Therapy-Induced Senescence Contributes to the Efficacy of Abemaciclib in Patients with Dedifferentiated Liposarcoma.

PURPOSE: We conducted research on CDK4/6 inhibitors (CDK4/6i) simultaneously in the preclinical and clinical spaces to gain a deeper understanding of how senescence influences tumor growth in humans. PATIENTS AND METHODS: We coordinated a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies interrogating the molecular basis of geroconversion. RESULTS: Thirty patients with progressing DDLS enrolled and were treated with 200 mg of abemaciclib twice daily. The median progression-free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI, 57.7%-90.1%). No new safety signals were identified. Concurrent preclinical work in liposarcoma cell lines identified ANGPTL4 as a necessary late regulator of geroconversion, the pathway from reversible cell-cycle exit to a stably arrested inflammation-provoking senescent cell. Using this insight, we were able to identify patients in which abemaciclib induced tumor cell senescence. Senescence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance later in therapy. These suggest that combining senolytics with abemaciclib in a subset of patients may improve the duration of response. CONCLUSIONS: Abemaciclib was well tolerated and showed promising activity in DDLS. The discovery of ANGPTL4 as a late regulator of geroconversion helped to define how CDK4/6i-induced cellular senescence modulates the immune tumor microenvironment and contributes to both positive and negative clinical outcomes. See related commentary by Weiss et al., p. 649.

Are There Racial Disparities in Perioperative Pain? A Retrospective Study of a Gynecological Surgery Cohort.

PURPOSE: The purpose of this study was to examine whether racial disparities exist in immediate postoperative pain scores and intraoperative analgesic regimens in a single surgical cohort. DESIGN: A single-center, retrospective analysis. METHODS: This retrospective study of a single surgical cohort was conducted via chart review of the existing electronic health record. A total of 203 patients who underwent minimally invasive hysterectomy were included in the analysis. Three initially reviewed patient records were excluded from the final analysis due to the small size of their racial cohorts (two Asian or Pacific Islander and one Native American). The White patients (n = 103) and Black patients (n = 100) were compared for differences in pain scores in the postanesthesia care unit (PACU). The patients' intraoperative analgesic regimens were also compared. FINDINGS: There were no significant differences between races in the postoperative pain scores in the PACU or in the analgesia administered by the anesthesia provider intraoperatively. CONCLUSIONS: In this specific population, there was no evidence of racial disparities in postoperative pain or intraoperative analgesia administration. Further research is needed to understand the unique factors of the perioperative period, to see if the absence of disparities in this study is repeated in other cohorts, and to mitigate any disparities that are found.

Outcomes and lessons learned from an interprofessional student training program in Screening, Brief Intervention, and Referral to Treatment (SBIRT) at an academic health sciences center.

BACKGROUND AND OBJECTIVES: Screening, Brief Intervention, and Referral to Treatment (SBIRT) is a public health intervention to address overuse and risky use of alcohol and illegal substances. In order to increase SBIRT in clinical practice, training should start with future health care provider students and faculty. The main objective of this program was to improve and enhance the training of health professions students to provide competent screening, brief intervention and referral to treatment for persons who have or are at-risk for substance use disorder. This paper shares the results of an SBIRT training program at an academic health sciences center for undergraduate nursing, graduate nursing, and medical students. DESIGN, SETTING AND PARTICIPANTS: 1229 undergraduate and graduate nursing students, medical students, faculty and preceptors at an academic medical center completed SBIRT coursework integrated into their existing curriculum. Coursework utilized an online learning platform as well as in-person skills training experiences. METHODS: An interprofessional team collaborated to create an online SBIRT curriculum consisting of 5 primary modules (total 3 h) and an SBIRT Booster module (0.5 h). The team also developed pre- and post-module quizzes and satisfaction surveys to measure changes in knowledge, confidence, and satisfaction; as well as simulations, videos, a screening tool, a provider pocket card, and an online resource library to support learning. Faculty and preceptors were trained in the program to model skills and answer student questions. A motivational interviewing specialist provided the in-person skills training sessions. RESULTS: A sustainable interprofessional SBIRT training program demonstrated gains in knowledge, confidence, and skills across all programs. The team used clinical opportunities and simulation with education to promote clinical proficiency. CONCLUSIONS: Interprofessional training mirrors real world clinical situations and encourages all providers to implement SBIRT in practice and decrease poor outcomes associated with substance use disorders.

Patient-Reported Opioid Consumption and Pain Intensity After Common Orthopedic and Urologic Surgical Procedures With Use of an Automated Text Messaging System.

Importance: Surgeons must balance management of acute postoperative pain with opioid stewardship. Patient-centered methods that immediately evaluate pain and opioid consumption can be used to guide prescribing and shared decision-making. Objective: To assess the difference between the number of opioid tablets prescribed and the self-reported number of tablets taken as well as self-reported pain intensity and ability to manage pain after orthopedic and urologic procedures with use of an automated text messaging system. Design, Setting, and Participants: This quality improvement study was conducted at a large, urban academic health care system in Pennsylvania. Adult patients (aged ≥18 years) who underwent orthopedic and urologic procedures and received postoperative prescriptions for opioids were included. Data were collected prospectively using automated text messaging until postoperative day 28, from May 1 to December 31, 2019. Main Outcomes and Measures: The primary outcome was the difference between the number of opioid tablets prescribed and the patient-reported number of tablets taken (in oxycodone 5-mg tablet equivalents). Secondary outcomes were self-reported pain intensity (on a scale of 0-10, with 10 being the highest level of pain) and ability to manage pain (on a scale of 0-10, with 10 representing very able to control pain) after orthopedic and urologic procedures. Results: Of the 919 study participants, 742 (80.7%) underwent orthopedic procedures and 177 (19.2%) underwent urologic procedures. Among those who underwent orthopedic procedures, 384 (51.8%) were women, 491 (66.7%) were White, and the median age was 48 years (interquartile range [IQR], 32-61 years); 514 (69.8%) had an outpatient procedure. Among those who underwent urologic procedures, 145 (84.8%) were men, 138 (80.7%) were White, and the median age was 56 years (IQR, 40-67 years); 106 (62%) had an outpatient procedure. The mean (SD) pain score on day 4 after orthopedic procedures was 4.72 (2.54), with a mean (SD) change by day 21 of -0.40 (1.91). The mean (SD) ability to manage pain score on day 4 was 7.32 (2.59), with a mean (SD) change of -0.80 (2.72) by day 21. The mean (SD) pain score on day 4 after urologic procedures was 3.48 (2.43), with a mean (SD) change by day 21 of -1.50 (2.12). The mean (SD) ability to manage pain score on day 4 was 7.34 (2.81), with a mean (SD) change of 0.80 (1.75) by day 14. The median quantity of opioids prescribed for patients who underwent orthopedic procedures was high compared with self-reported consumption (20 tablets [IQR, 15-30 tablets] vs 6 tablets used [IQR, 0-14 tablets]), similar to findings for patients who underwent urologic procedures (7 tablets [IQR, 5-10 tablets] vs 1 tablet used [IQR, 0-4 tablets]). Over the study period, 9452 of 15 581 total tablets prescribed (60.7%) were unused. A total of 589 patients (64.1%) used less than half of the amount prescribed, and 256 patients (27.8%) did not use any opioids (179 [24.1%] who underwent orthopedic procedures and 77 [43.5%] who underwent urologic procedures). Conclusions and Relevance: In this quality improvement study of adult patients reporting use of opioids after common orthopedic and urologic surgical procedures through a text messaging system, the quantities of opioids prescribed and the quantity consumed differed. Patient-reported data collected through text messaging may support clinicians in tailoring prescriptions and guide shared decision-making to limit excess quantities of prescribed opioids.

Transcranial Doppler Screening in a Current Cohort of Children With Sickle Cell Anemia: Results From the DISPLACE Study.

Stroke prevention guidelines for sickle cell anemia (SCA) recommend transcranial Doppler (TCD) screening to identify children at stroke risk; however, TCD screening implementation remains poor. This report describes results from Part 1 of the 28-site DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) study, a baseline assessment of TCD implementation rates. This report describes TCD implementation by consortium site characteristics; characteristics of TCDs completed; and TCD results based on age. The cohort included 5247 children with SCA, of whom 5116 were eligible for TCD implementation assessment for at least 1 study year. The majority of children were African American or Black, non-Hispanic and received Medicaid. Mean age at first recorded TCD was 5.9 and 10.5 years at study end. Observed TCD screening rates were unsatisfactory across geographic regions (mean 49.9%; range: 30.9% to 74.7%) independent of size, institution type, or previous stroke prevention trial participation. The abnormal TCD rate was 2.9%, with a median age of 6.3 years for first abnormal TCD result. Findings highlight real-world TCD screening practices and results from the largest SCA cohort to date. Data informed the part 3 implementation study for improving stroke screening and findings may inform clinical practice improvements.

Cancer Risk in a Large Inception Systemic Lupus Erythematosus Cohort: Effects of Demographic Characteristics, Smoking, and Medications.

OBJECTIVE: To assess cancer risk factors in incident systemic lupus erythematosus (SLE). METHODS: Clinical variables and cancer outcomes were assessed annually among incident SLE patients. Multivariate hazard regression models (overall risk and most common cancers) included demographic characteristics and time-dependent medications (corticosteroids, antimalarial drugs, immunosuppressants), smoking, and the adjusted mean Systemic Lupus Erythematosus Disease Activity Index 2000 score. RESULTS: Among 1,668 patients (average 9 years follow-up), 65 cancers occurred: 15 breast, 10 nonmelanoma skin, 7 lung, 6 hematologic, 6 prostate, 5 melanoma, 3 cervical, 3 renal, 2 each gastric, head and neck, and thyroid, and 1 each rectal, sarcoma, thymoma, and uterine cancers. Half of the cancers (including all lung cancers) occurred in past/current smokers, versus one-third of patients without cancer. Multivariate analyses indicated that overall cancer risk was related primarily to male sex and older age at SLE diagnosis. In addition, smoking was associated with lung cancer. For breast cancer risk, age was positively associated and antimalarial drugs were negatively associated. Antimalarial drugs and higher disease activity were also negatively associated with nonmelanoma skin cancer risk, whereas age and cyclophosphamide were positively associated. Disease activity was associated positively with hematologic and negatively with nonmelanoma skin cancer risk. CONCLUSION: Smoking is a key modifiable risk factor, especially for lung cancer, in SLE. Immunosuppressive medications were not clearly associated with higher risk except for cyclophosphamide and nonmelanoma skin cancer. Antimalarials were negatively associated with breast cancer and nonmelanoma skin cancer risk. SLE activity was associated positively with hematologic cancer and negatively with nonmelanoma skin cancer. Since the absolute number of cancers was small, additional follow-up will help consolidate these findings.

A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis.

Calcineurin inhibitors added to standard-of-care induction therapy for lupus nephritis (LN) may increase complete renal remission (CRR) rates. The AURA-LV study tested the novel calcineurin inhibitor voclosporin for efficacy and safety in active LN. AURA-LV was a Phase 2, multicenter, randomized, double-blind, placebo-controlled trial of two doses of voclosporin (23.7 mg or 39.5 mg, each twice daily) versus placebo in combination with mycophenolate mofetil (2 g/d) and rapidly tapered low-dose oral corticosteroids for induction of remission in LN. The primary endpoint was CRR at 24 weeks; the secondary endpoint was CRR at 48 weeks. Two hundred sixty-five subjects from 79 centers in 20 countries were recruited and randomized to treatment for 48 weeks. CRR at week 24 was achieved by 29 (32.6%) subjects in the low-dose voclosporin group, 24 (27.3%) subjects in the high-dose voclosporin group, and 17 (19.3%) subjects in the placebo group (OR=2.03 for low-dose voclosporin versus placebo). The significantly greater CRR rate in the low-dose voclosporin group persisted at 48 weeks, and CRRs were also significantly more common in the high-dose voclosporin group compared to placebo at 48 weeks. There were more serious adverse events in both voclosporin groups, and more deaths in the low-dose group compared to placebo and high-dose voclosporin groups (11.2%, 1.1%, and 2.3%, respectively). These results suggest that the addition of low-dose voclosporin to mycophenolate mofetil and corticosteroids for induction therapy of active LN results in a superior renal response compared to mycophenolate mofetil and corticosteroids alone, but higher rates of adverse events including death were observed.

Effect of an Evidence-based Inpatient Tobacco Dependence Treatment Service on 1-Year Postdischarge Health Care Costs.

BACKGROUND: In 2014, the Medical University of South Carolina (MUSC) implemented a Tobacco Dependence Treatment Service (TDTS) consistent with the Joint Commission (JC) standards recommending that hospitals screen patients for smoking, provide cessation support, and follow-up contact for relapse prevention within 1 month of discharge. We previously demonstrated that patients exposed to the MUSC TDTS were approximately half as likely to be smoking one month after discharge and 23% less likely to have a 30-day hospital readmission. This paper examines whether exposure to the TDTS influenced downstream health care charges 12 months after patients were discharged from the hospital. METHODS: Data from MUSC's electronic health records, the TDTS, and statewide health care utilization datasets (eg, hospitalization, emergency department, and ambulatory surgery visits) were linked to assess how exposure to the MUSC TDTS impacted health care charges. Total health care charges were compared for patients with and without TDTS exposure. To reduce potential TDTS exposure selection bias, propensity score weighting was used to balance baseline characteristics between groups. The cost of delivering the MUSC TDTS intervention was calculated, along with cost per smoker. RESULTS: The overall adjusted mean health care charges for smokers exposed to the TDTS were $7299 lower than for those who did not receive TDTS services (P=0.047). The TDTS cost per smoker was modest by comparison at $34.21 per smoker eligible for the service. DISCUSSION: Results suggest that implementation of a TDTS consistent with JC standards for smoking cessation can be affordably implemented and yield substantial health care savings that would benefit patients, hospitals, and insurers.

Effect of an Evidence-based Inpatient Tobacco Dependence Treatment Service on 30-, 90-, and 180-Day Hospital Readmission Rates.

INTRODUCTION: Smoking is a risk factor for hospitalization and interferes with patient care due to its effects on pulmonary function, wound healing, and interference with treatments and medications. Although benefits of stopping smoking are well-established, few hospitals provide tobacco dependence treatment services (TDTS) due to cost, lack of mandatory tobacco cessation standards and lack of evidence demonstrating clinical and financial benefits to hospitals and insurers for providing services. METHODS: This study explored the effect of an inpatient TDTS on 30-, 90-, and 180-day hospital readmissions. To carry out this work, 3 secondary datasets were linked, which included clinical electronic health record data, tobacco cessation program data, and statewide health care utilization data. Odds ratios (ORs) were calculated using inverse propensity score-weighted logistic regression models, with program exposure as the primary independent variable and 30 (90 and 180)-day readmission rates as the dependent variable, and adjustment for putative covariates. RESULTS: Odds of readmission were compared for patients who did and did not receive TDTS. At 30 days postdischarge, smokers exposed to the TDTS had a lower odds of readmission (OR=0.77, P=0.031). At 90 and 180 days, odds of readmission remained lower in the TDTS group (ORs=0.87 and 0.86, respectively), but were not statistically significant. DISCUSSION: Findings from the current study, which are supported by prior studies, provide evidence that delivery of TDTS is a strategy that may help to reduce hospital readmissions.

Effect of a smoking cessation intervention for women in subsidized neighborhoods: A randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness of a community based participatory research (CBPR) developed, multi-level smoking cessation intervention among women in subsidized housing neighborhoods in the Southeastern US. METHODS: A total of n=409 women in 14 subsidized housing neighborhoods in Georgia and South Carolina participated in this group randomized controlled trial conducted from 2009 to 2013. Intervention neighborhoods received a 24-week intervention with 1:1 community health worker contact, behavioral peer group sessions, and nicotine replacement. Control neighborhoods received written cessation materials at weeks 1, 6, 12, 18. Random coefficient models were used to compare smoking abstinence outcomes at 6 and 12months. Significance was set a p<0.05. RESULTS: The majority of participants (91.2%) were retained during the 12-month intervention period. Smoking abstinence rates at 12months for intervention vs. control were 9% vs. 4.3%, p=0.05. Additional analyses accounting for passive smoke exposure in these multi-unit housing settings demonstrated 12month abstinence rates of 12% vs. 5.3%, p=0.016. However, in the multivariate regression analyses, there was no significant effect of the intervention on the odds of being a non-smoker (OR=0.44, 95% CI: 0.18-1.07). Intervention participants who kept coach visits, attended group sessions, and used patches were more likely to remain abstinent. CONCLUSIONS: This CBPR developed intervention showed potential to engage smokers and reduce smoking among women in these high-poverty neighborhoods. Effectiveness in promoting cessation in communities burdened with fiscal, environmental and social inequities remains a public health priority.

Comparison and evaluation of lupus nephritis response criteria in lupus activity indices and clinical trials.

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.

Lymphoma risk in systemic lupus: effects of disease activity versus treatment.

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.

Non-lymphoma hematological malignancies in systemic lupus erythematosus.

OBJECTIVE: To describe non-lymphoma hematological malignancies in systemic lupus erythematosus (SLE). METHODS: A large SLE cohort was linked to cancer registries. We examined the types of non-lymphoma hematological cancers. RESULTS: In 16,409 patients, 115 hematological cancers [including myelodysplastic syndrome (MDS)] occurred. Among these, 33 were non-lymphoma. Of the 33 non-lymphoma cases, 13 were of lymphoid lineage: multiple myeloma (n = 5), plasmacytoma (n = 3), B cell chronic lymphocytic leukemia (B-CLL; n = 3), precursor cell lymphoblastic leukemia (n = 1) and unspecified lymphoid leukemia (n = 1). The remaining 20 cases were of myeloid lineage: MDS (n = 7), acute myeloid leukemia (AML; n = 7), chronic myeloid leukemia (CML; n = 2) and 4 unspecified leukemias. Most of these malignancies occurred in female Caucasians, except for plasma cell neoplasms (4/5 multiple myeloma and 1/3 plasmacytoma cases occurred in blacks). CONCLUSIONS: In this large SLE cohort, the most common non-lymphoma hematological malignancies were myeloid types (MDS and AML). This is in contrast to the general population, where lymphoid types are 1.7 times more common than myeloid non-lymphoma hematological malignancies. Most (80%) multiple myeloma cases occurred in blacks; this requires further investigation.

Cancer risk in systemic lupus: an updated international multi-centre cohort study.

OBJECTIVE: To update estimates of cancer risk in SLE relative to the general population. METHODS: A multisite international SLE cohort was linked with regional tumor registries. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers. RESULTS: Across 30 centres, 16,409 patients were observed for 121,283 (average 7.4) person-years. In total, 644 cancers occurred. Some cancers, notably hematologic malignancies, were substantially increased (SIR 3.02, 95% confidence interval, CI, 2.48, 3.63), particularly non-Hodgkin's lymphoma, NHL (SIR 4.39, 95% CI 3.46, 5.49) and leukemia. In addition, increased risks of cancer of the vulva (SIR 3.78, 95% CI 1.52, 7.78), lung (SIR 1.30, 95% CI 1.04, 1.60), thyroid (SIR 1.76, 95% CI 1.13, 2.61) and possibly liver (SIR 1.87, 95% CI 0.97, 3.27) were suggested. However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61-0.88), endometrial (SIR 0.44, 95% CI 0.23-0.77), and possibly ovarian cancers (0.64, 95% CI 0.34-1.10). The variability of comparative rates across different cancers meant that only a small increased risk was estimated across all cancers (SIR 1.14, 95% CI 1.05, 1.23). CONCLUSION: These data estimate only a small increased risk in SLE (versus the general population) for cancer over-all. However, there is clearly an increased risk of NHL, and cancers of the vulva, lung, thyroid, and possibly liver. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. Similarly, the etiology of the decreased breast, endometrial, and possibly ovarian cancer risk is uncertain, though investigations are ongoing.

Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.

OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. METHODS: The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. RESULTS: Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). CONCLUSION: The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-double-stranded DNA antibodies.

Gonadal failure with cyclophosphamide therapy for lupus nephritis: advances in fertility preservation.

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.

Nonrenal disease activity following mycophenolate mofetil or intravenous cyclophosphamide as induction treatment for lupus nephritis: findings in a multicenter, prospective, randomized, open-label, parallel-group clinical trial.

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.

Predictors of relapse and end stage kidney disease in proliferative lupus nephritis: focus on children, adolescents, and young adults.

BACKGROUND AND OBJECTIVES: The prevalence and significance of remission and relapse in children, adolescents, and young adults with lupus nephritis in the United States are poorly understood. Patterns and predictors of disease progression in a southeastern U.S. pediatric cohort with severe lupus nephritis are presented. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Individuals age 21 or less with kidney biopsy-proven lupus nephritis followed in the Glomerular Disease Collaborative Network were included. Cox regression models were used to evaluate predictors of relapse and end stage kidney disease (ESKD). RESULTS: Seventy-three subjects with a mean age of 15.6 +/- 3.4 yr were included. Five-year kidney survival was 77%. Complete and partial remission rates within 1 yr of induction therapy were 25 and 64%, respectively. Relapse and ESKD rates were similar between complete and partial responders. Relapse occurred in 35% of responders (complete or partial) in 45 +/- 32 mo. Disease relapse was a predictor of ESKD (HR = 10.12, P < 0.0001). Treatment resistance was documented in African Americans more often than non-African Americans (eight versus 0; P = 0.03). ESKD HR associated with treatment resistance was 6.25, P < 0.002. CONCLUSIONS: Remission whether complete or partial is associated with improved kidney survival in children with lupus nephritis. Nephritis relapse is a strong predictor of progression to ESKD. Treatment resistance portends a high risk of ESKD and disproportionately affects African American children with lupus nephritis.

Pharmacokinetics of mycophenolic acid in patients with lupus nephritis.

STUDY OBJECTIVES: To evaluate and describe the pharmacokinetics of mycophenolic acid and its metabolite, mycophenolic acid glucuronide (MPAG), in patients with lupus nephritis, and to determine the effects of clinical parameters (urinary protein excretion as measured by the urinary protein:creatinine ratio, serum albumin level, and creatinine clearance) and demographic variables (age, race, sex) on the pharmacokinetics of total and unbound mycophenolic acid and MPAG. DESIGN: Pharmacokinetic analysis. SETTING: University-affiliated general clinical research center. PATIENTS: Eighteen patients with biopsy-confirmed lupus nephritis who were receiving maintenance therapy with mycophenolic acid for at least 2 weeks. INTERVENTION: Plasma and urine samples were collected for 24 hours and were assayed by high-performance liquid chromatography with ultraviolet detection. MEASUREMENTS AND MAIN RESULTS: Time to maximum concentration was variable (0.5-8 hrs). Mean +/- SD fraction of unbound mycophenolic acid was 2.6 +/- 1.9%, and oral clearance (Cl/F) was about 2-fold higher (343 +/- 200 ml/min) than previously reported. Multiple regression analysis showed that Cl/F of mycophenolic acid was predicted by creatinine clearance and serum albumin level: ln Cl/F = 5.358 + 0.0092 (creatinine clearance) - 0.078 (ranked albumin), R(2)=51.1%, p=0.0195. Patients with urinary protein excretion of 1 g/day or higher had lower minimum (trough) concentrations and area under the concentration-time curve (AUC(0-12)) profiles and higher Cl/F values compared with patients with urinary protein excretion of less than 1 g/day. Patients with serum albumin levels less than 4 g/dl had higher mycophenolic acid unbound clearance and MPAG renal clearance from 0-12 hours versus those with serum albumin levels of 4 g/dl or greater. Recycling AUC (AUC(6-12)), as well as sex and age (both equally), predicted renal clearance of MPAG. CONCLUSION: Both creatinine clearance and serum albumin level were identified as primary contributors to mycophenolic acid exposure and should be considered when evaluating dosages. The results of future studies should clarify the interactions of other variables on drug exposure and treatment responses. Clinicians need to be mindful of clinical changes that occur throughout the course of lupus nephritis in order to maintain efficacy and reduce toxicity from mycophenolic acid therapy.

Therapy Insight: preserving fertility in cyclophosphamide-treated patients with rheumatic disease.

Cyclophosphamide remains a necessary treatment for severe rheumatic diseases, despite the continued search for alternative therapies with less gonadal toxicity. The risk of premature gonadal failure and sterility might lead young patients to delay treatment with cyclophosphamide. The patient's age at treatment and the cumulative dose received remain important risk factors for cyclophosphamide-induced gonadal failure in both males and females. Estrogen-containing oral contraceptives for females and testosterone for males are suggested to reduce the gonadal toxicity of cyclophosphamide, although few studies support these interventions. Owing to increased side effects, hormonal therapy is often avoided in patients with edema, hypertension, nephrotic syndrome or antiphospholipid antibodies. Agonists and antagonists of gonadotropin receptors are under study. Gonadotropin-receptor agonists might have beneficial effects in addition to suppression of sex-hormone production. The outcome of attempted cryopreservation of eggs, embryos or ovaries remains uncertain for women seeking to preserve their reproductive potential. Storing male gametes before chemotherapy is widely practiced and technically successful. As recovery of menses or production of testosterone does not predict individual fertility, identification of biomarkers of gonadal function and reserve, including serum levels of several hormones, ultrasonographic measurements of ovarian volume and antral follicle count, are necessary.