David Wofsy

Mycophenolate Mofetil versus Cyclophosphamide for Induction Treatment of 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.

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.).

Interleukin 6 promotes murine lupus in NZB/NZW F1 mice.

To investigate the role of IL-6 in systemic lupus erythematosus (SLE), we selectively inhibited IL-6 in lupus-prone NZB/NZW F1(B/W) mice by chronic administration of a rat mAb to mouse IL-6. Anti-IL-6 alone elicited an anti-rat response that blocked its biologic effects. To circumvent this problem, we rendered B/W mice tolerant to the rat mAb by administration of anti-CD4 concurrent with the first dose of anti-IL-6. Thereafter, the mice received weekly injections of anti-IL-6 alone. There were two control groups: one group received the tolerizing regimen of anti-CD4 along with a control rat IgG1 mAb (GL113) instead of anti-IL-6; the other control group received PBS. Mice that received anti-CD4 were tolerant to the rat mAb for 6 mo. Throughout this period, treatment with anti-IL-6 prevented production of anti-dsDNA, significantly reduced proteinuria, and prolonged life. Mice that received anti-IL-6 without anti-CD4 developed an immune response to the rat mAb and then developed anti-dsDNA antibodies, proteinuria, and mortality comparable with control mice. These findings establish that IL-6 promotes autoimmunity in B/W mice. They further indicate that, although mAb to IL-6 can suppress murine lupus, the development of host immunity to the mAb abrogates its beneficial effects. Finally, this is the first study to demonstrate that a brief course of anti-CD4 can induce tolerance to another therapeutic mAb, in this case an anti-cytokine mAb.

Professional Medical Associations and Their Relationships With Industry: A Proposal for Controlling Conflict of Interest

Professional medical associations (PMAs) play an essential role in defining and advancing health care standards. Their conferences, continuing medical education courses, practice guidelines, definitions of ethical norms, and public advocacy positions carry great weight with physicians and the public. Because many PMAs receive extensive funding from pharmaceutical and device companies, it is crucial that their guidelines manage both real and perceived conflict of interests. Any threat to the integrity of PMAs must be thoroughly and effectively resolved. Current PMA policies, however, are not uniform and often lack stringency. To address this situation, the authors first identified and analyzed conflicts of interest that may affect the activities, leadership, and members of PMAs. The authors then went on to formulate guidelines, both short-term and long-term, to prevent the appearance or reality of undue industry influence. The recommendations are rigorous and would require many PMAs to transform their mode of operation and perhaps, to forgo valuable activities. To maintain integrity, sacrifice may be required. Nevertheless, these changes are in the best interest of the PMAs, the profession, their members, and the larger society.

Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study

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/m2/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. Trial registration. National Institutes of Health, www.clinicaltrials.gov, registration number NCT00377637.

Cutting Edge: Reversal of Murine Lupus Nephritis with CTLA4Ig and Cyclophosphamide

Cyclophosphamide (CTX) prevents progression of nephritis and prolongs survival in (NZB × NZW)F1 (B/W) mice and is used to treat humans with lupus nephritis. To compare the efficacy of CTLA4Ig with CTX and determine whether there is an incremental benefit to combining CTLA4Ig with CTX, we treated B/W mice with CTX, CTLA4Ig, or both agents. In mice with mild renal disease, treatment delayed the onset of proteinuria and prolonged survival in all groups. In mice with advanced renal disease, treatment with both agents reduced proteinuria in 71% of mice, whereas mice treated with either agent alone had no such improvement. Survival was also markedly improved among mice treated with both agents. Thus, combination treatment with CTX and CTLA4Ig is more effective than either agent alone in reducing renal disease and prolonging survival of B/W mice with advanced nephritis. This striking reversal of proteinuria is unprecedented in animal models of SLE.

Chronic therapy with recombinant tumor necrosis factor-α in autoimmune NZB/NZW F1 mice

We studied the effects of recombinant murine tumor necrosis factor-α (TNF-α) on autoimmune disease in lupus-prone NZB/NZW F1 (B/W) mice. Treatment with TNF-α, begun after the onset of clinical disease, improved survival relative to control mice: at age 10 months, 92% of mice treated with TNF-α were alive compared with 42% of control mice (P < 0.05). Administration of TNF-α delayed the progression of renal disease, but sustained therapy did not prevent the eventual development of severe nephritis. Despite the imporvement in survival, treatment with TNF-α did not inhibit anti-dsDNA antibody production. However, it accelerated T lymphocytopenia and abolished natural killer cell activity. These observations suggest that TNF-α may retard murine lupus in B/W mice through effects on cellular rather than humoral mechanisms. Our findings also indicate that the beneficial effects of TNF-α cannot be sustained indefinitely by chronic therapy.

Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial)

Objectives Despite advances in systemic lupus erythematosus (SLE) treatment, many patients suffer from the disease and side effects. Atacicept is a fusion protein that blocks B-lymphocyte stimulator and a proliferation-inducing ligand, which are increased in patients with SLE. Methods In this double-blind, placebo-controlled study, patients with moderate-to-severe SLE were randomised to atacicept 75 mg or atacicept 150 mg administered subcutaneously, or placebo twice-weekly for 4 weeks, then weekly for 48 weeks. Primary and secondary efficacy measures were the proportion of patients experiencing at least one flare of British Isles Lupus Assessment Group A or B, and time to first flare, respectively. Results Enrolment in the atacicept 150 mg arm was discontinued prematurely due to two deaths. In the intention-to-treat population (n=461), there was no difference in flare rates or time to first flare between atacicept 75 mg and placebo. Analysis of patients treated with atacicept 150 mg suggested beneficial effect versus placebo in flare rates (OR: 0.48, p=0.002) and time to first flare (HR: 0.56, p=0.009). Both atacicept doses were associated with reductions in total Ig levels and anti-dsDNA antibodies, and increases in C3 and C4 levels. Most treatment-emergent adverse events were mild or moderate. Conclusions There was no difference between atacicept 75 mg and placebo for flare rate or time to first flare. Analysis of atacicept 150 mg suggested benefit. Trial registration number EudraCT: 2007-003698-13; NCT00624338.

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.

Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions.

OBJECTIVE Recent clinical trials in lupus nephritis have all used different criteria to assess complete response. The objective of this analysis was to compare several previously proposed criteria, using the same data set from a large trial of abatacept in lupus nephritis (IM101075). In so doing, we sought to determine which criteria are most sensitive to differences among treatment groups and to further examine the potential of abatacept in lupus nephritis. METHODS Patients in the IM101075 trial received abatacept at 1 of 2 different dose regimens or placebo, both on a background of mycophenolate mofetil and corticosteroids. Using data from this trial, we assessed rates of complete response at 12 months according to 5 sets of criteria, from 1) the trial protocol, 2) the Aspreva Lupus Management Study (ALMS) trial of mycophenolate mofetil, 3) the Lupus Nephritis Assessment with Rituximab (LUNAR) trial of rituximab, 4) an ongoing National Institutes of Health trial of abatacept (Abatacept and Cyclophosphamide Combination: Efficacy and Safety Study [ACCESS]), and 5) published recommendations of the American College of Rheumatology. RESULTS According to the complete response definition from the IM101075 study protocol, there was no difference among treatment groups in the IM101075 study. In contrast, according to the ALMS, LUNAR, and ACCESS criteria, rates of complete response among patients in the IM101075 study were higher in both treatment groups relative to control. The largest differences were obtained with use of the LUNAR criteria (complete response rate of 6% in the control group, compared to 22% and 24% in the 2 abatacept groups). CONCLUSION The choice of definition of complete response can determine whether a lupus nephritis trial is interpreted as a success or a failure. The results of this analysis provide an evidence-based rationale for choosing among alternative definitions and offer a strong rationale for conducting further studies of abatacept in lupus nephritis.