Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.
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SUBMITTER: Lai ZW
PROVIDER: S-EPMC5891154 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
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Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.
Lai Zhi-Wei ZW Kelly Ryan R Winans Thomas T Marchena Ivan I Shadakshari Ashwini A Yu Julie J Dawood Maha M Garcia Ricardo R Tily Hajra H Francis Lisa L Faraone Stephen V SV Phillips Paul E PE Perl Andras A
Lancet (London, England) 20180315 10126
<h4>Background</h4>Patients with systemic lupus erythematosus have T-cell dysfunction that has been attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. We assessed safety, tolerance, and efficacy of sirolimus in a prospective, biomarker-driven, open-label clinical trial.<h4>Methods</h4>We did a single-arm, open-label, phase 1/2 trial of ...[more]
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Project description:IntroductionIntractable lymphatic anomalies (LAs) include cystic lymphatic malformation (LM; macrocystic, microcystic, or mixed), generalized lymphatic anomaly, and Gorham-Stout disease. LAs can present with severe symptoms and poor prognosis. Thus, prospective studies for treatments are warranted. We conducted a prospective clinical trial of sirolimus for intractable LAs.MethodsThis was an open-label, single-arm, multicenter, prospective trial involving five institutions in Japan. All patients with LAs received oral sirolimus once daily, and the dose was adjusted to ensure that the trough concentration remained within 5-15 ng/mL. We prospectively assessed the drug response (response rate for radiological volumetric change in target lesion), performance state, change in respiratory function, visceral impairment (pleural effusion, ascites, bleeding, pain), laboratory examination data, quality of life (QOL), and safety at 12, 24, and 52 weeks of administration.ResultsEleven patients with LAs (9 generalized lymphatic anomaly, 1 cystic LM, 1 Gorham-Stout disease) were treated with sirolimus, of whom 6 (54.5%; 95% confidence interval: 23.4-83.3%) demonstrated a partial response on radiological examination at 52 weeks of administration. No patients achieved a complete response. At 12 and 24 weeks of administration, 8 patients (72.7%) already showed a partial response. However, patients with stable disease showed minor or no reduction after 12 weeks. Adverse events, such as stomatitis, acneiform dermatitis, diarrhea, and fever, were common with sirolimus. Sirolimus was safe and tolerable.ConclusionSirolimus can reduce the lymphatic tissue volume in LAs and may lead to improvements in clinical symptoms and QOL.
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Project description:BackgroundMycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy.MethodsThis multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed.FindingsBetween Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%]).InterpretationsMycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE.FundingThe National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
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Project description:IntroductionThe B cell survival factor B lymphocyte stimulator (BLyS) is elevated in patients with systemic lupus erythematosus (SLE) and associated with disease activity. Belimumab, a monoclonal antibody specific for soluble BLyS, is approved for the treatment of adults with active, autoantibody-positive SLE receiving standard therapy. Ethnicity is one of the factors that can potentially affect the pharmacokinetics (PK) of therapeutic monoclonal antibodies, and therefore their efficacy and safety.MethodsThis phase 1, open-label study (200909) evaluated the pharmacokinetics (PK, primary objective), pharmacodynamics (PD), and safety (secondary objectives) of belimumab in Chinese patients with SLE (N = 20). Blood samples were taken up to 84 days after a single intravenous (IV) dose of belimumab 10 mg/kg.ResultsPeak serum concentrations of belimumab (Cmax) were obtained within the 1-h infusion. Geometric mean Cmax, area under the concentration-time curve (time 0 to last quantifiable concentration), terminal half-life, systemic clearance, and volume of distribution were 221 μg/mL, 2395 day·μg/mL, 14.6 days, 4.06 mL/day/kg, and 85.7 mL/kg, respectively. Decreases in CD20+, CD20+/CD27- naïve, CD20+/CD69+ active, CD20+/CD138+ plasmacytoid, CD19+/CD27BRIGHT/CD38BRIGHT SLE subset, and CD20-/CD138+ plasma B Cells post-dose were accompanied by an increase in CD20+/CD27+ memory B cells. Four cases of upper respiratory tract infection (three mild, one moderate) and one case of mild pharyngitis were possibly drug-related; all resolved during the study.ConclusionPK of a single belimumab 10 mg/kg IV dose in Chinese patients with SLE were similar to those observed previously in Japanese and American (white and African-American) patients with SLE. PD results were consistent with belimumab inhibiting BLyS, and belimumab was well tolerated. These data support the use of belimumab in Chinese patients with SLE.Trial registrationClinicalTrials.gov identifier, NCT02880852.
| S-EPMC7021845 | biostudies-literature
Project description:ObjectivesPatients with systemic lupus erythematosus (SLE) are usually treated with glucocorticosteroids even during periods of clinically quiescent disease. A recent study showed that abrupt glucocorticoid withdrawal was associated with an increased likelihood of flare in the next 12 months. The aim of the present study was to assess clinical flare rates and damage accrual in patients who tapered glucocorticosteroids gradually.MethodsPatients from the Toronto Lupus Clinic with 2 consecutive years of clinically quiescent disease were retrieved from the database. Individuals who maintained a low prednisone dose (5 mg/day) comprised the maintenance group, whereas patients who gradually tapered prednisone within these two years comprised the withdrawal group. All individuals were followed for 2 years after prednisone discontinuation or the corresponding date for the maintenance group. Propensity score matching was implemented to adjust for certain baseline differences. Outcomes included clinical flares and damage accrual.ResultsOf 270 eligible patients, 204 were matched (102 in each group). Flare rate (any increase in clinical SLE Disease Activity Index 2000) was lower in the withdrawal group both at 12 (17.6% versus 29.4%; P = 0.023) and 24 months (33.3% versus 50%; P = 0.01). Moderate to severe flares (requiring systemic treatment escalation) were not different at 12 months (10.8% versus 13.7%; P = 0.467) but were less frequent at 24 months (14.7% versus 27.5%; P = 0.024). Damage accrual was less frequent in the withdrawal group (6.9% versus 17.6%; P = 0.022). No predictors for clinical flares were identified.ConclusionGradual glucocorticoid withdrawal is safe in clinically quiescent SLE and is associated with fewer clinical flares and less damage accrual at 24 months.
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Project description:ObjectiveWhile infection burden is high among patients with systemic lupus erythematosus (SLE), there is uncertainty about whether infection rates differ by immunosuppressive drug regimens. We undertook this study to compare infection rates among SLE patients newly initiating immunosuppressive therapy with mycophenolate mofetil (MMF), azathioprine (AZA), or cyclophosphamide (CYC).MethodsWithin the Medicaid Analytic eXtract database (2000-2010; 29 most populated US states), we identified adults with SLE starting MMF, AZA, or CYC treatment. We estimated propensity scores for receipt of MMF versus AZA and MMF versus CYC based on sociodemographic, comorbidity, and medication use information. After 1:1 propensity score matching, we estimated incidence rates of serious infections up to 6 and 12 months after drug initiation and used Cox regression to estimate hazard ratios (HRs) of first infection and death, with 95% confidence intervals (95% CIs). We performed primary intent-to-treat (ITT) and secondary as-treated analyses.ResultsWe studied 1,350 propensity score-matched pairs of MMF and AZA initiators and 674 propensity score-matched pairs of MMF and CYC initiators. In 6-month ITT analyses, the incidence rate per 100 person-years for first serious hospitalized infection was 14.6 in MMF users and 15.2 in AZA users (HR of MMF versus AZA 0.99 [95% CI 0.74-1.32]). Comparing MMF to CYC, the incidence rate per 100 person-years for first serious infection was 24.1 in MMF users and 24.6 in CYC users (HR 0.95 [95% CI 0.69-1.32]). There were no differences in mortality in either comparison. As-treated analyses yielded similar results.ConclusionIn a nationwide longitudinal study of Medicaid SLE patients at high risk of infection, rates of serious infection and mortality did not differ among new users of MMF, AZA, or CYC.
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Project description:IntroductionTreatment adherence plays a large role in chronic dermatologic diseases and may play an important role in the outcomes of patients with cutaneous lupus erythematosus (CLE). We sought to gauge what is currently known about adherence to topical and oral medications in patients with CLE.MethodsA review of MEDLINE was performed using a combination of the phrases "adherence", "compliance", "lupus", and "cutaneous". Studies were hand searched and prospective and cross-sectional studies evaluating medication adherence in patients with CLE and systemic lupus erythematosus (SLE) were included.ResultsOnly two articles explored adherence in patients with CLE, while 17 articles discussed treatment adherence in patients with SLE. Depression was consistently cited as detrimental to adherence. The impact that race, ethnicity, and education has on adherence is unclear. Three studies noted a clear connection between adherence and disease activity, while two others did not. Few studies investigated methods that have improved adherence to treatment which have showed promise.ConclusionMuch of what we know about adherence to medication in patients with lupus is limited to SLE. Although cutaneous symptoms are among the most common manifestations of SLE, cutaneous disease is often managed at least in part with topical agents, and adherence to topical treatment was not assessed in any of the articles, though one study investigated sunscreen usage in patients with CLE. Understanding adherence in patients with CLE may help contribute to better CLE treatment outcomes.
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Project description:ObjectiveTo provide real-world data and summarize current clinical evidence on the efficacy and safety of sirolimus in active systemic lupus erythematosus (SLE) patients.MethodsThis was a prospective real-world clinical study. Included SLE patients should have Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) ⩾ 2. They were treated with sirolimus and followed up regularly. The SLEDAI-2K, Physician Global Assessment (PGA), serological activity indices, and remission of organ manifestations were evaluated. We also performed a meta-analysis to integrate current evidence of sirolimus in SLE.ResultsA total of 49 patients were included in the final analysis. After treatment, the SLEDAI-2K (6.2 ± 3.1 versus 4.0 ± 3.4, p = 0.001) decreased significantly, and the prednisone dosage was tapered successfully (9.9 ± 8.8 mg/day versus 5.9 ± 4.0 mg/day, p = 0.002). Serological activity indices also improved [complement 3 (C3): 0.690 ± 0.209 g/l versus 0.884 ± 0.219 g/l, p < 0.001; complement 4: 0.105 ± 0.059 g/l versus 0.141 ± 0.069 g/l, p < 0.001; anti-dsDNA antibody, 200 ± 178 IU/ml versus 156 ± 163 IU/ml, p = 0.022]. The remission proportions of arthritis, skin rash, and thrombocytopenia were 100%, 88.8%, and 46.2%, respectively. A total of 41.2% of lupus nephritis (LN) patients achieved renal remission, but the average 24-h urine protein level was not significantly changed. Meta-analysis enrolled five studies with 149 patients included, and revealed similar results regarding the changes of SLEDAI-2K [-3.5 (-5.0, -2.1)], C3 [0.224 (0.136, 0.311) g/l] and daily dosage of prednisone [-12.7 (-19.9, -5.6) mg/day].ConclusionSirolimus might be effective and tolerated in SLE. The role of sirolimus in LN requires further study.
| S-EPMC7493251 | biostudies-literature
Project description:ObjectiveTo investigate long-term safety and tolerability of anifrolumab, a human monoclonal antibody to the type I interferon (IFN) receptor subunit 1, in patients with moderate-to-severe systemic lupus erythematosus (SLE).MethodsThis 3-year, multinational, open-label extension study included adult patients who completed treatment (48 weeks of anifrolumab or placebo; 12-week follow-up) in the MUSE phase IIb randomized controlled trial (RCT). Patients initially received 1,000 mg of anifrolumab intravenously every 4 weeks, which was reduced to 300 mg every 4 weeks based on the benefit/risk profile established in the MUSE trial. Adverse events (AEs) were assessed monthly. Exploratory end points included the SLE Disease Activity Index 2000 (SLEDAI-2K), Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), pharmacodynamics, and health-related quality of life (HRQoL).ResultsOf the 246 patients who completed the RCT, 218 (88.6%) enrolled in the open-label extension study, of which 139 (63.8%) completed 3 years of treatment. Approximately 69.7% of patients reported ≥1 AE during the first year of open-label extension treatment. Frequency and patterns of serious AEs and AEs of special interest over 3 years were consistent with those reported for 1 year of treatment in the RCT. Few patients (6.9%) discontinued treatment due to AEs. No new safety signals were identified. Improvement in the SLEDAI-2K was sustained over 3 years. SDI and Short Form 36 health survey scores remained stable. Neutralization of type I IFN gene signatures was maintained in the IFN-high population, and C3, C4, and anti-double-stranded DNA showed trends toward sustained improvement.ConclusionLong-term anifrolumab treatment demonstrates an acceptable safety profile with sustained improvement in SLE disease activity, HRQoL, and serologic measures.
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