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Our 2022 published working definition of disease modification in systemic lupus erythematosus (SLE) was 'minimising disease activity with the fewest treatment-associated toxicities and slowing or preventing organ damage progression'. The objective of this review was to classify current SLE treatments according to the proposed non-renal disease modification criteria excluding toxicities. Based on a review of select clinical trial (n=32) and observational study (n=54) publications for 14 SLE medications across different therapeutic classes, and the authors' clinical experience, we evaluated disease modification potential as per the proposed framework at three time points. Specific criteria used to determine disease modification potential included a drug's capacity to reduce: (1) non-renal disease activity, (2) severe flares, (3) use of steroids/immunosuppressants and (4) organ damage accrual. Criteria 1-3 were assessed at 1 year and 2-5 years and, when positive, were considered evidence for disease modification potential; criterion 4 was used to confirm disease modification at >5 years. Each treatment received one of four mutually exclusive designations at each time point: (a) criterion met, (b) indications of criterion met despite insufficient evidence in the literature, (c) inconclusive and (d) no available supportive data. This review excludes an assessment of potential toxicities. Eight of the 14 SLE treatments met ≥1 disease modification criteria up to year 5. Hydroxychloroquine improved overall survival at >5 years, suggesting long-term disease modification, but no data on specific organ systems were reported. Belimumab was the only treatment to meet all criteria. Belimumab and hydroxychloroquine met disease modification definitions across three time points. Evidence for other SLE therapies was incomplete, particularly at >5 years. Future studies are warranted for other treatments to meet the disease modification criteria. We discuss challenges to classification and possible updates to our published criteria.
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Inmunosupresores , Lupus Eritematoso Sistémico , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/complicaciones , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Progresión de la Enfermedad , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: Anifrolumab is a type I interferon (IFN) receptor 1 (IFNAR1) blocking antibody approved for treating patients with systemic lupus erythematosus (SLE). Here, we investigated the immunomodulatory mechanisms of anifrolumab using longitudinal transcriptomic and proteomic analyses of the 52-week, randomised, phase 3 TULIP-1 and TULIP-2 trials. METHODS: Patients with moderate to severe SLE were enrolled in TULIP-1 and TULIP-2 and received intravenous anifrolumab or placebo alongside standard therapy. Whole-blood expression of 18 017 genes using genome-wide RNA sequencing (RNA-seq) (pooled TULIP; anifrolumab, n=244; placebo, n=258) and 184 plasma proteins using Olink and Simoa panels (TULIP-1; anifrolumab, n=124; placebo, n=132) were analysed. We compared treatment groups via gene set enrichment analysis using MetaBase pathway analysis, blood transcriptome modules, in silico deconvolution of RNA-seq and longitudinal linear mixed effect models for gene counts and protein levels. RESULTS: Compared with placebo, anifrolumab modulated >2000 genes by week 24, with overlapping results at week 52, and 41 proteins by week 52. IFNAR1 blockade with anifrolumab downregulated multiple type I and II IFN-induced gene modules/pathways and type III IFN-λ protein levels, and impacted apoptosis-associated and neutrophil extracellular traps-(NET)osis-associated transcriptional pathways, innate cell activating chemokines and receptors, proinflammatory cytokines and B-cell activating cytokines. In silico deconvolution of RNA-seq data indicated an increase from baseline of mucosal-associated invariant and γδT cells and a decrease of monocytes following anifrolumab treatment. DISCUSSION: Type I IFN blockade with anifrolumab modulated multiple inflammatory pathways downstream of type I IFN signalling, including apoptotic, innate and adaptive mechanisms that play key roles in SLE immunopathogenesis.
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Anticuerpos Monoclonales Humanizados , Interferón Tipo I , Lupus Eritematoso Sistémico , Proteómica , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Masculino , Adulto , Persona de Mediana Edad , Receptor de Interferón alfa y beta/genética , TranscriptomaRESUMEN
OBJECTIVE: To evaluate safety and mechanism of action of mezagitamab (TAK-079), an anti-CD38 monoclonal antibody, in patients with moderate to severe systemic lupus erythematosus (SLE). METHODS: A phase 1b double-blind, placebo-controlled, multicentre study was conducted in patients with SLE receiving standard background therapy. Eligible patients were adults who met the 2012 SLICC or ACR criteria for diagnosis, had a baseline SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 and were positive for anti-double-stranded DNA antibodies and/or anti-extractable nuclear antigens antibodies. Patients received 45 mg, 90 mg or 135 mg of mezagitamab or placebo every 3 weeks over 12 weeks. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and pharmacodynamics. Exploratory assessments included disease activity scales, deep immune profiling and interferon pathway analysis. RESULTS: 22 patients received at least one dose of either mezagitamab or placebo. In patients exposed to mezagitamab (n=17), drug was well tolerated. Adverse event (AEs) were balanced across treatment groups, with no treatment emergent AEs exceeding grade 2. Responder analyses for Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and SLEDAI-2K did not reveal any observable differences across treatment groups. However, there was a trend for more profound skin responses among patients with higher CLASI scores (>10) at baseline. Pharmacodynamic analysis showed median CD38 receptor occupancy up to 88.4% on CD38+ natural killer cells with concurrent depletion of these cells up to 90% in the 135 mg group. Mean reductions in IgG and autoantibodies were less than 20% in all dose groups. Cytometry by time of flight and type 1 interferon gene analysis revealed unique fingerprints that are indicative of a broad immune landscape shift following CD38 targeting. CONCLUSIONS: Mezagitamab had a favourable safety profile in patients with moderate to severe SLE and elicited a pharmacodynamic effect consistent with CD38+ cell depletion. These findings reveal novel insights into the drug's mechanism of action and support the continued investigation of mezagitamab in autoimmune diseases.
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Anticuerpos Monoclonales , Lupus Eritematoso Sistémico , Adulto , Humanos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Interferones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Resultado del TratamientoRESUMEN
OBJECTIVES: To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence. METHODS: An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item. RESULTS: The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease. CONCLUSION: The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion.
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Azatioprina , Lupus Eritematoso Sistémico , Humanos , Azatioprina/uso terapéutico , Tacrolimus/uso terapéutico , Rituximab/uso terapéutico , Metotrexato/uso terapéutico , Lupus Eritematoso Sistémico/complicaciones , Inmunosupresores/uso terapéutico , Ciclofosfamida/uso terapéutico , Hidroxicloroquina/uso terapéutico , Glucocorticoides/uso terapéutico , Inhibidores Enzimáticos/uso terapéuticoRESUMEN
OBJECTIVE: To determine whether adding obinutuzumab to standard-of-care lupus nephritis (LN) therapy could improve the likelihood of long-term preservation of kidney function and do so with less glucocorticoids. METHODS: Post hoc analyses of the phase II NOBILITY trial were performed. Time to unfavorable kidney outcome (a composite of treatment failure, doubling of serum creatinine, or death), LN flare, first 30% and 40% declines in estimated glomerular filtration rate (eGFR) from baseline, and chronic eGFR slope during the trial were compared between patients with active LN who were randomized to take obinutuzumab (n = 63) or placebo (n = 62) in combination with mycophenolate mofetil and glucocorticoids. The number of patients who achieved complete renal response (CRR) on 7.5 mg or less per day of prednisone was also determined. RESULTS: Obinutuzumab reduced the risk of developing the composite kidney outcome by 60%, LN flare by 57%, and first eGFR decline of 30% or 40% by 80% and 91%, respectively. Patients receiving obinutuzumab had a significantly slower decline in eGFR than patients receiving placebo, with an annualized eGFR slope advantage of 4.1 ml/min/1.73 m2 /year (95% confidence interval 0.14-8.08). Overall, 38% of patients receiving obinutuzumab compared with 16% of patients receiving placebo achieved CRR at week 76 while receiving 7.5 mg or less per day of prednisone (P < 0.01); at week 104, the difference did not achieve significance (38% vs 22%; P = 0.06). CONCLUSION: Post hoc analyses of NOBILITY demonstrated that compared with standard-of-care therapy, obinutuzumab treatment resulted in superior preservation of kidney function and prevention of LN flares. More patients achieved CRR at week 76 with less glucocorticoid use in the obinutuzumab group.
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Anticuerpos Monoclonales Humanizados , Nefritis Lúpica , Humanos , Nefritis Lúpica/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Prednisona/uso terapéutico , Riñón , Glucocorticoides/uso terapéutico , Tasa de Filtración Glomerular , Resultado del TratamientoRESUMEN
BACKGROUND: Baricitinib is an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata. In a 24-week phase 2 study in patients with systemic lupus erythematosus (SLE), baricitinib 4 mg significantly improved SLE disease activity compared with placebo. The objective of this trial was to evaluate the efficacy and safety of baricitinib in patients with active SLE in a 52-week phase 3 study. METHODS: In a multicentre, double-blind, randomised, placebo-controlled, parallel-group, phase 3 study, SLE-BRAVE-I, patients (aged ≥18 years) with active SLE receiving stable background therapy were randomly assigned 1:1:1 to baricitinib 4 mg, 2 mg, or placebo once daily for 52 weeks with standard of care. Glucocorticoid tapering was encouraged but not required per protocol. The primary endpoint was the proportion of patients reaching an SLE Responder Index (SRI)-4 response at week 52 in the baricitinib 4 mg treatment group compared with placebo. The primary endpoint was assessed by logistic regression analysis with baseline disease activity, baseline corticosteroid dose, region, and treatment group in the model. Efficacy analyses were done on a modified intention-to-treat population, comprising all participants who were randomly assigned and received at least one dose of investigational product. Safety analyses were done on all randomly assigned participants who received at least one dose of investigational product and who did not discontinue from the study for the reason of lost to follow-up at the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT03616912. FINDINGS: 760 participants were randomly assigned and received at least one dose of baricitinib 4 mg (n=252), baricitinib 2 mg (n=255), or placebo (n=253). A significantly greater proportion of participants who received baricitinib 4 mg (142 [57%]; odds ratio 1·57 [95% CI 1·09 to 2·27]; difference with placebo 10·8 [2·0 to 19·6]; p=0·016), but not baricitinib 2 mg (126 [50%]; 1·14 [0·79 to 1·65]; 3·9 [-4·9 to 12·6]; p=0·47), reached SRI-4 response compared with placebo (116 [46%]). There were no significant differences between the proportions of participants in either baricitinib group reaching any of the major secondary endpoints compared with placebo, including glucocorticoid tapering and time to first severe flare. 26 (10%) participants receiving baricitinib 4 mg had serious adverse events, 24 (9%) participants receiving baricitinib 2 mg, and 18 (7%) participants receiving placebo. The safety profile of baricitinib in participants with SLE was consistent with the known baricitinib safety profile. INTERPRETATION: The primary endpoint in this study was met for the 4 mg baricitinib group. However, key secondary endpoints were not. No new safety signals were observed. FUNDING: Eli Lilly and Company.
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Artritis Reumatoide , Lupus Eritematoso Sistémico , Humanos , Adolescente , Adulto , Glucocorticoides/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Método Doble Ciego , Resultado del TratamientoRESUMEN
OBJECTIVES: In patients with systemic lupus erythematosus (SLE), lupus low disease activity state (LLDAS) attainment is associated with improved outcomes. We investigated LLDAS attainment in anifrolumab-treated patients. METHODS: We performed post hoc analysis of pooled Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP-1) (NCT02446912) and TULIP-2 (NCT02446899) anifrolumab phase 3 trial data in patients with moderate to severe SLE receiving standard therapy. LLDAS was defined as: SLE Disease Activity Index 2000 ≤4 without major organ activity, no new disease activity, Physician's Global Assessment ≤1, prednisone ≤7.5 mg/day and no non-standard immunosuppressant dosing. Time to first LLDAS attainment was compared between groups using Cox regression modelling; responses were compared using logistic regression. RESULTS: Agnostic to treatment, 205/819 (25.0%) patients attained LLDAS at week 52; 186/205 (90.7%) were also British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA)-responders. Among BICLA-responders at week 52, 186/318 (58.5%) attained LLDAS; 203/380 (53.4%) SLE Responder Index-4 (SRI(4)) responders attained LLDAS. Improvements from baseline in patient global assessment scores at week 52 were threefold greater in LLDAS-attainers. At week 52, 30.0% of anifrolumab-treated patients and 19.6% of placebo were in LLDAS (OR 1.8, 95% CI 1.3 to 2.5, p=0.0011). Compared with placebo, anifrolumab treatment was associated with earlier LLDAS attainment (time to first LLDAS, HR 1.76, 95% CI 1.35 to 2.30, p<0.0001), increased cumulative time in LLDAS (p<0.0001) and higher likelihood of sustained LLDAS (p<0.001). Anifrolumab treatment was also associated with higher rates of Definition of Remission in SLE remission at week 52 (15.3% vs 7.6%; OR 2.2, 95% CI 1.4 to 3.6, p=0.0013). CONCLUSIONS: LLDAS attainment was highly associated with, but more stringent than, BICLA and SRI(4) responses. Compared with placebo, anifrolumab treatment was associated with earlier, more frequent, and more prolonged and sustained LLDAS. TRIAL REGISTRATION NUMBERS: NCT02446912 and NCT02446899.
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Lupus Eritematoso Sistémico , Tulipa , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVES: Glucocorticoid sparing is a key priority for SLE management. We evaluated the effects of sustained glucocorticoid tapering in patients with SLE. MATERIAL AND METHODS: This was a post hoc analysis of the randomized, placebo-controlled, 52-week phase 3 Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-1 and TULIP-2 trials of anifrolumab (300 mg i.v. once every 4 weeks for 48 weeks) plus standard therapy in patients with moderate to severe SLE. In a cohort of patients receiving glucocorticoids (prednisone or equivalent) 10 mg or more per day at baseline, we assessed changes in glucocorticoid dosage, patient-reported outcomes (PROs) and safety. Outcome measures were compared between sustained glucocorticoid taper responders (7.5 mg or less per day by week 40 sustained through week 52) and non-responders, regardless of treatment group, and between patients receiving anifrolumab or placebo. RESULTS: Among the 726 patients in the TULIP trials, 375 patients received glucocorticoids 10 mg or more per day at baseline, and of these, 155 (41%) patients were sustained glucocorticoid taper responders. Compared with non-responders (n = 220), sustained glucocorticoid taper responders reduced their mean cumulative glucocorticoid dose by 32%, improved PRO scores, reduced blood pressure and experienced fewer serious adverse events. Sustained glucocorticoid tapering was achieved by 51% (96/190) of patients receiving anifrolumab vs 32% (59/185) receiving placebo. Compared with placebo, more anifrolumab-treated patients achieved both sustained glucocorticoid taper and reduced overall disease activity [38% (72/190) vs 23% (43/185)]. CONCLUSIONS: Sustained glucocorticoid tapering is associated with clinical benefits. Anifrolumab treatment has potential to reduce disease activity and glucocorticoid exposure, a key goal of SLE management. STUDY REGISTRATION: ClinicalTrials.gov identifier: NCT02446912 and NCT02446899.
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Lupus Eritematoso Sistémico , Tulipa , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Glucocorticoides , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inducido químicamente , Resultado del TratamientoRESUMEN
OBJECTIVE: Quinolinic acid (QA), a kynurenine (KYN)/tryptophan (TRP) pathway metabolite, is an N-methyl-D-aspartate receptor agonist that can produce excitotoxic neuron damage. Type I and II interferons (IFNs) stimulate the KYN/TRP pathway, producing elevated QA/kynurenic acid (KA), a potential neurotoxic imbalance that may contribute to SLE-mediated cognitive dysfunction. We determined whether peripheral blood interferon-stimulated gene (ISG) expression associates with elevated serum KYN:TRP and QA:KA ratios in SLE. METHODS: ISG expression (whole-blood RNA sequencing) and serum metabolite ratios (high-performance liquid chromatography) were measured in 72 subjects with SLE and 73 healthy controls (HCs). ISG were identified from published gene sets and individual IFN scores were derived to analyse associations with metabolite ratios, clinical parameters and neuropsychological assessments. SLE analyses were grouped by level of ISG expression ('IFN high', 'IFN low' and 'IFN similar to HC') and level of monocyte-associated gene expression (using CIBERSORTx). RESULTS: Serum KYN:TRP and QA:KA ratios were higher in SLE than in HC (p<0.01). 933 genes were differentially expressed ≥2-fold in SLE versus HC (p<0.05). 70 of the top 100 most highly variant genes were ISG. Approximately half of overexpressed genes that correlated with KYN:TRP and QA:KA ratios (p<0.05) were ISG. In 36 IFN-high subjects with SLE, IFN scores correlated with KYN:TRP ratios (p<0.01), but not with QA:KA ratios. Of these 36 subjects, 23 had high monocyte-associated gene expression, and in this subgroup, the IFN scores correlated with both KY:NTRP and QA:KA ratios (p<0.05). CONCLUSIONS: High ISG expression correlated with elevated KYN:TRP ratios in subjects with SLE, suggesting IFN-mediated KYN/TRP pathway activation, and with QA:KA ratios in a subset with high monocyte-associated gene expression, suggesting that KYN/TRP pathway activation may be particularly important in monocytes. These results need validation, which may aid in determining which patient subset may benefit from therapeutics directed at the IFN or KYN/TRP pathways to ameliorate a potentially neurotoxic QA/KA imbalance.
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Disfunción Cognitiva , Lupus Eritematoso Sistémico , Humanos , Quinurenina/metabolismo , Triptófano/metabolismo , Interferones , Lupus Eritematoso Sistémico/complicaciones , Ácido Quinurénico/metabolismo , Ácido Quinolínico/metabolismo , Disfunción Cognitiva/etiologíaRESUMEN
BACKGROUND: Antibody-binding of blood dendritic cell antigen 2 (BDCA2), which is expressed exclusively on plasmacytoid dendritic cells, suppresses the production of type I interferon that is involved in the pathogenesis of systemic lupus erythematosus (SLE). The safety and efficacy of subcutaneous litifilimab, a humanized monoclonal antibody that binds to BDCA2, in patients with SLE have not been extensively studied. METHODS: We conducted a phase 2 trial of litifilimab involving participants with SLE. The initial trial design called for randomly assigning participants to receive litifilimab (at a dose of 50, 150, or 450 mg) or placebo administered subcutaneously at weeks 0, 2, 4, 8, 12, 16, and 20, with the primary end point of evaluating cutaneous lupus activity. The trial design was subsequently modified; adults with SLE, arthritis, and active skin disease were randomly assigned to receive either litifilimab at a dose of 450 mg or placebo. The revised primary end point was the change from baseline in the total number of active joints (defined as the sum of the swollen joints and the tender joints) at week 24. Secondary end points were changes in cutaneous and global disease activity. Safety was also assessed. RESULTS: A total of 334 adults were assessed for eligibility, and 132 underwent randomization (64 were assigned to receive 450-mg litifilimab, 6 to receive 150-mg litifilimab, 6 to receive 50-mg litifilimab, and 56 to receive placebo). The primary analysis was conducted in the 102 participants who had received 450-mg litifilimab or placebo and had at least four tender and at least four swollen joints. The mean (±SD) baseline number of active joints was 19.0±8.4 in the litifilimab group and 21.6±8.5 in the placebo group. The least-squares mean (±SE) change from baseline to week 24 in the total number of active joints was -15.0±1.2 with litifilimab and -11.6±1.3 with placebo (mean difference, -3.4; 95% confidence interval, -6.7 to -0.2; P = 0.04). Most of the secondary end points did not support the results of the analysis of the primary end point. Receipt of litifilimab was associated with adverse events, including two cases of herpes zoster and one case of herpes keratitis. CONCLUSIONS: In a phase 2 trial involving participants with SLE, litifilimab was associated with a greater reduction from baseline in the number of swollen and tender joints than placebo over a period of 24 weeks. Longer and larger trials are required to determine the safety and efficacy of litifilimab for the treatment of SLE. (Funded by Biogen; LILAC ClinicalTrials.gov number, NCT02847598.).
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Anticuerpos Monoclonales Humanizados , Lectinas Tipo C , Lupus Eritematoso Sistémico , Glicoproteínas de Membrana , Receptores Inmunológicos , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Método Doble Ciego , Humanos , Lectinas Tipo C/inmunología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Glicoproteínas de Membrana/inmunología , Receptores Inmunológicos/inmunología , Enfermedades de la Piel , Resultado del TratamientoRESUMEN
BACKGROUND: Blood dendritic cell antigen 2 (BDCA2) is a receptor that is exclusively expressed on plasmacytoid dendritic cells, which are implicated in the pathogenesis of lupus erythematosus. Whether treatment with litifilimab, a humanized monoclonal antibody against BDCA2, would be efficacious in reducing disease activity in patients with cutaneous lupus erythematosus has not been extensively studied. METHODS: In this phase 2 trial, we randomly assigned adults with histologically confirmed cutaneous lupus erythematosus with or without systemic manifestations in a 1:1:1:1 ratio to receive subcutaneous litifilimab (at a dose of 50, 150, or 450 mg) or placebo at weeks 0, 2, 4, 8, and 12. We used a dose-response model to assess whether there was a response across the four groups on the basis of the primary end point, which was the percent change from baseline to 16 weeks in the Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity score (CLASI-A; scores range from 0 to 70, with higher scores indicating more widespread or severe skin involvement). Safety was also assessed. RESULTS: A total of 132 participants were enrolled; 26 were assigned to the 50-mg litifilimab group, 25 to the 150-mg litifilimab group, 48 to the 450-mg litifilimab group, and 33 to the placebo group. Mean CLASI-A scores for the groups at baseline were 15.2, 18.4, 16.5, and 16.5, respectively. The difference from placebo in the change from baseline in CLASI-A score at week 16 was -24.3 percentage points (95% confidence interval [CI] -43.7 to -4.9) in the 50-mg litifilimab group, -33.4 percentage points (95% CI, -52.7 to -14.1) in the 150-mg group, and -28.0 percentage points (95% CI, -44.6 to -11.4) in the 450-mg group. The least squares mean changes were used in the primary analysis of a best-fitting dose-response model across the three drug-dose levels and placebo, which showed a significant effect. Most of the secondary end points did not support the results of the primary analysis. Litifilimab was associated with three cases each of hypersensitivity and oral herpes infection and one case of herpes zoster infection. One case of herpes zoster meningitis occurred 4 months after the participant received the last dose of litifilimab. CONCLUSIONS: In a phase 2 trial involving participants with cutaneous lupus erythematosus, treatment with litifilimab was superior to placebo with regard to a measure of skin disease activity over a period of 16 weeks. Larger and longer trials are needed to determine the effect and safety of litifilimab for the treatment of cutaneous lupus erythematosus. (Funded by Biogen; LILAC ClinicalTrials.gov number, NCT02847598.).
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Anticuerpos Monoclonales Humanizados , Lectinas Tipo C , Lupus Eritematoso Cutáneo , Glicoproteínas de Membrana , Receptores Inmunológicos , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Herpes Zóster/etiología , Humanos , Lectinas Tipo C/antagonistas & inhibidores , Lectinas Tipo C/inmunología , Lupus Eritematoso Cutáneo/tratamiento farmacológico , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/inmunología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/inmunología , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVES: In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results. METHODS: TULIP-1, TULIP-2 (both phase 3) and MUSE (phase 2b) were randomised, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks, 48 weeks; TULIP-1/TULIP-2: n=180; MUSE: n=99) or placebo (TULIP-1: n=184, TULIP-2: n=182; MUSE: n=102). Week 52 BICLA and SRI(4) outcomes were assessed for each patient. RESULTS: Most patients (78%-85%) had concordant BICLA and SRI(4) outcomes (Cohen's Kappa 0.6-0.7, nominal p<0.001). Dual BICLA/SRI(4) response rates favoured anifrolumab over placebo in TULIP-1, TULIP-2 and MUSE (all nominal p≤0.004). A discordant TULIP-1 BICLA non-responder/SRI(4) responder subgroup was identified (40/364, 11% of TULIP-1 population), comprising more patients receiving placebo (n=28) than anifrolumab (n=12). In this subgroup, placebo-treated patients had lower baseline disease activity, joint counts and glucocorticoid tapering rates, and more placebo-treated patients had arthritis response than anifrolumab-treated patients. CONCLUSIONS: Across trials, most patients had concordant BICLA/SRI(4) outcomes and dual BICLA/SRI(4) responses favoured anifrolumab. A BICLA non-responder/SRI(4) responder subgroup was identified where imbalances of key factors driving the BICLA/SRI(4) discordance (disease activity, glucocorticoid taper) disproportionately favoured the TULIP-1 placebo group. Careful attention to baseline disease activity and monitoring glucocorticoid taper variation will be essential in future SLE trials. TRIAL REGISTRATION NUMBERS: NCT02446912 and NCT02446899.
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Glucocorticoides , Lupus Eritematoso Sistémico , Alprostadil/uso terapéutico , Anticuerpos Monoclonales Humanizados , Glucocorticoides/uso terapéutico , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects multiple organ systems. The most prevalent manifestations include constitutional symptoms, arthritis, and rash. An SLE flare is defined as a measurable increase in disease activity that may prompt a change in treatment. According to the European Alliance of Associations for Rheumatology guidance, SLE treatments should be aimed at reducing disease activity and flares, as well as preventing organ damage. Standard-of-care treatment of SLE includes glucocorticoids, but their long-term use is associated with damage accrual. Repository corticotropin injection (RCI; Acthar® Gel) is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides that has anti-inflammatory and immunomodulatory effects beyond its steroidogenic effect, and has been US Food and Drug Administration-approved for the treatment of SLE flares and as a maintenance therapy. This review summarizes data from three clinical trials that evaluated the efficacy and safety of RCI in the treatment of patients with moderate-severe refractory SLE. These clinical trials confirmed that RCI improved global disease activity scores and some SLE clinical manifestations. Analysis of pooled data from these trials showed that RCI treatment significantly improved the British Isles Lupus Assessment Group 2004 (BILAG-2004) index scores after 8 weeks of treatment, and tender and swollen joint counts after 4 weeks. These clinical trials demonstrated an acceptable safety profile with few serious adverse events reported. The distinct mechanisms of action from standard-of-care therapies and the favorable safety and good efficacy profiles support the use of RCI as therapy for patients with refractory SLE.
Asunto(s)
Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Reumatología , Hormona Adrenocorticotrópica/uso terapéutico , Glucocorticoides/efectos adversos , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológicoRESUMEN
This study aimed to elucidate the pharmacokinetic/pharmacodynamic and pharmacodynamic/efficacy relationships of anifrolumab, a type I interferon receptor antibody, in patients with moderate to severe systemic lupus erythematosus. Data were pooled from the randomized, 52-week, placebo-controlled TULIP-1 and TULIP-2 trials of intravenous anifrolumab (150 mg/300 mg, every 4 weeks for 48 weeks). Pharmacodynamic neutralization was measured with a 21-gene type I interferon gene signature (21-IFNGS) in patients with high IFNGS. The pharmacokinetic/pharmacodynamic relationship was analyzed graphically and modeled with a nonlinear mixed-effects model. British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rates were compared across 21-IFNGS neutralization quartiles. Overall, 819 patients received ≥1 dose of anifrolumab or placebo, of whom 676 were IFNGS high. Over 52 weeks, higher average anifrolumab serum concentrations were associated with increased median 21-IFNGS neutralization, which was rapid and sustained with anifrolumab 300 mg (>80%, weeks 12-52), lower and delayed with anifrolumab 150 mg (>50%, week 52), and minimal with placebo. The proportion of patients with week 24 anifrolumab trough concentration exceeding the IC80 (3.88 µg/mL) was greater with anifrolumab 300 mg vs anifrolumab 150 mg (≈83% vs ≈27%), owing to the higher estimated median trough concentration (15.6 vs 0.2 µg/mL). BICLA response rates increased with 21-IFNGS neutralization; more patients had a BICLA response in the highest vs lowest neutralization quartiles at week 52 (58.1% vs 37.6%). In conclusion, anifrolumab 300 mg every 4 weeks rapidly, substantially, and sustainably neutralized the 21-IFNGS and was associated with clinical efficacy, supporting this dosing regimen in patients with systemic lupus erythematosus.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Lupus Eritematoso Sistémico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVES: To characterise the efficacy and safety of anifrolumab in patients with systemic lupus erythematosus (SLE) according to interferon gene signature (IFNGS), demographic and clinical subgroups. METHODS: We performed post hoc analyses of pooled data from the 52-week phase III TULIP-1/TULIP-2 placebo-controlled trials of intravenous anifrolumab in moderate-to-severe SLE. Outcomes were assessed in predefined subgroups: IFNGS (high/low), age, sex, body mass index, race, geographic region, age of onset, glucocorticoid use, disease activity and serological markers. RESULTS: In pooled data, patients received anifrolumab 300 mg (360/726) or placebo (366/726); 82.6% were IFNGS-high. IFNGS-high patients had greater baseline disease activity and were more likely to have abnormal serological markers versus IFNGS-low patients. In the total population, a greater proportion of patients treated with anifrolumab versus placebo achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response at week 52 (difference 16.6%; nominal p<0.001). BICLA response treatment differences with anifrolumab versus placebo were comparable to the total population across most predefined subgroups, including subgroups for baseline glucocorticoid dosage (<10/≥10 mg/day prednisone/equivalent) and for clinical disease activity (SLE Disease Activity Index 2000 score <10/≥10). Subgroups with larger treatment differences included IFNGS-high patients (18.2%), patients with abnormal baseline serological markers (23.1%) and Asian patients (29.2%). The safety profile of anifrolumab was similar across subgroups. CONCLUSIONS: Overall, this study supports the consistent efficacy and safety of anifrolumab across a range of patients with moderate-to-severe SLE. In a few subgroups, small sample sizes limited conclusions from being drawn regarding the treatment benefit with anifrolumab. TRIAL REGISTRATION NUMBER: NCT02446912, NCT02446899.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Interferón Tipo I , Lupus Eritematoso Sistémico , Anticuerpos Monoclonales Humanizados/efectos adversos , Biomarcadores , Método Doble Ciego , Femenino , Glucocorticoides/uso terapéutico , Humanos , Interferón Tipo I/efectos adversos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/genética , Masculino , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of iberdomide in patients with SLE. Iberdomide is a high-affinity cereblon ligand that targets the hematopoietic transcription factors Ikaros and Aiolos for proteasomal degradation. METHODS: A 12-week, multicentre, double-blind, placebo-controlled, dose-escalation study in active SLE was followed by a 2-year, open-label active treatment extension phase (ATEP) (NCT02185040). In the dose-escalation phase, adults with active SLE were randomised to oral placebo or iberdomide (0.3 mg every other day, 0.3 mg once daily, 0.6 mg and 0.3 mg alternating once daily, or 0.6 mg once daily). Primary endpoints were safety and tolerability. RESULTS: The dose-escalation phase enrolled 42 patients, with 33 completing this phase and 17 patients enrolling into the ATEP. In the dose-escalation phase, the most common treatment-emergent adverse events (TEAEs; iberdomide/placebo groups) were nausea (20.6%/12.5%), diarrhoea (17.6%/12.5%) and upper respiratory tract infection (11.8%/12.5%). Most TEAEs were mild or moderate in severity and more common in the highest dose groups in both study phases. In the dose-escalation phase, Physician's Global Assessment and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity scores improved relative to baseline and placebo in all iberdomide groups, with a trend toward continued score improvements in the ATEP. In the dose-escalation phase, iberdomide treatment resulted in dose-dependent reductions in total B cells and plasmacytoid dendritic cells in blood. Improvements in CLASI activity scores correlated with plasmacytoid dendritic cell depletion. CONCLUSIONS: These proof-of-concept findings suggest a favourable benefit/risk ratio in SLE for iberdomide, a drug with a novel immunomodulatory mechanism of action, supporting further clinical investigation.
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Lupus Eritematoso Sistémico , Piperidonas , Relación Dosis-Respuesta a Droga , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Morfolinas/uso terapéutico , Ftalimidas , Piperidonas/uso terapéuticoRESUMEN
OBJECTIVE: To assess the efficacy and safety of the type I interferon receptor antibody, anifrolumab, in patients with active, biopsy-proven, Class III/IV lupus nephritis. METHODS: This phase II double-blinded study randomised 147 patients (1:1:1) to receive monthly intravenous anifrolumab basic regimen (BR, 300 mg), intensified regimen (IR, 900 mg ×3, 300 mg thereafter) or placebo, alongside standard therapy (oral glucocorticoids, mycophenolate mofetil). The primary endpoint was change in baseline 24-hour urine protein-creatinine ratio (UPCR) at week (W) 52 for combined anifrolumab versus placebo groups. The secondary endpoint was complete renal response (CRR) at W52. Exploratory endpoints included more stringent CRR definitions and sustained glucocorticoid reductions (≤7.5 mg/day, W24-52). Safety was analysed descriptively. RESULTS: Patients received anifrolumab BR (n=45), IR (n=51), or placebo (n=49). At W52, 24-hour UPCR improved by 69% and 70% for combined anifrolumab and placebo groups, respectively (geometric mean ratio=1.03; 95% CI 0.62 to 1.71; p=0.905). Serum concentrations were higher with anifrolumab IR versus anifrolumab BR, which provided suboptimal exposure. Numerically more patients treated with anifrolumab IR vs placebo attained CRR (45.5% vs 31.1%), CRR with UPCR ≤0.5 mg/mg (40.9% vs 26.7%), CRR with inactive urinary sediment (40.9% vs 13.3%) and sustained glucocorticoid reductions (55.6% vs 33.3%). Incidence of herpes zoster was higher with combined anifrolumab vs placebo (16.7% vs 8.2%). Incidence of serious adverse events was similar across groups. CONCLUSION: Although the primary endpoint was not met, anifrolumab IR was associated with numerical improvements over placebo across endpoints, including CRR, in patients with active lupus nephritis. TRIAL REGISTRATION NUMBER: NCT02547922.
Asunto(s)
Interferón Tipo I , Lupus Eritematoso Sistémico , Nefritis Lúpica , Anticuerpos Monoclonales Humanizados/uso terapéutico , Creatinina , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Nefritis Lúpica/tratamiento farmacológico , Masculino , Resultado del TratamientoRESUMEN
OBJECTIVE: Randomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a humanised type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, with placebo for the treatment of LN in combination with standard therapies. METHODS: Patients with LN receiving mycophenolate and corticosteroids were randomised to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint was complete renal response (CRR) at week 52. Exploratory analyses through week 104 were conducted. The prespecified alpha level was 0.2. RESULTS: A total of 125 patients were randomised and received blinded infusions. Achievement of CRR was greater with obinutuzumab at week 52 (primary endpoint, 22 (35%) vs 14 (23%) with placebo; percentage difference, 12% (95% CI -3.4% to 28%), p=0.115) and at week 104 (26 (41%) vs 14 (23%); percentage difference, 19% (95% CI 2.7% to 35%), p=0.026). Improvements in other renal response measures, serologies, estimated glomerular filtration rate and proteinuria were greater with obinutuzumab. Obinutuzumab was not associated with increases in serious adverse events, serious infections or deaths. Non-serious infusion-related reactions occurred more frequently with obinutuzumab. CONCLUSIONS: Improved renal responses through week 104 were observed in patients with LN who received obinutuzumab plus standard therapies compared with standard therapies alone. Obinutuzumab was well tolerated and no new safety signals were identified. TRIAL REGISTRATION NUMBER: NCT02550652.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos B/efectos de los fármacos , Nefritis Lúpica/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Adulto , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos Inmunológicos/farmacología , Método Doble Ciego , Quimioterapia Combinada , Inhibidores Enzimáticos/uso terapéutico , Femenino , Tasa de Filtración Glomerular , Humanos , Nefritis Lúpica/fisiopatología , Masculino , Ácido Micofenólico/uso terapéutico , Placebos/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: To characterize the relationship of anifrolumab pharmacokinetics with efficacy and safety in patients with moderate to severe SLE despite standard therapy, using pooled data from two phase 3 trials. METHODS: TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (every 4 weeks for 48 weeks). For the exposure-response analysis, BILAG-based Composite Lupus Assessment (BICLA) or SLE Responder Index [SRI(4)] response rates at week 52 in each quartile/tertile of average anifrolumab serum concentration (Cave) were compared for anifrolumab and placebo in all-comers, patients who completed treatment, and IFN gene signature (IFNGS)-high patients who completed treatment, using average marginal effect logistic regression. Relationships between exposure and key safety events were assessed graphically. RESULTS: Of patients in TULIP-1/TULIP-2 who received anifrolumab (150 mg, n = 91; 300 mg, n = 356) or placebo (n = 366), 574 completed treatment, of whom 470 were IFNGS high. In the exposure-efficacy analyses, BICLA and SRI(4) treatment differences favouring anifrolumab 300 mg vs placebo were observed across Cave subgroups and all analysis populations. Logistic regression identified Cave as a significant covariate for predicted BICLA response, as higher anifrolumab Cave predicted greater efficacy. There was no evidence of exposure-driven incidence of key safety events through week 52 in patients receiving anifrolumab 150 or 300 mg. CONCLUSION: While higher Cave predicted greater efficacy, consistent positive benefit favouring anifrolumab 300 mg vs placebo was observed in BICLA and SRI(4) responses across Cave subgroups in the TULIP trials. There was no evidence of exposure-driven safety events. CLINICALTRIAL.GOV NUMBERS: NCT02446912, NCT02446899.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Lupus Eritematoso Sistémico , Administración Intravenosa , Anticuerpos Monoclonales Humanizados/uso terapéutico , Método Doble Ciego , Humanos , Hiperplasia , Lupus Eritematoso Sistémico/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
BACKGROUND: The British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) is a validated global measure of treatment response in systemic lupus erythematosus (SLE) clinical trials but does not include patient-reported outcomes. To evaluate the clinical meaningfulness of a BICLA response from the patient perspective, we aimed to analyse patient-reported outcomes by BICLA responses with anifrolumab or placebo in patients with moderate to severe SLE. METHODS: We did a post-hoc analysis of pooled data from the phase 3 TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials of anifrolumab, which assessed health-related quality of life using the Short Form 36 Health Survey (SF-36; version 2) and Lupus Quality of Life, fatigue using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), pain using the Numerical Rating Scale, and disease activity using Patient Global Assessment. Changes from baseline and proportions of patients reporting improvements in patient-reported outcomes greater than or equal to the minimum clinically important differences and scores greater than or equal to the normative values were compared in BICLA responders and non-responders and by treatment group (intravenous anifrolumab 300 mg or placebo). FINDINGS: 726 patients were included in the TULIP trials, of whom 366 received placebo (184 patients in TULIP-1 and 182 in TULIP-2) and 360 received anifrolumab 300 mg (180 patients in each trial). The mean patient age was 41·8 years (SD 11·9). 674 (93%) patients were female, 52 (7%) were male, and 479 (66%) were White; 283 (39%) were BICLA responders and 443 (61%) were BICLA non-responders. Compared with non-responders, BICLA responders reported greater mean improvements from baseline at week 52 in Patient Global Assessment, SF-36, Lupus Quality of Life, FACIT-F, and pain Numerical Rating Scale scores (all nominal p<0·0053). Compared with non-responders, a greater proportion of BICLA responders reported improvements greater than or equal to the minimum clinically important difference across all SF-36 domains; eg, Physical Component Summary (165 [60%] of 277 for responders vs 63 [15%] of 416 for non-responders), Mental Component Summary (140 [51%] of 276 vs 59 [15%] of 416), and role physical (184 [70%] of 264 vs 76 [19%] of 398); Lupus Quality of Life domains; eg, physical health (151 [58%] of 262 vs 60 [15%] of 396), and intimate relationships (77 [41%] of 187 vs 33 [11%] of 286), and FACIT-F (155 [56%] of 276 vs 66 [15%] of 439). Similarly, a greater proportion of BICLA responders had scores equal to or greater than the normative values across all SF-36 domains and FACIT-F compared with BICLA non-responders at week 52. Patients who received anifrolumab reported greater numerical improvements in Patient Global Assessment, SF-36, Lupus Quality of Life, FACIT-F, and pain Numerical Rating Scale scores than those who received placebo. INTERPRETATION: BICLA responders reported significant and clinically meaningful improvements in Patient Global Assessment, health-related quality of life, fatigue, and pain compared with BICLA non-responders. More patients with moderate to severe SLE who received anifrolumab were BICLA responders and had improved health-related quality of life, fatigue, and pain than those who received placebo. FUNDING: AstraZeneca.