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Objectives: This study aims to determine the independent impact of definitions of remission/low disease activity (LDA) on direct/indirect costs (DCs, ICs) in a multicentre inception cohort., Methods: Patients from 31 centres in 10 countries were enrolled within 15 months of diagnosis and assessed annually. Five mutually exclusive disease activity states (DAS) were defined as (1) remission off-treatment: clinical (c) SLEDAI-2K=0, without prednisone/immunosuppressants; (2) remission on-treatment: cSLEDAI-2K=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; (3) LDA-Toronto Cohort (TC): cSLEDAI-2K≤2, without prednisone/immunosuppressants; (4) modified lupus LDA state (mLLDAS): SLEDAI-2K≤4, no activity in major organs/systems, no new activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants and (5) active: all remaining assessments.At each assessment, patients were stratified into the most stringent DAS fulfilled and the proportion of time in a DAS since cohort entry was determined. Annual DCs/ICs (2021 Canadian dollars) were based on healthcare use and lost workforce/non-workforce productivity over the preceding year.The association between the proportion of time in a DAS and annual DC/IC was examined through multivariable random-effects linear regressions., Results: 1692 patients were followed a mean of 9.7 years; 49.0% of assessments were active. Remission/LDA (per 25% increase in time in a remission/LDA state vs active) were associated with lower annual DC/IC: remission off-treatment (DC -$C1372; IC -$C2507), remission on-treatment (DC -$C973; IC -$C2604,) LDA-TC (DC -$C1158) and mLLDAS (DC -$C1040). There were no cost differences between remission/LDA states., Conclusions: Our data suggest that systemic lupus erythematosus patients who achieve remission, both off and on-therapy, and reductions in disease activity incur lower costs than those experiencing persistent disease activity., Competing Interests: Competing interests: MRWB has received consulting fees, speaking fees and/or honoraria from AbbVie, AstraZeneca, GlaxoSmithKline, Janssen and Sanofi Genzyme. MFU-G has received consulting and/or speaking fees from AstraZeneca, GlaxoSmithKline, Ferrer and a research grant from Janssen. CG has received consulting fees, speaking fees, and/or honoraria from AstraZeneca, Abbvie, Amgen, Sanofi, and UCB (less than $10 000 each). DJW has received consulting fees from Merck, EMD Serono, Pfizer, Lilly and Glenmark (less than $10 000 each). PRF has received consulting fees from AstraZeneca and GlaxoSmithKline (less than $10 000 each). DDG received consulting fees and/or honoraria from GlaxoSmithKline and AstraZeneca (less than $10 000). INB has received consulting fees, speaking fees, and/or honoraria from Eli Lilly, UCB, Roche, Merck Serono, MedImmune (less than $10 000 each) and grants from UCB, Genzyme Sanofi, and GlaxoSmithKline. EMG has paid consultation with investment analysts Guidepoint Global Gerson Lerman Group. RR-G has received consulting fees from Cabaletta, BristolMyersSquibb, Biogen, Merck, and Ampel Solutions (all less than $10 000 each). RFvV has received consulting fees, speaking fees and/or honoraria from AbbVie, AstraZeneca, Biotest, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Lilly, Novartis, Pfizer, and UCB (less than $10 000 each) and research support from AbbVie, Bristol Myers Squibb, GlaxoSmithKline, Pfizer and UCB. MI has received consulting fees from UCB and Amgen (less than $10 000 each). KK has received grants from UCB, Human Genome Sciences/GlaxoSmithKline, Takeda, Ablynx, Bristol-Myers Squibb, Pfizer, and Kyowa Hakko Kirin, and has received consulting fees from Exagen Diagnostics, Genentech, Eli Lilly, Bristol-Myers Squibb and Anthera (less than $10 000 each). AEC has received consulting fees, speaking fees, and/or honoraria from AstraZeneca, BristolMyersSquibb, GlaxoSmithKline, Roche and Otsuka (less than $10 000 each) and a research grant from GlaxoSmithKline. No other disclosures relevant to this article were reported., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: There is a paucity of data regarding health care costs associated with damage accrual in systemic lupus erythematosus. The present study was undertaken to describe costs associated with damage states across the disease course using multistate modeling., Methods: Patients from 33 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multistate model., Results: A total of 1,687 patients participated; 88.7% were female, 49.0% were white, mean ± SD age at diagnosis was 34.6 ± 13.3 years, and mean time to follow-up was 8.9 years (range 0.6-18.5 years). Mean annual costs were higher for those with higher SDI scores as follows: $22,006 (Canadian) (95% confidence interval [95% CI] $16,662, $27,350) for SDI scores ≥5 versus $1,833 (95% CI $1,134, $2,532) for SDI scores of 0. Similarly, 10-year cumulative costs were higher for those with higher SDI scores at the beginning of the 10-year interval as follows: $189,073 (Canadian) (95% CI $142,318, $235,827) for SDI scores ≥5 versus $21,713 (95% CI $13,639, $29,788) for SDI scores of 0., Conclusion: Patients with the highest SDI scores incur 10-year cumulative costs that are ~9-fold higher than those with the lowest SDI scores. By estimating the damage trajectory and incorporating annual costs, data on damage can be used to estimate future costs, which is critical knowledge for evaluating the cost-effectiveness of novel therapies., (© 2020, American College of Rheumatology.)

Practicing physicians have requested efficacy and safety data for belimumab, when used with specific systemic lupus erythematosus (SLE) medications. This was a post hoc analysis of pooled efficacy and safety data from patients who received belimumab 10 mg/kg plus standard of care (SoC) or placebo (SoC) in two Phase III, randomized trials, BLISS-52 and BLISS-76. Patients were categorized into four groups based on baseline concomitant medication usage: steroids only; antimalarials (AM) only; steroids + AM; or steroids + AM + immunosuppressants (IS). The primary endpoint was the SLE Responder Index (SRI) at Week 52. SRI over time and individual SRI components were secondary endpoints. Time to first flare and changes in concomitant medications were exploratory endpoints. Safety was assessed using adverse event (AE) reporting. Across 834 patients, steroids + AM was the largest group (n = 346, 41.5%) and AM only was the smallest (n = 77, 9.2%). Disease duration was shortest in the steroids + AM group (5.7 years vs 6.4-7.1 years); SELENA-SLEDAI scores were similar across groups. At Week 52, the percentage of SRI responders was greatest in the steroids + AM group for belimumab 10 mg/kg (59%) compared with placebo (44%); treatment response and SRI component improvements were also observed across other groups. The probability of experiencing an SLE flare was reduced in the steroids-only group for patients who received belimumab 10 mg/kg compared with placebo (64.3% vs 78.1%; hazard ratio 0.64; 95% confidence interval: 0.42-0.96). There was little or no change in daily AM or IS dose in any group. For all groups, there was a general decrease in steroid dose over time; a quarter to a third of patients experienced decreased steroid doses at Week 52. The overall safety profile was similar across treatment arms and concomitant medication groups, with the exception of serious AEs in the steroids + AM group (belimumab 10 mg/kg 16%, placebo 8%). The efficacy and safety of belimumab in combination with SoC was demonstrated for various groupings of steroids, AM and IS. These findings may improve the understanding of the safety and efficacy of adding belimumab to different treatments., (© The Author(s) 2016.)

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with diverse manifestations. Although the approval of new therapies includes only one agent in 50 years, a number of promising new drugs are in development. Lupus nephritis is a dreaded complication of SLE as it is associated with significant morbidity and mortality. Advancing the treatment of lupus nephritis requires well-designed clinical trials and this can be challenging in SLE. The major obstacles involve identifying the correct population of patients to enroll and ensuring that a clinically appropriate and patient-centered endpoint is being measured. In this review, we will first discuss the clinical utility of endpoints chosen to represent lupus nephritis in global disease activity scales. Second, we will review completed and active trials focused on lupus nephritis and discuss the endpoints chosen. There are many important lessons to be learned from existing assessment tools and clinical trials. Reviewing these points will help ensure that future efforts will yield meaningful disease activity measures and well-designed clinical trials to advance our understanding of lupus management.

Objective: To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE)., Methods: We performed case-cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated in regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarial drugs, glucocorticoids) demographics, calendar year, Sjogren's syndrome, SLE duration and disease activity. We used adjusted mean SLE Disease Activity Index scores (SLEDAI-2K) over time, and drugs were treated both categorically (ever/never) and as estimated cumulative doses., Results: We studied 75 patients with lymphoma (72 non-Hodgkin, three Hodgkin) and 4961 cancer-free controls. Most lymphomas were of B-cell origin. As is seen in the general population, lymphoma risk in SLE was higher in male than female patients and increased with age. Lymphomas occurred a mean of 12.4 years (median 10.9) after SLE diagnosis. Unadjusted and adjusted analyses failed to show a clear association of disease activity with lymphoma risk. There was a suggestion of greater exposure to cyclophosphamide and to higher cumulative steroids in lymphoma cases than the cancer-free controls., Conclusions: In this large SLE sample, there was a suggestion of higher lymphoma risk with exposure to cyclophosphamide and high cumulative steroids. Disease activity itself was not clearly associated with lymphoma risk. Further work will focus on genetic profiles that might interact with medication exposure to influence lymphoma risk in SLE.

A pooled post-hoc analysis of the phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus (SLE)) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline, and to explore whether belimumab offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. In addition to belimumab or placebo, all patients received standard SLE therapy. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, although the between-group differences in most renal outcomes were not significant. Among the 267 patients with renal involvement at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater renal organ disease improvement with belimumab than with placebo. Limitations of this analysis included the small patient numbers and the post-hoc nature of this pooled analysis. The results suggest that belimumab may offer renal benefit in patients with SLE. Further study is warranted in patients with severe active lupus nephritis.

Background: Maintenance therapy, often with azathioprine or mycophenolate mofetil, is required to consolidate remission and prevent relapse after the initial control of lupus nephritis., Methods: We carried out a 36-month, randomized, double-blind, double-dummy, phase 3 study comparing oral mycophenolate mofetil (2 g per day) and oral azathioprine (2 mg per kilogram of body weight per day), plus placebo in each group, in patients who met response criteria during a 6-month induction trial. The study group underwent repeat randomization in a 1:1 ratio. Up to 10 mg of prednisone per day or its equivalent was permitted. The primary efficacy end point was the time to treatment failure, which was defined as death, end-stage renal disease, doubling of the serum creatinine level, renal flare, or rescue therapy for lupus nephritis. Secondary assessments included the time to the individual components of treatment failure and adverse events., Results: A total of 227 patients were randomly assigned to maintenance treatment (116 to mycophenolate mofetil and 111 to azathioprine). Mycophenolate mofetil was superior to azathioprine with respect to the primary end point, time to treatment failure (hazard ratio, 0.44; 95% confidence interval, 0.25 to 0.77; P = 0.003), and with respect to time to renal flare and time to rescue therapy (hazard ratio, <1.00; P < 0.05). Observed rates of treatment failure were 16.4% (19 of 116 patients) in the mycophenolate mofetil group and 32.4% (36 of 111) in the azathioprine group. Adverse events, most commonly minor infections and gastrointestinal disorders, occurred in more than 95% of the patients in both groups (P = 0.68). Serious adverse events occurred in 33.3% of patients in the azathioprine group and in 23.5% of those in the mycophenolate mofetil group (P = 0.11), and the rate of withdrawal due to adverse events was higher with azathioprine than with mycophenolate mofetil (39.6% vs. 25.2%, P = 0.02)., Conclusions: Mycophenolate mofetil was superior to azathioprine in maintaining a renal response to treatment and in preventing relapse in patients with lupus nephritis who had a response to induction therapy. (Funded by Vifor Pharma [formerly Aspreva]; ALMS ClinicalTrials.gov number, NCT00377637.).

Intravenous cyclophosphamide remains an important therapy for patients with severe systemic lupus erythematosus--including lupus nephritis, which primarily affects women in their reproductive years. As prognosis improves, the chronic toxicity of this therapy assumes greater importance. This article reviews cyclophosphamide use, its effect on gonadal function, and protection of gonadal reserve during therapy. Egg, embryo, or gonadal tissue cryopreservation and alternative therapeutic strategies are considered., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: To compare the efficacy and safety of mycophenolate mofetil (MMF) and intravenous cyclophosphamide (IVC) as induction treatment for lupus nephritis (LN), by race, ethnicity and geographical region., Methods: A total of 370 patients with active Class III-V LN received MMF (target dose 3.0 g/day) or IVC (0.5-1.0 g/m(2)/month), plus tapered prednisone, for 24 weeks. Renal function, global disease activity, immunological complement (C3 and C4) and anti-dsDNA levels are the outcomes that were assessed in this study., Results: MMF was not superior to IVC as induction treatment (primary objective). There were important pre-specified interactions between treatment and race (P = 0.047) and treatment and region (P = 0.069) (primary endpoint). MMF and IVC response rates were similar for Asians (53.2 vs 63.9%; P = 0.24) and Whites (56.0 vs 54.2%; P = 0.83), but differed in the combined Other and Black group (60.4 vs 38.5%; P = 0.03). Fewer patients in the Black (40 vs 53.9%; P = 0.39) and Hispanic (38.8 vs 60.9%; P = 0.011) groups responded to IVC. Latin American patients had lower response to IVC (32 vs 60.7%; P = 0.003). Baseline disease characteristics were not predictive of response. The incidence of adverse events (AEs) was similar across groups. Serious AEs were slightly more prevalent among Asians., Conclusions: MMF and IVC have similar efficacy overall to short-term induction therapy for LN. However, race, ethnicity and geographical region may affect treatment response; more Black and Hispanic patients responded to MMF than IVC. As these factors are inter-related, it is difficult to draw firm conclusions about their importance.

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/m(2)/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.

Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. Here, we report the comparison of MMF and IVC as induction treatment for active lupus nephritis in a multinational, two-phase (induction and maintenance) study. We randomly assigned 370 patients with classes III through V lupus nephritis to open-label MMF (target dosage 3 g/d) or IVC (0.5 to 1.0 g/m(2) in monthly pulses) in a 24-wk induction study. Both groups received prednisone, tapered from a maximum starting dosage of 60 mg/d. The primary end point was a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary end points included complete renal remission, systemic disease activity and damage, and safety. Overall, we did not detect a significantly different response rate between the two groups: 104 (56.2%) of 185 patients responded to MMF compared with 98 (53.0%) of 185 to IVC. Secondary end points were also similar between treatment groups. There were nine deaths in the MMF group and five in the IVC group. We did not detect significant differences between the MMF and IVC groups with regard to rates of adverse events, serious adverse events, or infections. Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis.

Objective: To examine if, in systemic lupus erythaematosus (SLE), exposure to immunosuppressive therapy (cyclophosphamide, azathioprine, methotrexate) increases cancer risk., Methods: A case-cohort study was performed within a multi-site international SLE cohort; subjects were linked to regional tumour registries to determine cancer cases occurring after entry into the cohort. We calculated the hazard ratio (HR) for cancer after exposure to an immunosuppressive drug, in models that controlled for other medications (anti-malarial drugs, systemic glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin), smoking, age, sex, race/ethnicity, geographic location, calendar year, SLE duration, and lupus damage scores. In the primary analyses, exposures were treated categorically (ever/never) and as time-dependent., Results: Results are presented from 246 cancer cases and 538 controls without cancer. The adjusted HR for overall cancer risk after any immunosuppressive drug was 0.82 (95% CI 0.50-1.36). Age > or = 65, and the presence of non-malignancy damage were associated with overall cancer risk. For lung cancer (n = 35 cases), smoking was also a prominent risk factor. When looking at haematological cancers specifically (n = 46 cases), there was a suggestion of an increased risk after immunosuppressive drug exposures, particularly when these were lagged by a period of 5 years (adjusted HR 2.29, 95% CI 1.02-5.15)., Conclusions: In our SLE sample, age > or = 65, damage, and tobacco exposure were associated with cancer risk. Though immunosuppressive therapy may not be the principal driving factor for overall cancer risk, it may contribute to an increased risk of haematological malignancies. Future studies are in progress to evaluate independent influence of medication exposures and disease activity on risk of malignancy.

Improved patient survival after treatment of lupus nephritis with corticosteroids, immunosuppressants, and renal replacement therapy allows greater emphasis on long-term management issues. In particular, the recent focus has been on therapies to treat nephritis with fewer adverse effects compared with cyclophosphamide and immunosuppressive regimens. Issues complicating clinical trial design in lupus nephritis have severely limited comparisons across trials. These issues, including recognition and stratification of high-risk populations, comparable remission and response criteria, and appropriate use and interpretation of activity and damage indices have been the subject of much discussion and emerging consensus. Mycophenolate mofetil (MMF) has been used in the field of transplantation for more than 10 years. After initial anecdotal reports describing the benefits of MMF in the treatment of lupus nephritis, randomized controlled trials have established a role for MMF in the treatment of lupus nephritis. A host of newer agents including rituximab, abatacept, and monoclonal antibodies blocking costimulatory targets are in current clinical trials for lupus nephritis. As long-term outcomes in lupus nephritis improve, the toxicity of therapy and risk of relapse become increasingly important determinants of the choice of therapeutic agents.

There has been unprecedented growth in new therapeutic approaches for the treatment of systemic lupus erythematosus (SLE). These approaches include re-evaluation of the doses and duration of therapy with traditional agents, including intravenous cyclophosphamide and azathioprine. Drugs that were developed for other uses are being applied to specific SLE manifestations, and have spurred larger scale trials for overall disease activity. In addition, several new agents show promise in clinical trials; many have safer toxicity profiles than do traditional therapies. Some of these agents have multiple immunomodulatory effects, whereas others interfere with a specific immunologic process in one of the pathogenetic pathways of SLE activity.

Improved patient survival following lupus nephritis with the institution of corticosteroids, immunosuppressants and renal replacement therapy allows greater emphasis on long-term management issues. In particular, the recent focus has been on therapies to treat nephritis with fewer adverse effects of cyclophosphamide-including immunosuppressive regimens. Mycophenolate mofetil (MMF) has been used in the field of transplantation for more than 10 years. Following initial anecdotal reports describing benefits of MMF in the treatment of lupus nephritis, randomized, controlled trials have established a role for MMF in the treatment of lupus nephritis. MMF use to treat other lupus manifestations has been evaluated only in anecdotal case reports or series with few well-designed trials. Issues complicating clinical trial design in lupus including appropriate use and interpretation of activity and damage indices, comparable remission and response criteria and stratification of high risk populations have been the subject of much discussion and emerging consensus. As long-term outcomes in lupus improve, the toxicity of therapy and risk of relapse become increasingly important determinants of choice of therapeutic agents.

Background: Since anecdotal series and small, prospective, controlled trials suggest that mycophenolate mofetil may be effective for treating lupus nephritis, larger trials are desirable., Methods: We conducted a 24-week randomized, open-label, noninferiority trial comparing oral mycophenolate mofetil (initial dose, 1000 mg per day, increased to 3000 mg per day) with monthly intravenous cyclophosphamide (0.5 g per square meter of body-surface area, increased to 1.0 g per square meter) as induction therapy for active lupus nephritis. A change to the alternative regimen was allowed at 12 weeks in patients who did not have an early response. The study protocol specified adjunctive care and the use and tapering of corticosteroids. The primary end point was complete remission at 24 weeks (normalization of abnormal renal measurements and maintenance of baseline normal measurements). A secondary end point was partial remission at 24 weeks., Results: Of 140 patients recruited, 71 were randomly assigned to receive mycophenolate mofetil and 69 were randomly assigned to receive cyclophosphamide. At 12 weeks, 56 patients receiving mycophenolate mofetil and 42 receiving cyclophosphamide had satisfactory early responses. In the intention-to-treat analysis, 16 of the 71 patients (22.5 percent) receiving mycophenolate mofetil and 4 of the 69 patients receiving cyclophosphamide (5.8 percent) had complete remission, for an absolute difference of 16.7 percentage points (95 percent confidence interval, 5.6 to 27.9 percentage points; P=0.005), meeting the prespecified criteria for noninferiority and demonstrating the superiority of mycophenolate mofetil to cyclophosphamide. Partial remission occurred in 21 of the 71 patients (29.6 percent) and 17 of the 69 patients (24.6 percent), respectively (P=0.51). Three patients assigned to cyclophosphamide died, two during protocol therapy. Fewer severe infections and hospitalizations but more diarrhea occurred among those receiving mycophenolate., Conclusions: In this 24-week trial, mycophenolate mofetil was more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis and had a more favorable safety profile., (Copyright 2005 Massachusetts Medical Society.)

Controlled clinical trials in renal transplantation have demonstrated that mycophenolate mofetil is well tolerated and has lower renal transplant rejection rates than azathioprine regimens. This study reports on the clinical experiences at two institutions with mycophenolate mofetil (MMF) for severe lupus nephritis. Twelve patients with relapsing or resistant nephritis previously treated with cyclophosphamide therapy and one patient who refused cyclophosphamide as initial therapy for diffuse proliferative nephritis but accepted MMF were included. During combined MMF/prednisone therapy, serum creatinine values remained normal or declined from elevated values: mean change in serum creatinine was -0.26+/-0.46 microM/L, P = 0.039. Proteinuria significantly decreased: mean change in urine protein-to-creatinine ratios was -2.53+/-3.76, P = 0.039. Decreased serum complement component C3 and elevated anti-double-stranded DNA antibody levels at baseline improved in some, but not all, patients. The mean initial dose of MMF was 0.92 g/d (range, 0.5 to 2 g/d). The mean duration of therapy was 12.9 mo (range, 3 to 24 mo). Adverse events included herpes simplex stomatitis associated with severe leukopenia (n = 1), asymptomatic leukopenia (n = 2), nausea/ diarrhea (n = 2), thinning of scalp hair (n = 1), pancreatitis (n = 1), and pneumonia without leukopenia (n = 1). Recurrence of the pancreatitis led to discontinuation of MMF in this patient; all other adverse events resolved with dose reduction. It is concluded that MMF is well tolerated and has possible efficacy in controlling major renal manifestations of systemic lupus erythematosus. Controlled clinical trials are needed to define the role of MMF in the management of lupus nephritis.

Aggressive immunosuppressive therapy should be considered for patients with proliferative lupus nephritis as the risk for progression to end stage renal disease is high. Intermittent intravenous cyclophosphamide therapy improves renal survival; longer duration of therapy is associated with fewer relapse of nephritis and decreased risk of diminished renal function. While azathioprine therapy does not differ statistically from steroids alone in prolonging renal survival, this therapy may be considered in patients with few risk factors for progression to renal insufficiency. Methylprednisolone as a single therapy does not prolong renal survival compared with regimens including cyclophosphamide. Plasmapheresis remains under study but has not shown additional benefit in treatment of severe lupus nephritis. The potential roles for cyclosporin A and mycophenylate mofetil in the therapy of proliferative lupus nephritis remain to be defined. Supportive care including rigorous control of hypertension, consideration of angiotensin receptor inhibition or blockade to reduce proteinuria and prolong renal function, control of hyperlipidemia, prevention of osteoporosis, and prevention of pregnancy remain important clinical goals. Current research efforts focus on genetic and socioeconomic factors involved in racial differences in expression of lupus nephritis, hormonal manipulation to preserve gonadal function during cyclophosphamide therapy, and the potential impact on lupus activity of estrogen-containing oral contraceptives or postmenopausal hormone replacement therapy.

Intravenous cyclophosphamide is widely used to treat severe lupus nephritis. Yet interpretation of the literature is limited by the small number of patients evaluated with varied renal histology. We analyzed the renal outcome of cyclophosphamide therapy for diffuse proliferative lupus glomerulonephritis in a cohort of 89 patients from the Glomerular Disease Collaborative Network. Statistical analysis included Wilcoxon rank sum tests or continuity-adjusted chi-square for comparisons between groups. Kaplan-Meier survival function estimates were calculated for renal survival curves. Cox's proportional hazards models were employed for multivariate evaluation. The renal survival rate declined yearly from 89%, to 86%, 81%, 75%, and 71% at year 5. Renal survival was significantly worse in blacks compared with white patients. Among white patients 95% retained renal function at year 5 whereas black patients showed a progressive yearly decline from 85% at year 1, to 79%, 72%, 62%, and 58% at year 5. Racial differences in renal outcome were independent of age, duration of lupus, history of hypertension, hypertension control during therapy, and activity or chronicity indices on renal biopsy. The factors that predispose black patients to more aggressive and treatment-resistant lupus nephritis are not apparent.

BackgroundWe aimed to identify factors associated with a significant reduction in SLE disease activity over 12 months assessed by the BILAG Index.MethodsIn an international SLE cohort, we studied patients from their 'inception enrolment' visit. We also defined an 'active disease' cohort of patients who had active disease similar to that needed for enrolment into clinical trials. Outcomes at 12 months were; Major Clinical Response (MCR: reduction to classic BILAG C in all domains, steroid dose of ≤7.5 mg and SLEDAI ≤ 4) and 'Improvement' (reduction to ≤1B score in previously active organs; no new BILAG A/B; stable or reduced steroid dose; no increase in SLEDAI). Univariate and multivariate logistic regression with Least Absolute Shrinkage and Selection Operator (LASSO) and cross-validation in randomly split samples were used to build prediction models.Results'Inception enrolment' (n = 1492) and 'active disease' (n = 924) patients were studied. Models for MCR performed well (ROC AUC = .777 and .732 in the inception enrolment and active disease cohorts, respectively). Models for Improvement performed poorly (ROC AUC = .574 in the active disease cohort). MCR in both cohorts was associated with anti-malarial use and inversely associated with active disease at baseline (BILAG or SLEDAI) scores, BILAG haematological A/B scores, higher steroid dose and immunosuppressive use.ConclusionBaseline predictors of response in SLE can help identify patients in clinic who are less likely to respond to standard therapy. They are also important as stratification factors when designing clinical trials in order to better standardize overall usual care response rates.

ObjectiveThe Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) predicts mortality and damage accrual in systemic lupus erythematosus (SLE), but its association with hospitalizations has not been described. Our objective was to estimate the association of baseline SLICC-FI values with future hospitalizations in the SLICC inception cohort.MethodsBaseline SLICC-FI scores were calculated. The number and duration of inpatient hospitalizations during follow-up were recorded. Negative binomial regression was used to estimate the association between baseline SLICC-FI values and the rate of hospitalizations per patient-year of follow-up. Linear regression was used to estimate the association of baseline SLICC-FI scores with the proportion of follow-up time spent in the hospital. Multivariable models were adjusted for relevant baseline characteristics.ResultsThe 1,549 patients with SLE eligible for this analysis were mostly female (88.7%), with a mean ± SD age of 35.7 ± 13.3 years and a median disease duration of 1.2 years (interquartile range 0.9-1.5) at baseline. Mean ± SD baseline SLICC-FI was 0.17 ± 0.08. During mean ± SD follow-up of 7.2 ± 3.7 years, 614 patients (39.6%) experienced 1,570 hospitalizations. Higher baseline SLICC-FI values (per 0.05 increment) were associated with more frequent hospitalizations during follow-up, with an incidence rate ratio of 1.21 (95% confidence interval [95% CI] 1.13-1.30) after adjustment for baseline age, sex, glucocorticoid use, immunosuppressive use, ethnicity/location, SLE Disease Activity Index 2000 score, SLICC/American College of Rheumatology Damage Index score, and disease duration. Among patients with ≥1 hospitalization, higher baseline SLICC-FI values predicted a greater proportion of follow-up time spent hospitalized (relative rate 1.09 [95% CI 1.02-1.16]).ConclusionThe SLICC-FI predicts future hospitalizations among incident SLE patients, further supporting the SLICC-FI as a valid health measure in SLE.

ObjectiveThe Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) has been shown to predict mortality, but its association with other important outcomes is unknown. We examined the association of baseline SLICC FI values with damage accrual in the SLICC inception cohort.MethodsThe baseline visit was defined as the first visit at which both organ damage (SLICC/American College of Rheumatology Damage Index [SDI]) and health-related quality of life (Short Form 36) were assessed. Baseline SLICC FI scores were calculated. Damage accrual was measured by the increase in SDI between the baseline assessment and the last study visit. Multivariable negative binomial regression was used to estimate the association between baseline SLICC FI values and the rate of increase in the SDI during follow-up, adjusting for relevant demographic and clinical characteristics.ResultsThe 1,549 systemic lupus erythematosus (SLE) patients eligible for this analysis were mostly female (88.7%) with a mean ± SD age of 35.7 ± 13.3 years and a median disease duration of 1.2 years (interquartile range 0.9-1.5 years) at baseline. The mean ± SD baseline SLICC FI was 0.17 ± 0.08. Over a mean ± SD follow-up of 7.2 ± 3.7 years, 653 patients (42.2%) had an increase in SDI. Higher baseline SLICC FI values (per 0.05 increase) were associated with higher rates of increase in the SDI during follow-up (incidence rate ratio [IRR] 1.19 [95% confidence interval 1.13-1.25]), after adjusting for age, sex, ethnicity/region, education, baseline SLE Disease Activity Index 2000, baseline SDI, and baseline use of glucocorticoids, antimalarials, and immunosuppressive agents.ConclusionOur findings indicate that the SLICC FI predicts damage accrual in incident SLE, which further supports the SLICC FI as a valid health measure in SLE.