Differences in rituximab use between pediatric rheumatologists and nephrologists for the treatment of refractory lupus nephritis and renal flare in childhood-onset SLE.

BACKGROUND: Consensus treatment plans have been developed for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in childhood-onset systemic lupus erythematosus. However, patients who do not respond to initial therapy, or who develop renal flare after remission, warrant escalation of treatment. Our objective was to assess current practices of pediatric nephrologists and rheumatologists in North America in treatment of refractory proliferative LN and flare. METHODS: Members of Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the American Society for Pediatric Nephrology (ASPN) were surveyed in November 2015 to assess therapy choices (other than modifying steroid dosing) and level of agreement between rheumatologists and nephrologists for proliferative LN patients. Two cases were presented: (1) refractory disease after induction treatment with corticosteroid and cyclophosphamide (CYC) and (2) nephritis flare after initial response to treatment. Survey respondents chose treatments for three follow up scenarios for each case that varied by severity of presentation. Treatment options included CYC, mycophenolate mofetil (MMF), rituximab (RTX), and others, alone or in combination. RESULTS: Seventy-six respondents from ASPN and foty-one respondents from CARRA represented approximately 15 % of the eligible members from each organization. Treatment choices between nephrologists and rheumatologists were highly variable and received greater than 50 % agreement for an individual treatment choice in only the following 2 of 6 follow up scenarios: 59 % of nephrologists, but only 38 % of rheumatologists, chose increasing dose of MMF in the case of LN refractory to induction therapy with proteinuria, hematuria, and improved serum creatinine. In a follow up scenario showing severe renal flare after achieving remission with induction therapy, 58 % of rheumatologists chose CYC and RTX combination therapy, whereas the top choice for nephrologists (43 %) was CYC alone. Rheumatologists in comparison to nephrologists chose more therapy options that contained RTX in all follow up scenarios except one (p < 0.05). CONCLUSIONS: Therapy choices for pediatric rheumatologists and nephrologists in the treatment of refractory LN or LN flare were highly variable with rheumatologists more often choosing rituximab. Further investigation is necessary to delineate the reasons behind this finding. This study highlights the importance of collaborative efforts in developing consensus treatment plans for pediatric LN.

Kidney biopsy-based management of maintenance immunosuppression is safe and may ameliorate flare rate in lupus nephritis.

The optimal duration of maintenance immunosuppressive therapy for patients with lupus nephritis who have achieved clinical remission has not been established. Furthermore, clinical and histologic remissions are often discordant. We postulated that continuing therapy for patients with persistent histologic activity on kidney biopsies done during maintenance and discontinuing therapy only for patients without histologic activity would minimize subsequent lupus nephritis flares. To test this, a cohort of 75 prospectively-followed patients with proliferative lupus nephritis was managed using kidney biopsies performed during maintenance therapy. These patients had been on immunosuppression for at least 42 months, had responded, and had maintained their clinical response for at least 12 months before the kidney biopsy was repeated. Maintenance therapy was withdrawn if the biopsy showed an activity index of zero, but was continued if the biopsy showed an activity index of one or more. A lupus nephritis flare developed in seven patients during the average 50 months from the third biopsy and the final clinic visit for a flare rate of 1.5/year; significantly less than reported flare rates. Baseline clinical parameters (serum creatinine, proteinuria) and serologic parameters (complement C3, C4 and anti-dsDNA) did not predict an activity index of zero on the third biopsy or who would have a lupus nephritis flare. No patients developed end-stage kidney disease. Four patients developed de novo chronic kidney disease. There were no serious adverse events related to biopsy. Thus, at an experienced center, biopsy-informed management of maintenance immunosuppression is safe and may improve the lupus nephritis flare rate compared to conventional clinical management.

Moving Forward With Biologics in Lupus Nephritis.

The majority of patients with systemic lupus erythematosus develop lupus nephritis (LN) which significantly contributes to increased risks of hospitalizations, ESRD, and death. Unfortunately, treatments for LN have not changed over the past 15 years. Despite continued efforts to elucidate the pathogenesis of LN, no new drugs have yet replaced the standard-of-care regimens of cyclophosphamide or mycophenolate mofetil plus high-dose corticosteroids. The significant limitations of standard-of-care are low complete response rates, risk of flares, and ongoing inflammation in the kidney leading to progressive renal dysfunction. Repeat and prolonged treatments are often needed to control disease, leading to a high level of severe side effects. The development of targeted drugs with better efficacy and safety are desperately needed. The rationale for targeting key immunologic pathways in LN continues to be strongly supported by basic and translational research and has generated the hope and excitement of testing these therapies in human LN. This review provides an overview of biologics studied to date in clinical trials of LN, discusses the potential reasons for their failure, and addresses the challenges moving forward.

Mycophenolate mofetil or cyclophosphamide in indian patients with lupus nephritis: Which is better? A single-center experience.

Mycophenolate mofetil (MMF) is used extensively for the induction therapy of lupus nephritis (LN) and has even outpaced intravenous (i.v.) cyclophosphamide (CyP) as the initial choice of therapy. There are no studies comparing the response of MMF with standard dose i.v. CyP in Indian patients with LN. We conducted a 24-week prospective, randomized, open-label trial comparing oral MMF with monthly i.v. CyP as induction therapy for active biopsy proven Class III and IV LN. The primary end-point was response to treatment at 24 weeks, and the secondary end-points were complete remission, Systemic Lupus Erythematosus Disease Activity Index scores (SLEDAI) and adverse reactions. Of the 40 patients, 17 were randomized to the MMF group and 23 to the i.v. CyP group. Complete remission was seen in nine (52.94%) patients in the MMF group and 11 (47.82%) in the i.v. CyP group. Partial remission was seen in six (35.30%) in the MMF group and nine (39.13%) in the i.v. CyP group. At six months, the cumulative probability of response was not statistically significant between the two groups (P = 1.000). MMF is comparable to i.v. CyP in the management of LN in Indian patients having an equal safety profile. The dose of MMF required was lower than the conventional doses used in other studies suggesting genetic or environmental factors in the Indian population influencing the metabolism of MMF, which requires further evaluation. The cost of MMF is a limiting factor in its use. The use of i.v. CyP is favorable as the monthly doses ensure compliance and is also cost-effective.

A 4-year observation in lupus nephritis patients treated with an intensified B-lymphocyte depletion without immunosuppressive maintenance treatment-Clinical response compared to literature and immunological re-assessment.

BACKGROUND: B cells (BC) play a critical role in systemic lupus erythematosus (SLE). BC depletion therapy still remains an attractive option, despite the disappointing results of randomized controlled trials (RTCs). METHODS: Twelve patients with SLE [3 males, mean age 43.8 yrs (25-55)] with severe multiorgan involvement all including kidney (3 patients with Class IV, 4 with Class III/V and 5 with Class V, according to the International Society of Nephrology/Renal Pathology Society glomerulonephritis classification), skin lesions [10], severe polyarthralgias with arthritis [10], polyserositis [2], and lymphadenopathy [5] have been prospectively treated with an intensified B cell depletion therapy (IBCDT) protocol due to their resistance or intolerance to previous therapy (six cases) or as a front line immunosuppressive treatment in 6 women with unsatisfactory therapeutic compliance or as a specific request of a short-time immunosuppression for gestational perspectives. PROTOCOL: Rituximab (RTX) 375 mg/sm on days 1, 8, 15, 22, and 2 more doses after 1 and 2 months, associated with 2 IV administrations of 10mg/kg of cyclophosphamide and 3 methylprednisolone pulses (15mg/kg) followed by oral prednisone (0.8 mg/kg/day, rapidly tapered to 5mg/day by the end of the 3rd month after RTX). No further immunosuppressive maintenance therapy has been given. RESULTS: Patients had been followed-up for a mean of 44.5 (24-93)months. Significant decreases (p<0.05) were found in the levels of ESR (baseline mean value: 55.0mm; 3 months: 36; end of follow-up: 13), anti-dsDNA antibodies (baseline: 185 U; 3 months: 107; end of follow-up: 15), and proteinuria (baseline: 4.9 g/24h; 3 months: 0.97; end of follow-up: 0.22). C4 values (baseline 11 mg/dl) significantly increased (p<0.05) after 3 months (22 mg/dl) and at the end of the follow-up (20mg/dl). Of the 12 patients, 9 (75%) have remained well after one cycle of IBCDT, with no flare (mean 51.6 months [25-93]). Three patients relapsed after 36, 41, and 72 months, respectively. Following re-treatment, they again showed complete remission over 18-48 months of observation. CONCLUSIONS: A promising role of RTX in an intensified protocol of induction therapy can be envisaged in patients for whom avoiding immunosuppressive maintenance therapy and sparing steroids are particularly appealing. Moreover, our data confirm in one of the longest follow-up available, the opportunity to reconsider the regimens of BL depletion in the treatment of the most severe or refractory forms of SLE despite the disappointing results of RCTs.

Biologic therapy in lupus nephritis.

This position paper critically analyzes the available controlled data regarding biologic therapy in lupus nephritis (LN). Rather than an exhaustive review of all published evidence, the stress is put on the unmet medical needs in LN, the design of trials aimed at testing the effect of a biologic in LN, the possible reasons for LN trial failures and the future of biological therapy in LN.

Prospective assessment of C4d deposits on circulating cells and renal tissues in lupus nephritis: a pilot study.

Complement activation plays a key role in the pathogenesis of lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE). We prospectively evaluated 15 LN subjects and two control groups: 13 non-SLE renal subjects (control A) and 239 SLE subjects without LN (control B). All had C4d levels on circulating erythrocytes (E-C4d), reticulocytes (R-C4d) and platelets (P-C4d) measured by flow cytometry, while C4d deposition in renal tissue was semiquantitatively assessed in LN subjects and control A using immunoperoxidase staining. Compared with control A, LN biopsies had higher glomerular-C4d scores (p = 0.003), which were associated with more frequent granular glomerular immunofluorescence staining and electron dense deposits (p < 0.001). Compared with control A and B groups, LN subjects had higher E-C4d (p = 0.002 and p = 0.005) and R-C4d levels (p = 0.002 and p = 0.008), respectively. LN subjects were more likely to have P-C4d compared with control A (p = 0.016). In LN, only E-C4d correlated with National Institutes of Health (NIH) activity index (r = 0.55, p = 0.04). In conclusion, LN biopsies showed frequent glomerular-C4d staining associated with immune complex deposits. LN subjects had higher E-C4d and R-C4d levels compared with both control groups. E-C4d levels also correlated with NIH activity index. These findings suggest a potential role of C4d on circulating cells as a biomarker for lupus nephritis.

Epidemiology and management of refractory lupus nephritis.

Although the survival of patients with lupus nephritis (LN) has improved considerably in recent years, refractory LN appears in a substantial proportion of patients and, therefore, treatment of LN remains a real challenge today. We will use the term "refractory" LN, for those cases with none or partial response to first-line therapies. In this sense, numerous epidemiological factors, including racial, socioeconomic, histological and serological parameters, may influence treatment response and, therefore, may have an impact on the outcome of renal involvement. Initial conventional therapy will depend somewhat on these epidemiological factors. If this initial therapy fails, fortunately today we have alternative therapies that include the multitarget therapy and the use of biologics. Published evidence about these therapies is presented in this review. Important terms in the management of LN, such as the definition of complete response, partial response, sustained response and renal flare as well as the discrimination of different types of flare, are also discussed here according to the European consensus statement on the terminology used in the management of lupus glomerulonephritis.

The BILAG-2004 index is sensitive to change for assessment of SLE disease activity.

OBJECTIVE: To determine if the BILAG-2004 index is sensitive to change for assessment of SLE disease activity. METHODS: This was a prospective multi-centre longitudinal study of SLE patients. At every assessment, data were collected on disease activity (BILAG-2004 index) and treatment. Analyses were performed using overall BILAG-2004 index score (as determined by the highest score achieved by any of the individual systems) and all the systems scores. Sensitivity to change was assessed by determining the relationship between change in disease activity and change in therapy between two consecutive visits. Statistical analyses were performed using multinomial logistic regression. RESULTS: There were 1761 assessments from 347 SLE patients that contributed 1414 observations for analysis. An increase in therapy between visits occurred in 22.7% observations, while 37.3% had a decrease in therapy and in 40.0% therapy was unchanged. Increase in overall BILAG-2004 index score was associated with increase in therapy and inversely associated with decrease in therapy. Decrease in overall BILAG-2004 index score was associated with decrease in therapy and was inversely associated with increase in therapy. Changes in overall BILAG-2004 index score were differentially related to change in therapy, with greater change in score having greater predictive power. Increase in the scores of most systems was independently associated with an increase in treatment and there was no significant association between decreases in the score of any system with an increase in therapy. CONCLUSIONS: The BILAG-2004 index is sensitive to change and is suitable for use in longitudinal studies of SLE.

Diagnostic value of anti-nucleosome antibodies in the assessment of disease activity of systemic lupus erythematosus: a prospective study comparing anti-nucleosome with anti-dsDNA antibodies.

OBJECTIVE: To determine the diagnostic value of anti-nucleosome antibodies in the assessment of clinically active systemic lupus erythematosus (SLE) and active nephritis. METHODS: A 12 month prospective study of 87 patients diagnosed with SLE. At each evaluation, disease activity was scored by SLE Disease Activity Index and Lupus Activity Criteria Count, and blood samples were collected for laboratory tests. Autoantibodies were detected by ELISA. RESULTS: Nearly all patients were female (96.6%). The mean age was 33 years and the mean disease duration was 60.7 months. About half the patients presented with nephritis (49.4%) and active SLE (50.6%) at the first clinical examination. During the study period, the prevalence of active SLE decreased from 50.6% to 29.1%. The prevalence of anti-nucleosome and anti-dsDNA antibodies was 40.0%-58.6% and 10.9%-21.8%, respectively, throughout the study period. The sensitivity of anti-nucleosome and anti-dsDNA antibodies for active SLE was 72.7%-100% and 31.3%-54.8%, respectively. The specificity of anti-nucleosome and anti-dsDNA antibodies for active SLE was 66.7%-83.7% and 88.7%-100%, respectively. The sensitivity and specificity of anti-nucleosome antibodies for active nephritis were 32.0%-67.5% and 46.2%-67.3%, respectively. The sensitivity and specificity for anti-dsDNA antibodies for active nephritis were 16.0%-35.4% and 85.1-97.5%, respectively. CONCLUSION: Anti-nucleosome antibodies are more sensitive than anti-dsDNA antibodies to active SLE and active nephritis. Thus, anti-nucleosome antibody reactivity may be a useful marker in the diagnosis and assessment of active SLE.

The value of complement activation products in the assessment of systemic lupus erythematosus flares.

Complement activation products (CAP) have been reported as sensitive markers of disease activity in systemic lupus erythematosus (SLE). We have measured seven parameters of the complement system (C3, C4, factor B, C3a, C4a, iC3b, and the terminal complement complex-TCC-) in 61 SLE patients to study their interrelationship and relative efficacy as diagnostic indicators of lupus activity. Disease activity was judged according to a clinical index (SLEDAI) to be active in 22 and inactive in 39 patients. Subjects with active SLE showed increased levels of C3a, C4a, and TCC compared with those of stable lupus and normal controls, and plasma concentrations of these CAP manifested a positive correlation with disease activity scores. However, values of factor B and iC3b did not correlate with lupus flares. Serum C3 levels were a better reflection of the degree of SLE activity than were C4 levels. The anaphylatoxins were extremely sensitive markers of disease activity but they lacked enough specificity, and iC3b was not at all informative for this purpose. On the whole, TCC concentration was the most useful parameter (77% sensitivity, 80% specificity) to monitor lupus activity, correlating the best with the activity scoring system, and thus offers a better laboratory marker of lupus severity than conventional measurements of complement.

The value of complement measurements in the assessment of lupus activity.

The complement system was studied prospectively in 29 patients, predominantly renal (25), with systemic lupus erythematosus (SLE) to examine the value of complement assays in the distinction between active and inactive disease. Disease activity was evaluated primarily by clinical, biochemical and histological parameters which were obtained at the time of assessment. Fourteen patients had active disease, as assessed by clinical and laboratory criteria. C1q, C4, C4a, C2, C3, C3a, C5, total haemolytic activity (CH50) and complement inhibitors were measured in each patient. The ratios of C4a:C4 and C3a:C3 were also calculated. Values for all components except C5 were different between control subjects and active patients while only CH50 was different between inactive patients and controls. All parameters except C4a:C4 and C5 were different between active and inactive patients. There was a highly significant difference in the number of active patients with reduced levels of C2, C3 and C3a:C3 compared to inactive patients (i.e. p less than 0.001) whereas lesser or no difference was observed for other parameters. The concentration of complement inhibitors was elevated in both groups. We conclude that, among readily available complement parameters, C2 and C3 provide the best assessment of disease activity in patients with SLE.