat renal biopsies were obtained in 30 patients (16 AZA and 14 MMF) at 2 years (±6 months). Baseline and follow-up biopsies were graded according to the International Society of Nephrology/Renal Pathological Society (ISN/RPS) classification. The activity and chronicity indices (AI, CI) were calculated using two different semiquantitative scoring systems (Morel-Maroger and National Institutes of Health). Statistics were performed by non-parametric tests. RESULTS The clinical characteristics of the 30 re-biopsied patients only marginally differ from the entire MAINTAIN cohort (105 patients). Clinical baseline and follow-up characteristics of AZA- and MMF-treated re-biopsied patients did not differ. Time (SD) to repeat renal biopsy was 25.0 (2.0) and 26.5 (3.3) months in AZA and MMF patients, respectively. More patients had normal renal biopsies or Classes I/II/V LN at follow-up compared to baseline and conversely, less patients had Class IV LN at follow-up. In both groups, the AI statistically decreased at follow-up compared to baseline, while the CI slightly, but significantly, increased. No differences could be detected between the groups. CONCLUSION Centralized pathological analyses, including ISN/RPS classification and comparisons of AI/CI, failed to find differences between MMF and AZA at 2 years, a result well in line with the absence of difference in long-term clinical outcome reported elsewhere.

Oral pamidronate prevents high-dose glucocorticoid-induced lumbar spine bone loss in premenopausal connective tissue disease (mainly lupus) patients.

Glucocorticoid (GC)-induced osteoporosis contributes to chronic damage in patients suffering from connective tissue diseases (CTD) such as systemic lupus erythematosus (SLE). In this study, performed in an highly selected cohort of premenopausal female CTD (mostly lupus) patients, given high-dose GC therapy for severe disease, we show that lumbar spine bone loss can be averted by treatment with oral disodium pamidronate combined with calcium salts and vitamin D3 supplements and not by calcium salts and vitamin D3 supplements alone. We stress the need for optimal GC-induced bone loss prevention therapy in premenopausal patients, a too often neglected issue in patients whose survival has dramatically improved over the last decades.

Interest of a Prescreening Questionnaire to Reduce the Cost of Bone Densitometry

Abstract: Bone mineral density (BMD) measurement is widely recognized as the best single tool to identify patients with a high lifetime risk of developing an osteoporosis-related fracture. However, the cost/benefit value of screening the whole population has been repeatedly challenged and demonstrated to be rather poor. In many countries, BMD scan is not or no longer reimbursed because of lack of validated criteria to identify patients who should benefit from this procedure. Based on the proposals of a nationwide expert panel, a simple questionnaire identifying historical, clinical and behavioral risk factors for osteoporosis was developed. The aim of this study was to assess the diagnostic accuracy of the proposed criteria; to determine the extent to which this questionnaire could be useful for optimizing the use of densitometry tests; and, more specifically, to estimate the diagnostic costs per osteoporotic or osteopenic patient detected. For this purpose, we applied the questionnaire to 3998 consecutive individuals at least 20 years old, of both genders, either consulting spontaneously or referred for a BMD measurement to an outpatient osteoporosis center. BMD was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and at the hip (both total hip and femoral neck). Diagnostic accuracies were evaluated through measures of sensitivity, specificity, and positive and negative predictive values. After determining a benchmark value for age, different strategies were compared in order to identify the most cost-effective one in terms of cost per patient detected. According to the WHO operational definition of osteoporosis (T-score <–2.5), 31% of the subjects were classified as osteoporotic at one or more of the measured sites. If only patients with at least one of the proposed risk factors had been referred for scans, 33.3% of the BMD measurements would have been avoided. Among those, less than 5% were missclassified as they did have osteoporosis at the total hip and up to 23% at one or more of the considered sites. On the other hand, of the subjects who would be recommended for a densitometry test, only a small fraction were identified correctly (the positive predictive values varied from 11.3% at the total hip to 34.8% at any site). In this first setting, the suggested criteria seem useful chiefly for excluding subjects who do not need a DXA scan rather than selecting osteoporotic patients. When applied only to patients aged 61 years or more, the positive predictive values rose to 15.1% (total hip) and 42.9% (any site), whereas the corresponding negative predictive values were set at 93% and 68.6%. In comparison, with a mass screening scenario the estimated diagnostic costs (costs associated with the DXA procedure) per osteoporotic patient detected at any of the considered sites would be reduced by more than 9% (59.4 instead of 65.3 Euros) if the suggested indications are taken into account for prescreening patients. And when the questionnaire is applied only to women over the age of 60 years these costs would be further reduced to 50.6 Euros, representing a 23% decrease. Then, a prescreening strategy based on these indications concomitantly with an age-selective criterion could represent a promising way toward a more rational use of BMD measurement.

Serum soluble interleukin 7 receptor is strongly associated with lupus nephritis in patients with systemic lupus erythematosus

Background The soluble form of the interleukin 7 receptor (sIL-7R) is produced by fibroblasts after stimulation with proinflammatory cytokines. Increased sIL-7R serum and synovial fluid levels were recently demonstrated in patients with rheumatoid arthritis. Objectives To investigate whether sIL-7R production is dysregulated in systemic lupus erythematosus (SLE), and whether this correlates with disease activity. Methods Serum and urine sIL-7R concentrations were measured by ELISA, and sIL-7R quantitative PCR (qPCR) studies were performed in peripheral blood mononuclear cells (PBMCs). IL-7R, tumour necrosis factor α (TNFα), IL-1β and IL-17 immunostainings were performed on kidney sections. Results sIL-7R concentrations were significantly higher in SLE sera than in controls, and correlated with SLE Disease Activity Index (SLEDAI) scores. Accordingly, serum sIL-7R levels were strongly raised in patients with nephritis. Moreover in patients with lupus nephritis, serum sIL-7R decreased upon treatment. sIL-7R gene expression in PBMCs was similar in patients with lupus nephritis and controls. By contrast, abundant perivascular IL-7R expression was seen in SLE kidney biopsy specimens, which was associated with expression of TNFα in the surrounding tissue. Conclusions Our data indicate that sIL-7R is a marker of SLE disease activity, especially nephritis. In contrast to conventional disease activity markers, sIL-7R is not produced by immune cells, but might instead reflect activation of tissue cells in the target organ.