Nancy J. Olsen

Mycophenolate versus Azathioprine as Maintenance Therapy for 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.).

Two‐year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate

OBJECTIVE Three 6-12-month, double-blind, randomized, controlled trials have shown leflunomide (LEF; 20 mg/day, loading dose 100 mg x 3 days) to be effective and safe for the treatment of rheumatoid arthritis (RA). This analysis of the North American trial assessed whether the clinical benefit evident at month 12 was sustained over 24 months of treatment with LEF as compared with the efficacy and safety of methotrexate (MTX), an equivalent disease-modifying antirheumatic drug, at 24 months. METHODS The year-2 cohort, comprising patients continuing into the second year of treatment with > or = 1 dose of study medication and > or = 1 followup visit after week 52, consisted of 235 patients (LEF n = 98; placebo n = 36; MTX n = 101). The mean (+/- SD) maintenance dose of LEF was 19.6 +/- 1.99 mg/day in year 2 and that of MTX was 12.6 +/- 4.69 mg/week. Statistical analyses used an intent-to-treat (ITT) approach. Statistical comparisons of the active treatments only were prospectively defined in the protocol. RESULTS In total, 85% and 79% of LEF and MTX patients, respectively, who entered year 2 completed 24 months of treatment. From month 12 to month 24, the American College of Rheumatology improvement response rates of > or = 20% (LEF 79% versus MTX 67%; P = 0.049), > or = 50% (LEF 56% versus MTX 43%; P = 0.053), and > or = 70% (LEF 26% versus MTX 20%; P = 0.361) were sustained in both of the active treatment groups. The mean change in total Sharp radiologic damage scores at year 2 compared with year 1 and baseline (LEF 1.6 versus MTX 1.2) showed statistically equivalent sustained retardation of radiographic progression in the active treatment groups. Maximal improvements evident at 6 months in the Health Assessment Questionnaire (HAQ) disability index (HAQ DI) and the physical component score of the Medical Outcomes Survey 36-item short form were sustained over 12 months and 24 months; improvement in the HAQ DI with LEF4(-0.60) was statistically significantly superior to that with MTX (-0.37) at 24 months (P = 0.005). Over 24 months in the ITT cohort, serious treatment-related adverse events were reported in 1.6% of the LEF-treated patients and 3.7% of the MTX-treated patients. Frequently reported adverse events included upper respiratory tract infections, diarrhea, nausea and vomiting, rash, reversible alopecia, and transient liver enzyme elevations. CONCLUSION The safety and efficacy of LEF and MTX were maintained over the second year of this 2-year trial. Both active treatments retarded radiographic progression over 24 months. LEF was statistically significantly superior to MTX in improving physical function as measured by the HAQ DI over 24 months of treatment. Results indicate that LEF is a safe and effective initial treatment for active RA, with clinical benefit sustained over 2 years of treatment without evidence of new or increased toxicity.

Self-Report Questionnaire Scores in Rheumatoid Arthritis Compared with Traditional Physical, Radiographic, and Laboratory Measures

STUDY OBJECTIVE To assess whether scores on a simple self-report questionnaire to depict the clinical status of patients with rheumatoid arthritis are correlated with traditional measures of physical, radiographic, laboratory, functional, and global status. DESIGN The self-report questionnaire was administered at the same time the following variables were assessed: American Rheumatism Association functional class, joint count, hand radiograph, erythrocyte sedimentation rate, rheumatoid factor titer, walking time, grip strength, button test, and global self-assessment. SETTING University rheumatology clinic, the rheumatology clinic of a Veterans Administration hospital, and a private rheumatology practice. PATIENTS The study included 259 patients who met the criteria of the American Rheumatism Association for a diagnosis of definite or classic rheumatoid arthritis. INTERVENTIONS Standard rheumatologic care for patients with rheumatoid arthritis. MEASUREMENTS AND MAIN RESULTS Self-report questionnaire scores were significantly correlated with the joint count, radiographic score, erythrocyte sedimentation rate, grip strength, button test, walking time, American Rheumatism Association functional class, and global self-assessment. Patients were categorized into five questionnaire score categories of 1.00, indicating no dysfunction, and 1.01 to 1.50, 1.51 to 2.00, 2.01 to 3.00, and 3.01 to 4.00, indicating progressive dysfunction. In these five categories, more than ten involved joints were seen in 11%, 37%, 67%, 79%, and 100% of patients, respectively, and erythrocyte sedimentation rates greater than 20 mm/h in 29%, 49%, 64%, 74%, and 85% of patients, respectively. Similar results were seen for other physical and radiographic measures. The questionnaire score was as effective in explaining other measures of clinical status as was any other available measure. CONCLUSIONS A simple self-report questionnaire provides information similar to many traditional measures in rheumatoid arthritis and appears to be an attractive, cost-effective approach to assessing and monitoring quantitatively the status of an individual patient.

Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension

Hypertension is a leading cause of cardiovascular, cerebral, and renal disease morbidity and mortality. Here we show that disruption of the Cyp 4a14 gene causes hypertension, which is, like most human hypertension, more severe in males. Male Cyp 4a14 (−/−) mice show increases in plasma androgens, kidney Cyp 4a12 expression, and the formation of prohypertensive 20-hydroxyarachidonate. Castration normalizes the blood pressure of Cyp 4a14 (−/−) mice and minimizes Cyp 4a12 expression and arachidonate ω-hydroxylation. Androgen replacement restores hypertensive phenotype, Cyp 4a12 expression, and 20-hydroxy-arachidonate formation. We conclude that the androgen-mediated regulation of Cyp 4a arachidonate monooxygenases is an important component of the renal mechanisms that control systemic blood pressures. These results provide direct evidence for a role of Cyp 4a isoforms in cardiovascular physiology, establish Cyp 4a14 (−/−) mice as a monogenic model for the study of cause/effect relationships between blood pressure, sex hormones, and P450 ω-hydroxylases, and suggest the human CYP 4A homologues as candidate genes for the analysis of the genetic and molecular basis of human hypertension.

Cutting Edge: Molecular Portrait of Human Autoimmune Disease

Autoimmune diseases affect 3–5% of the population, are mediated by the immune response to self-Ags, and are characterized by the site of tissue destruction. We compared expression levels of >4,000 genes in PBMC of control individuals before and after immunization to those of individuals with four distinct autoimmune diseases. The gene expression profile of the normal immune response exhibits coordinate changes in expression of genes with related functions over time. In contrast, each individual from all autoimmune diseases displays a similar gene expression profile unrelated to the pattern of the immunized group. To our surprise, genes with a distinct expression pattern in autoimmunity are not necessarily “immune response” genes, but are genes that encode proteins involved in apoptosis, cell cycle progression, cell differentiation, and cell migration.

Safety profile and clinical activity of sifalimumab, a fully human anti-interferon α monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study

Background Type I interferons (IFNs) appear to play a central role in disease pathogenesis in systemic lupus erythematosus (SLE), making them potential therapeutic targets. Methods Safety profile, pharmacokinetics, immunogenicity, pharmacodynamics and clinical activity of sifalimumab, an anti-IFNα monoclonal antibody, were assessed in a phase I, multicentre, randomised, double-blind, dose-escalation study with an open-label extension in adults with moderately active SLE. Subjects received one intravenous dose of sifalimumab (n=33 blinded phase, 0.3, 1, 3, 10 or 30 mg/kg; n=17 open-label, 1, 3, 10 or 30 mg/kg) or placebo (n=17). Each phase lasted 84 days. Results Adverse events (AEs) were similar between groups; about 97% of AEs were grade 1 or 2. All grade 3 and 4 AEs and all serious AEs (2 placebo, 1 sifalimumab) were deemed unrelated to the study drug. No increase in viral infections or reactivation was observed. Sifalimumab caused dose-dependent inhibition of type I IFN-induced mRNAs (type I IFN signature) in whole blood and corresponding changes in related proteins in affected skin. Exploratory analyses showed consistent trends toward improvement in disease activity in sifalimumab-treated versus placebo-treated subjects. A lower proportion of sifalimumab-treated subjects required new or increased immunosuppressive treatments (12% vs 41%; p=0.03) and had fewer Systemic Lupus Erythematosus Disease Activity Index flares (3% vs 29%; p=0.014). Conclusions Sifalimumab had a safety profile that supports further clinical development. This trial demonstrated that overexpression of type I IFN signature in SLE is at least partly driven by IFNα, and exploratory analyses suggest that IFNα inhibition may be associated with clinical benefit in SLE. Trial registration number NCT00299819.

Protein array autoantibody profiles for insights into systemic lupus erythematosus and incomplete lupus syndromes

The objective of this study was to investigate the prevalence and clinical significance of a spectrum of autoantibodies in systemic lupus erythematosus and incomplete lupus syndromes using a proteome microarray bearing 70 autoantigens. Microarrays containing candidate autoantigens or control proteins were printed on 16‐section slides. These arrays were used to profile 93 serum samples from patients with systemic lupus erythematosus (SLE (n = 33), incomplete LE (ILE; n = 23), first‐degree relatives (FDRs) of SLE patients (n = 20) and non‐autoimmune controls (NC; n = 17). Data were analysed using the significance analysis of microarray (SAM) and clustering algorithms. Correlations with disease features were determined. Serum from ILE and SLE patients contained high levels of IgG autoantibodies to 50 autoantigens and IgM autoantibodies to 12 autoantigens. Elevated levels of at least one IgG autoantibody were detected in 26% of SLE and 19% of ILE samples; elevated IgM autoantibodies were present in 13% of SLE and 17% of ILE samples. IgG autoantibodies segregated into seven clusters including two specific for DNA and RNA autoantigens that were correlated with the number of lupus criteria. Three IgG autoantibody clusters specific for collagens, DNA and histones, were correlated with renal involvement. Of the four IgM autoantibody clusters, two were correlated negatively with the number of lupus criteria; none were correlated with renal disease. The IgG : IgM autoantibody ratios generally showed a stepwise increase in the groups following disease burden from NC to SLE. Insights derived from the expanded autoantibody profiling made possible with the antigen array suggest differences in autoreactivity in ILE and SLE. Determining whether the IgM aurotreactivity that predominates in ILE represents an early stage prior to IgG switching or is persistent and relatively protective will require further longitudinal studies.

Comparison of Tripterygium wilfordii Hook F Versus Sulfasalazine in the Treatment of Rheumatoid Arthritis: A Randomized Trial

Context In Chinese medicine, extracts of Tripterygium wilfordii Hook F (TwHF, known as lei gong teng or thunder god vine) are used to treat autoimmune and inflammatory conditions. Small clinical trials suggest that TwHF may benefit patients with rheumatoid arthritis. Contribution This trial compared TwHF extract with sulfasalazine in 121 patients with active rheumatoid arthritis who could continue oral prednisone and nonsteroidal anti-inflammatory drugs but not disease-modifying antirheumatic drugs. Among patients who continued treatment for 24 weeks, achievement of 20% improvement in American College of Rheumatology criteria was greater with TwHF than with sulfasalazine. Adverse event rates were similar. Caution Only 62% and 41% of patients continued TwHF and sulfasalazine treatment, respectively, and provided 24 weeks of data. The Editors Rheumatoid arthritis is characterized by chronic inflammation of the joint lining (synovial membrane) (1), which causes pain and swelling of diarthrodial joints. Over time, uncontrolled disease results in progressive joint damage, disability, and increased mortality (2). The evolving understanding of the immune mechanisms that perpetuate the inflammatory response has led to effective targeted therapies, including inhibitors of inflammatory cytokines (tumor necrosis factor, interleukin-1, and interleukin-6), modulators of activation of CD4+ T cells and dendritic cells, and agents that deplete B cells (3, 4). Despite the clinical efficacy of these therapies, many patients have no clinically meaningful response or discontinue treatment because of adverse events. Furthermore, the limited availability of effective biologics in developing countries, the need for parenteral administration of the biologics, and the relatively high cost all restrict access to these therapies in many patients with rheumatoid arthritis around the world (5). In traditional Chinese medicine, extracts of the roots of the medicinal vine Tripterygium wilfordii Hook F (TwHF) (known in China as lei gong teng or thunder god vine) have shown therapeutic promise in treating autoimmune and inflammatory conditions as well as cancer (68). More recently, different extracts of TwHF have been used in Chinese allopathic medicine for the treatment of autoimmune and inflammatory diseases, and small controlled trials reported good responses with TwHF extracts in patients with cadaveric kidney transplants (9, 10) and Crohn disease (11). Of the approximately 380 metabolites isolated from the plant, 95% are terpenoids (12, 13). Three diterpenoidstriptolide, tripdiolide, and triptonide (13)are the most abundant and account for the immunosuppressive and anti-inflammatory effects observed with the root extracts in both in vitro and in vivo studies (6). In 2 previous single-center trials of patients with rheumatoid arthritis, the extract was standardized by the content of triptolide and tripdiolide (14). This made it possible to use optimal doses identified in an open-label trial (15) for the design of a subsequent small placebo-controlled study (16). Although the number of patients was small, the apparent clinical impact and experimental results indicating potent inhibition of the expression of proinflammatory genes both in vitro and in vivo in animal models (1721) provided the rationale for our multicenter, double-blind, active comparator trial of a standardized TwHF extract in patients with active rheumatoid arthritis. Methods Design Overview This randomized, controlled, 24-week study was conducted between March 2004 and October 2005. All participants provided written informed consent to enter the trial, and the institutional review boards at the participating sites approved the protocol. All investigators and outcome assessors were blinded to group assignment of the patients. Our objective was to determine whether therapy with TwHF extract, 180 mg/d, was statistically significantly better than therapy with sulfasalazine, 2 g/d, over 24 weeks in patients with rheumatoid arthritis by using standard outcome measures. Setting and Participants Our study was conducted at 11 U.S. centers: 2 academic centers (National Institutes of Health, Bethesda, Maryland, and University of Texas, Dallas, Texas) and 9 rheumatology subspecialty clinics (1 each in Dallas and Austin, Texas; Tampa and Fort Lauderdale, Florida; Arlington, Virginia; Duncanville, Pennsylvania; Wheaton and Greenbelt, Maryland; and Lansing, Michigan). Eligible patients had to be at least 18 years of age and have established rheumatoid arthritis, defined by the American College of Rheumatology (ACR) classification criteria (22) as rheumatoid arthritis lasting longer than 6 months. Eligible patients had active disease, defined as 6 or more painful and swollen joints, a visual analogue scale score for pain of at least 3 (on a scale of 1 to 10, with 1 being mild), and a C-reactive protein (CRP) level of 57.14 nmol/L or greater (0.6 mg/dL) or an erythrocyte sedimentation rate (ESR) greater than 25 mm/h. Patients who were taking any disease-modifying antirheumatic drug at screening underwent a 28-day washout period. The use of oral prednisone, at stable doses up to 7.5 mg/d, and nonsteroidal anti-inflammatory drugs were allowed as long as the dose was not changed for 28 days before randomization and the patient agreed to continue to take the medication during the study. Table 1 lists baseline patient characteristics. Table 1. Patient Characteristics at Baseline Randomization and Interventions We used a computer-generated, pseudo-random code (with random, permuted blocks) to assign patients to treatment groups across all centers. We assigned eligible patients at a 1:1 ratio to receive either TwHF extract, 180 mg/d, or sulfasalazine, 2 g/d. In the event of gastrointestinal intolerance, the protocol allowed for temporary dose reduction of 50%. As described elsewhere (15, 16), the triptolide and tripdiolide content of the ethanol and ethylacetate extract (measured by high-performance liquid chromatography [22]) was used to standardize the drug preparation for this study. On the basis of data on in vitro activity and in vivo toxicity, 30 mg of TwHF extract were formulated per capsule. Our study was conducted under the U.S Food and Drug Administrationapproved Investigational New Drug application 39191. Outcomes and Measurements Patients were evaluated clinically and by laboratory measures at baseline, 2 weeks, and every 4 weeks for a total of 24 weeks. A rheumatologist or trained staff member masked to treatment allocation assessed the patients. Serum or plasma specimens were obtained from the patients at baseline, 4 weeks, and 24 weeks and stored at 80C until analysis. Radiographs of hands and feet were obtained at baseline and 24 weeks or at study discontinuation. The primary end point was a 20% improvement at 24 weeks, as defined by ACR criteria (ACR 20) (23). To meet criteria, a patient must have 20% or greater improvement in both tender and swollen joints (68 tender and 66 swollen joints were assessed) and 20% or greater improvement in 3 or more of the following: the physicians or patients assessment of global health status, the patients assessment of pain on a visual analogue scale, the patients assessment of function (using a modified version of the Health Assessment Questionnaire [HAQ]), and the serum CRP level. Secondary end points included the efficacy of TwHF in achieving ACR 50 and ACR 70 responses at 24 weeks, the improvement in the European League Against Rheumatism Disease Activity Score 28 (DAS 28) measure, and a change in the Sharpvan der Heijde score of the hand and foot radiographs (24). Radiographs were obtained at baseline and at the end of the study and were scored by 2 independent readers who were blinded to the randomization schedule and the radiograph sequence. Drug adherence was assessed by using a daily diary and by pill counts. Body weight, blood pressure, and serum glucose level were measured at each visit. Laboratory assessments included ESR (Westergren method); high-sensitivity CRP with normal levels up to 38.1 nmol/L (0.4 mg/dL), which was analyzed in a central laboratory; and interleukin-6 levels, which were measured at baseline, 4 weeks, and 24 weeks by using high-sensitivity enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, Minnesota). Rheumatoid factor was measured by immunonephelometry with a BNII analyzer (Siemens Medical Solutions Diagnostics, Newark, Delaware), cortisol and adrenocorticotropic hormone levels by immunochemiluminescence methods with an Immulite 2500 (Siemens Medical Solutions Diagnostics, Los Angeles, California), and plasma lipids by Synchron LX-20 automated analyzers (Beckman Coulter, Brea, California). Safety assessments consisted of all patients marking adverse events in their drug diaries, which were reviewed on each visit. Vital signs and safety laboratory measures, including a complete blood count and a chemistry profile (electrolyte and liver and kidney function tests), were recorded at each visit. Adverse events were graded by severity according to the National Cancer Institute Common Toxicity Criteria guidelines. An electrocardiogram (ECG) was obtained from all patients at baseline, 2 weeks, and the end of study. After 24 weeks, no follow-up was conducted. Statistical Analysis We designed our study to detect differences in the primary end point with greater than 90% power at a 2-sided level of significance of 0.05. To properly account for missing end point data due to dropouts, we used mixed-effects analyses to predict each patients ACR response at the end of study visit and to properly account for uncertainty in that prediction. The response was categorized according to the ACR 20, ACR 50, and ACR 70 criteria. In a similar manner, we compared changes in DAS 28 from baseline visit between treatment groups. We modeled the treatment group, visit number (2 random-effect terms for visit number and visit nu

Effects of androgens on T and B lymphocyte development.

The sexually dimorphic nature of normal immune responses and the remarkably higher incidence of autoimmune diseases in females have suggested a role for gonadal steroid hormones as modulators of immune system function. We have investigated the effects of androgens on the development of lymphocytes in the thymus and bone marrow. Expression of the androgen receptor, the ligand-activated transcription factor that mediates hormone actions, has been documented in lymphoid and nonlymphoid cells of thymus and bone marrow, but not in mature peripheral lymphocytes. This expression pattern suggests that the major impact of androgens must be on the developmental maturation of T and B lymphocytes rather than on the mature effector cells. Recent experiments have explored whether developing lymphoid precursors are the direct targets of androgen action or whether supporting cells, such as thymic epithelial cells and bone marrow stromal cells, are required for the receptor-mediated effects of androgens on lymphoid cell development. Bone marrow transplantation techniques using an androgen-resistant mouse strain permit the creation of chimeric mice with androgen receptor-defective lymphoid or epithelial/stromal cellular compartments. Hormonalmanipulation experiments in these chimeric animals have suggested that thymic epithelial cells and bone marrow stromal cells are mediators of androgenic effects on immature lymphocytes. The long-range goal of these studies is to understand the basis for the disproportionate occurrence of autoimmune diseases in females.

Treatment of Lupus Nephritis with Abatacept: The Abatacept and Cyclophosphamide Combination Efficacy and Safety Study

To assess the efficacy and safety of a 24‐week course of abatacept in the treatment of active lupus nephritis and to assess the potential of abatacept to induce “clinical tolerance,” defined as sustained clinical quiescence of lupus nephritis after discontinuation of immunosuppressive therapy.