Prognosis of proliferative lupus nephritis subsets in the Louvain Lupus Nephritis inception Cohort.

OBJECTIVE: The objective of this paper is to evaluate whether the different International Society of Nephrology/Renal Pathology Society (ISN/RPS) classes of proliferative lupus nephritis (LN) have a distinct baseline presentation, short-term response to immunosuppression (IS) and long-term prognosis. METHODS: Ninety-eight patients with new onset (first renal biopsy) ISN/RPS proliferative LN (Class III: n=24; IV-S: n=23; IV-G: n=51) were diagnosed at our institution between 1995 and 2012 (Louvain Lupus Nephritis inception Cohort). Their baseline renal parameters, primary response to IS at one year, survival and long-term renal outcome (mean follow-up: 77 months) were compared. RESULTS: At baseline, serum creatinine and 24-hour proteinuria were higher in Class IV-G, as was activity index on renal biopsy in Class IV-S and IV-G compared to III. Upon treatment, renal parameters improved with the same kinetics and to the same extent in the three pathological classes. On repeat renal biopsies (n=43), activity indices dropped similarly. Poor outcomes (death, end-stage renal disease, renal impairment defined by an eGFR <60 ml/min/1.73 m(2)) did not statistically differ between groups, although there was a trend toward more renal impairment at follow-up in Class IV-G compared to IV-S and III. Finally, the presence of even mild chronic lesions on baseline biopsy was clearly predictive of late renal outcome. CONCLUSION: Subsetting proliferative LN into Class III, IV-S and IV-G provides less clinically discriminant prognostic information than baseline chronicity index.

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.

A pilot study of mycophenolate mofetil combined to intravenous methylprednisolone pulses and oral low-dose glucocorticoids in severe early systemic sclerosis.

OBJECTIVE: This pilot study was aimed at evaluating the efficacy and safety of a protocol-based treatment strategy combining mycophenolate mofetil (MMF), intravenous (IV) methylprednisolone (MP) pulses and low-dose glucocorticoids (GC) in early systemic sclerosis (SSc) patients suffering from either active interstitial lung disease (ILD) or extensive skin disease. PATIENTS AND METHODS: Sixteen SSc patients were recruited in the study, 9 based on the severity of their skin involvement (modified Rodnan total skin score [TSS] >or= 15) and 7 based on the presence of active ILD. Patients received 3 consecutive daily IV MP pulses, followed by 5 additional monthly IV MP pulses. MMF (0.5 g bid for one week; then, 1 g bid) and low-dose (5-10 mg/day) oral prednisolone were prescribed for one year. Patients were assessed at baseline, month 6 and 12. Statistics were by ANOVA. RESULTS: TSS and Health Assessment Questionnaire significantly improved over time. In ILD patients, the vital capacity, forced expiratory volume in one second and carbon monoxide diffusing capacity significantly improved. Although the difference was not statistically significant, ground glass lesions decreased, based on semi-quantitative planimetry analyses performed on chest high-resolution computerized tomography. Toxicity was low and none of the patients suffered from renal crisis. CONCLUSION: The results of this pilot study suggest that the combination of MMF, IV MP and low-dose GC might achieve good clinical, functional and radiological results in patients suffering from severe early SSc.

Systemic lupus erythematosus in Europe at the change of the millennium: lessons from the "Euro-Lupus Project".

The "Euro-Lupus Cohort" is composed by 1000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium--the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors.

Treatment of the vertebral crush fracture syndrome with enteric-coated sodium fluoride tablets and calcium supplements.

A cohort of 101 patients were treated with enteric-coated sodium fluoride tablets and calcium supplements. Vitamin D was also given in supra-physiologic doses in 70% of the cases. Lumbar bone mineral density (BMD), as measured by dual-photon absorptiometry, increased in a linear fashion up to four years, irrespective of the value of initial BMD and of the underlying condition, be it involutional osteoporosis (the vast majority), glucocorticoid osteoporosis, or even osteogenesis imperfecta. Estrogen replacement therapy (ERT) seemed to promote the fluoride-induced increase in lumbar BMD, as did the vitamin D supplements. Of these patients, 17% proved "resistant" to the therapy. There was no way of predicting who would be in this category. Compared with an age- and sex-matched control group, women showed significantly different behavior of their bone mass. In the control group, the losses were highly significant at the lumbar spine and at all three scanning sites of the forearm, as measured by single-photon absorptiometry. In contrast, the fluoride group had a significant gain of BMD at the lumbar spine and changes of BMC at the forearm were not significant. Fluoride thus preserved bone mass at the appendicular skeleton, while increasing it at the axial skeleton. When comparing the patients who received vitamin D supplements and those who did not, there was a significant difference in the appendicular skeleton. The distal forearm in the vitamin D-supplemented group tended to gain, whereas the midforearm lost significant bone mass. The trend was reversed in the group without vitamin D-supplementation, a more favorable pattern. Therefore, vitamin D supplements should not, as a rule, be provided to such patients. The biochemical hallmark of the fluoride-induced changes is a slight rise of the alkaline phosphatase within the normal range. Alkaline phosphatase levels that exceed the upper limit of normal signal a warning that too much fluoride and/or too little calcium supplements are being administered, or that a fluoride-related complication is impending or has occurred (e.g., a stress fracture). Osteosclerosis was achieved in 69% of the cases who had a radiological followup of at least four years (average period of appearance: 1.8 years). Stress fractures in the lower limbs occurred in 17 patients, almost exclusively in females, and appeared on average 2.2 years after initiation of therapy. In this group of stress fractures there was significant cortical bone loss at midforearm.(ABSTRACT TRUNCATED AT 400 WORDS)

Evaluation of the simple calculated osteoporosis risk estimation (SCORE) in a sample of white women from Belgium.

Identifying patients at risk of developing an osteoporosis-related fracture will continue to be a challenge. The "gold standard" for osteoporosis diagnosis is bone densitometry. However, economic issues or availability of the technology may prevent its use under a mass screening scenario. A risk assessment instrument, the "simple calculated osteoporosis risk estimation" (SCORE), has been reported to appropriately identify women likely to have low (t score < or = -2 SD) bone mineral density (BMD) and who should be referred for bone densitometry. The aim of our study is to evaluate the discriminatory performance of SCORE in a random sample of postmenopausal white women from Belgium. For this purpose, we gathered medical data on 4035 consecutive patients aged > or = 45 years, either consulting spontaneously or referred for a BMD measurement to an outpatient osteoporosis center located at the University of Liège, Belgium. BMD measurements, using dual-energy X-ray absorptiometry (DXA) technology, were taken at the hip (total and neck) and lumbar spine (L2-4). At the recommended cutoff point of 6, SCORE had a sensitivity of 91.5% to detect low BMD at any of the measured sites, a specificity of 26.5%, a positive predictive value of 52.8%, and a negative predictive value of 77.7%. According to SCORE, 18% of the patients would not be recommended for densitometry. Among these, 10.9% were misclassified as they had osteoporosis (t score < or = -2.5 SD) at one or more of the sites investigated. The negative predictive errors of SCORE, when failing to detect osteoporosis, were only 1% for the total hip, 3.2% for the femoral neck, and 8.8% for the lumbar spine. We conclude that, notwithstanding the high values of sensitivity, SCORE specificity is too low to be useful as a diagnostic tool for screening patients at high risk to later develop osteoporosis. Nevertheless, from a resource allocation perspective, this instrument can be used with relative confidence to exclude patients who do not need a BMD measurement, and would therefore provide an opportunity to realize substantial cost savings in comparison to a mass screening strategy.

Evaluation of bone mineral density after renal transplantation under a tacrolimus-based immunosuppression: a pilot study.

BACKGROUND: Progressive bone loss consistently complicates renal transplantation (TP) in patients given an immunosuppression including prednisolone. The adjunction of cyclosporine in the immunosuppressive regimen does not reverse the negative impact of renal TP on the skeleton. The post-transplant effect of tacrolimus on bone mass is still unknown. METHODS: We evaluated the evolution of bone mineral density (BMD) and various biochemical markers over the first 12 months following renal TP in 23 patients given an immunosuppression combining tacrolimus and low-dose prednisolone. BMD of lumbar spine, total hip and hip subregions was measured by dual-energy X-ray absorptiometry within the first 15 days and 1 year after TP. RESULTS: At the time of TP, the average BMD was low in both the lumbar spine and the hip. After TP, a normalization of serum creatinine and a decrease in serum phosphate and iPTH levels occurs. Serum alkaline phosphatase level significantly rose transiently within the first 6 months and decreased thereafter. At 1 year post TP, BMD remained unchanged in the lumbar and in the trochanter subregions and rose in the other sites. BMD increased by at least 2% in 8, 13, 10 and 10 out of the 23 patients in the lumbar, neck, trochanter and total hip subregions, respectively. No correlation was found between evolution in BMD and age, sex, dialysis duration, level of hyperparathyroidism, prednisolone and tacrolimus cumulative intake and prescription of calcium, vitamin D or hormone replacement therapy. CONCLUSIONS: An immunosuppression combining tacrolimus and low-dose prednisolone might avoid the usual post-TP bone loss. Further randomized double-blind studies evaluating a larger cohort of patients should be undertaken to compare the effect of cyclosporine and tacrolimus on bone mass.

The effect of low dosage glucocorticoids on bone mass in rheumatoid arthritis: a cross-sectional and a longitudinal study using single photon absorptiometry.

The cross-sectional study of patients with RA receiving LDGC, compared with those on NSAID alone (or patients with AS) showed that LDGC significantly affects bone mass at midshaft and even more so at the distal radius. The loss of bone seems to be brisk but continuous on the long run, at least at the distal scanning site, and thus increases the C/T ratio, especially in aged men. The loss of bone mass in the LDGC group correlates with the duration of the disease as well as with carpal destruction (especially at mid shaft radius), with both parameters being correlated with one another. At equal carpal destruction, LDGC still affects bone mass. Whether receiving NSAID alone or LDGC in addition, patients with RA, as compared with controls, are more liable to lose bone when they grow older. In a longitudinal study, premenopausal women were unaffected by the administration of LDGC at both scanning sites. In contrast, postmenopausal women receiving LDGC lost at least twice as much bone as did normal women after the menopause. Men of all ages on LDGC lost bone at a rate equal to that of normal women after the menopause. Men with RA or with AS on NSAID alone did not significantly lose bone. It is concluded that LDGC may be given to premenopausal women without harm to their bone mass. After the menopause, hormonal replacement therapy, if not contra-indicated, should be given in association with LDGC. Men fortunately have a higher peak bone mass and therefore can afford to lose bone during a decade before they attain the same situation as women at the time of their menopause. If treatment is then continued for another two decades, their bone mass might behave as does that of postmenopausal women if bone loss is continuous over such long periods of time. This latter assumption has yet to be verified.

[Metabolic investigation of a population of institutionalized epileptics (author's transl)]. / Bilan métabolique d'une population d'épileptiques institutionnalisés.

77 epileptics receiving a combination of anticonvulsants have been studied. 25(OH)D3 levels were diminished in 38% of the patients, markedly so in 25%. iPTH levels were elevated in 13%. Total, as well as ionized, serum calcium levels were significantly lower in the epileptic patients, as compared with a control population. Serum P, Mg, and plasma total CO2 levels remained unaltered. Alkaline phosphatase levels were increased, as well as gamma-GT levels. A transiliac bone biopsy was performed in 15 patients and histomorphometric studies were achieved on decalcified and undecalcified sections. Osteomalacia was present in 4 out of the 15 cases, hyperosteoidosis in one. Three biological features distinguished the cases with osteomalacia : iPTH levels and alkaline phosphatase values were significantly higher, and serum P levels were significantly lower (all were below 2,4 mg/dl) as compared with the non-osteomalacic patients. In an epileptic population, the serum Ca value is lower than in a control population by 0,5 mg/dl. When in addition the serum P is low (which was a feature of male patients), the danger exists for osteomalacia to develop. The former abnormality is connected with low 25(OH)D3 levels, the primary event, while the latter is probably related to high (secondary) iPTH levels.

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.

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

We prospectively followed 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 glucocorticoids and 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.

Longitudinal analysis of bone mineral density in pre-menopausal female systemic lupus erythematosus patients: deleterious role of glucocorticoid therapy at the lumbar spine.

OBJECTIVE: To evaluate whether bone loss occurs over time in pre-menopausal systemic lupus erythematosus (SLE) patients. METHODS: We performed a longitudinal bone mineral density (BMD) analysis in a group of 35 pre-menopausal female SLE patients. Lumbar spine and hip (total and sub-regions) BMDs were measured twice 21 +/- 11 (mean +/- S.D.) months apart by dual-energy X-ray absorptiometry. RESULTS: In the whole cohort of SLE patients, significant bone loss was observed at the lumbar spine (-1.22%/yr) but not at the total hip. Further analyses indicated that lumbar spine bone loss (-2.12%/yr) occurred exclusively in the subgroup of patients who had taken a mean prednisolone daily dose >7.5 mg between the two BMD measurements. Moreover, bone loss was more important in patients who had previously received a cumulative prednisolone dose 7.5 mg.

Trabecular and cortical bone loss in systemic lupus erythematosus.

We measured lumbar spine, hip (total and sub-regions) and total body bone mineral densities (BMDs) by dual-energy X-ray absorptiometry (DXA) in 47 premenopausal female patients suffering from systemic lupus erythematosus (SLE). As compared to health controls, SLE patients had lower BMDs at all trabecular and cortical sites. Comparison of BMDs between patients ever and never treated with glucocorticoids indicated that patients who had ever received glucocorticoids had a significantly lower lumbar spine BMD compared to those who never did. Moreover, bone loss in patients ever treated with glucocorticoids was commensurate with their cumulated oral glucocorticoid intake. Interestingly, patients never treated with glucocorticoids had a lower hip BMD compared to controls, thereby suggesting that the disease per se might induce some bone loss. Taken together, SLE patients suffer from a significant trabecular and cortical bone loss indicative of an increased risk of future fracture.

Interest of a prescreening questionnaire to reduce the cost of bone densitometry.

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.

Magnetic resonance imaging-detected avascular osteonecrosis in systemic lupus erythematosus: lack of correlation with antiphospholipid antibodies.

We determined prospectively the prevalence of avascular osteonecrosis (AON) by magnetic resonance imaging (MRI) of both lower limbs in a group of 40 systemic lupus erythematosus (SLE) patients, and correlated the results with their serum antiphospholipid antibody (APL Ab) status and their glucocorticoid (GC) intake. APL Ab were detected by anticardiolipin ELISA and by lupus anticoagulant assays. Cumulated prednisolone doses were computed by chart review. The prevalence of AON was 37.5%, with most patients being asymptomatic despite involvement of multiple sites. The number of epiphyseal, metaphyseal and diaphyseal AON sites per patient did not differ between APL Ab-positive and APL Ab-negative patients nor between patients with high and low APL Ab titres. By contrast, a striking correlation was found between the prevalence and severity of AON and GC therapy. In conclusion, this prospective MRI study indicates that the prevalence of AON in SLE patients correlates strongly with GC therapy, but not with APL Ab status.

Hematological changes in anorexia nervosa are correlated with total body fat mass depletion.

OBJECTIVE: To assess the relationships between total body fat mass (FM) and hematological abnormalities in anorexia nervosa (AN). METHOD: Peripheral blood parameters and body composition were determined in 10 anorectic patients and 19 age- and sex-matched healthy subjects. In patients with AN, magnetic resonance imaging (MRI) studies of bone marrow were also performed. RESULTS: Compared with controls, patients with AN had -41% body weight, -81% FM, -18.8% lean tissue mass (LTM), and -22.6% bone mineral content; they also had lower mean total leukocyte (4.52 +/- 0.47 vs. 6.28 +/- 0.33 x 10(3)/microliter, p < .005), neutrophil (2.45 +/- 0.34 vs. 3.46 +/- 0.20 x 10(3)/microliter, p < .005), monocyte (0.24 +/- 0.03 vs. 0.37 +/- 0.03 x 10(3)/microliter, p < .05), and platelet counts (184 +/- 17 vs. 238 +/- 9 x 10(3)/microliter, p < .005). Hemoglobin level was normal and comparable in both groups. In patients with AN, but not in controls, total leukocyte, neutrophil, eosinophil, and monocyte counts as well as hemoglobin level were highly correlated with FM expressed in absolute values or in percentage of body weight, but not with LTM. Moreover, AN patients with signal intensity patterns suggestive of serous atrophy of bone marrow at MRI had not only lower erythrocyte, leukocyte, neutrophil, and platelet counts, but they also had lower FM than AN patients with normal MRI patterns. DISCUSSION: Hematological changes in AN, as assessed by peripheral blood parameters and MRI patterns of bone marrow, are correlated with total body FM depletion, suggesting that the reduction of adipose tissue adversely affects hematopoiesis.

Lessons from the "Euro-Lupus Cohort".

The "Euro-Lupus Cohort" is composed by 1,000 patients with systemic lupus erythematosus (SLE) that have been followed prospectively since 1991. These patients have been gathered by a European consortium - the "Euro-Lupus Project Group". This consortium was originated as part of the network promoted by the "European Working Party on SLE", a working group created in 1990 in order to promote research in Europe on the different problems related to this disease. The "Euro-Lupus Cohort" provides an updated information on the SLE morbidity and mortality characteristics in the present decade as well as defines several clinical and immunological prognostic factors.