RESUMEN
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treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn.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
BACKGROUND: In adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or cyclophosphamide-azathioprine), are unknown. METHODS: In a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial conducted at 107 sites in 21 countries, we assigned adults with biopsy-proven, active lupus nephritis in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. The primary end point at week 104 was a primary efficacy renal response (a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate [eGFR] that was no worse than 20% below the value before the renal flare (pre-flare value) or ≥60 ml per minute per 1.73 m2 of body-surface area, and no use of rescue therapy), and the major secondary end point was a complete renal response (a ratio of urinary protein to creatinine of <0.5, an eGFR that was no worse than 10% below the pre-flare value or ≥90 ml per minute per 1.73 m2, and no use of rescue therapy). The time to a renal-related event or death was assessed. RESULTS: A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval [CI], 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials. CONCLUSIONS: In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (Funded by GlaxoSmithKline; BLISS-LN ClinicalTrials.gov number, NCT01639339.).
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunosupresores/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Azatioprina/uso terapéutico , Creatinina/orina , Ciclofosfamida/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Inhibidores Enzimáticos/uso terapéutico , Femenino , Tasa de Filtración Glomerular , Humanos , Inmunosupresores/efectos adversos , Infusiones Intravenosas , Análisis de Intención de Tratar , Nefritis Lúpica/mortalidad , Masculino , Ácido Micofenólico/uso terapéutico , Inducción de RemisiónRESUMEN
The current treatment paradigm in lupus nephritis consists of an initial phase aimed at inducing remission and a subsequent remission maintenance phase. With this so-called sequential treatment approach, complete renal response is achieved in a disappointing proportion of 20-30% of the patients within 6-12 months, and 5-20% develop end-stage kidney disease within 10 years. Treat-to-target approaches are detained owing to uncertainty as to whether the target should be determined based on clinical, histopathological, or immunopathological features. Until reliable non-invasive biomarkers exist, tissue-based evaluation remains the gold standard, necessitating repeat kidney biopsies for treatment evaluation and therapeutic decision-making. In this viewpoint, we discuss the pros and cons of voclosporin and belimumab as add-on agents to standard therapy, the first drugs to be licenced for lupus nephritis after recent successful randomised phase III clinical trials. We also discuss the prospect of obinutuzumab and anifrolumab, also on top of standard immunosuppression, currently tested in phase III trials after initial auspicious signals. Undoubtably, the treatment landscape in lupus nephritis is changing, with combination treatment regimens challenging the sequential concept. Meanwhile, the enrichment of the treatment armamentarium shifts the need from lack of therapies to the challenge of how to select the right treatment for the right patient. This has to be addressed in biomarker surveys along with tissue-level mapping of inflammatory phenotypes, which will ultimately lead to person-centred therapeutic approaches. After many years of trial failures, we may now anticipate a heartening future for patients with lupus nephritis.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Inhibidores de la Calcineurina/uso terapéutico , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Antineoplásicos Inmunológicos/uso terapéutico , Quimioterapia Combinada , Humanos , Quimioterapia de Mantención , Medicina de Precisión , Inducción de RemisiónRESUMEN
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.
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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
In order to address the main challenges related to the rare diseases (RDs) the European Commission launched the European Reference Networks (ERNs), virtual networks involving healthcare providers (HCPs) across Europe. The mission of the ERNs is to tackle low prevalence and RDs that require highly specialised treatment and a concentration of knowledge and resources. In fact, ERNs offer the potential to give patients and healthcare professionals across the EU access to the best expertise and timely exchange of lifesaving knowledge, trying to make the knowledge travelling more than patients. For this reason, ERNs were established as concrete European infrastructures, and this is particularly crucial in the framework of rare and complex diseases in which no country alone has the whole knowledge and capacity to treat all types of patients.It has been five years since their kick-off launch in Vilnius in 2017. The 24 ERNs have been intensively working on different transversal areas, including patient management, education, clinical practice guidelines, patients' care pathways and many other fundamental topics. The present work is therefore aimed not only at reporting a summary of the main activities and milestones reached so far, but also at celebrating the first 5 years of the ERN on Rare and Complex Connective Tissue and Musculo-skeletal Diseases (ReCONNET), in which the members of the network built together one of the 24 infrastructures that are hopefully going to change the scenario of rare diseases across the EU.
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Enfermedades Musculoesqueléticas , Enfermedades Raras , Tejido Conectivo , Europa (Continente) , Personal de Salud , Humanos , Enfermedades Musculoesqueléticas/diagnóstico , Enfermedades Musculoesqueléticas/terapia , Enfermedades Raras/epidemiología , Enfermedades Raras/terapiaRESUMEN
ABSTRACT: Lupus nephritis (LN) affects about a third of patients with systemic lupus erythematosus. Although the use of conventional therapy has significantly improved the prognosis of LN, the response to treatment remains suboptimal, with high rates of relapse and the occurrence of end-stage kidney disease. The implementation of new diagnostic and treatment strategies aimed at improving these outcomes represents a necessary paradigm shift in the management of LN.Herein, we discuss different points of view regarding these still unresolved issues; these comments represent a debate that took place during the virtual congress of the Pan American League of Associations for Rheumatology (PANLAR) and which was organized by the PANLAR Lupus Study Group, GLADEL (Grupo Latino Americano De Estudio del Lupus) on August 15, 2021.
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Fallo Renal Crónico , Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/terapia , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/epidemiología , Nefritis Lúpica/terapia , PronósticoRESUMEN
BACKGROUND: Quality of care is receiving increased attention in systemic lupus erythematosus (SLE). We developed quality indicators (QIs) for SLE based on the 2019 update of European League Against Rheumatism recommendations. METHODS: A total of 44 candidate QIs corresponding to diagnosis, monitoring and treatment, were independently rated for validity and feasibility by 12 experts and analysed by a modified Research and Development Corporation/University of California Los Angeles model. Adherence to the final set of QIs and correlation with disease outcomes (flares, hospitalisations and organ damage) was tested in a cohort of 220 SLE patients with a median monitoring of 2 years (IQR 2-4). RESULTS: The panel selected a total of 18 QIs as valid and feasible. On average, SLE patients received 54% (95% CI 52.3% to 56.2%) of recommended care, with adherence ranging from 44.7% (95% CI 40.8% to 48.6%) for diagnosis-related QIs to 84.3% (95% CI 80.6% to 87.5%) for treatment-related QIs. Sustained remission or low disease activity were achieved in 26.8% (95% CI 21.1% to 33.2%). Tapering of prednisone dose to less than 7.5 mg/day was achieved in 93.6% (95% CI 88.2% to 97.0%) while 73.5% (95% CI 66.6% to 79.6%) received the recommended hydroxychloroquine dose. Higher adherence to monitoring-related QIs was associated with reduced risk for a composite adverse outcome (flare, hospitalisation or damage accrual) during the last year of observation (OR 0.97 per 1% adherence rate, 95% CI 0.96 to 0.99). CONCLUSION: We developed QIs for assessing and improving the care of SLE patients. Initial real-life data suggest face validity, but a variable degree of adherence and a need for further improvement.
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Lupus Eritematoso Sistémico/terapia , Indicadores de Calidad de la Atención de Salud , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antirreumáticos/administración & dosificación , Aspirina/uso terapéutico , Reducción Gradual de Medicamentos , Europa (Continente) , Femenino , Glucocorticoides/administración & dosificación , Adhesión a Directriz/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Humanos , Hidroxicloroquina/administración & dosificación , Inmunosupresores/uso terapéutico , Riñón/patología , Lupus Eritematoso Sistémico/diagnóstico , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/terapia , Masculino , Tamizaje Masivo , Osteoporosis/diagnóstico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Guías de Práctica Clínica como Asunto , Preeclampsia/prevención & control , Prednisona/administración & dosificación , Embarazo , Inducción de Remisión , Reproducibilidad de los Resultados , Medición de Riesgo , Sociedades Médicas , Brote de los SíntomasRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of the immunotherapeutic vaccine interferon-α kinoid (IFN-K) in a 36-week (W) phase IIb, randomised, double-blind, placebo (PBO)-controlled trial in adults with active systemic lupus erythematosus (SLE) despite standard of care. METHODS: Patients with SLE (185) with moderate to severe disease activity and positive interferon (IFN) gene signature were randomised to receive IFN-K or PBO intramuscular injections (days 0, 7 and 28 and W12 and W24). Coprimary endpoints at W36 were neutralisation of IFN gene signature and the BILAG-Based Composite Lupus Assessment (BICLA) modified by mandatory corticosteroid (CS) tapering. RESULTS: IFN-K induced neutralising anti-IFN-α2b serum antibodies in 91% of treated patients and reduced the IFN gene signature (p<0.0001). Modified BICLA responses at W36 did not statistically differ between IFN-K (41%) and PBO (34%). Trends on Systemic Lupus Erythematosus Responder Index-4, including steroid tapering at W36, favoured the IFN-K and became significant (p<0.05) in analyses restricted to patients who developed neutralising anti-IFN-α2b antibodies. Attainment of lupus low disease activity state (LLDAS) at W36 discriminated the two groups in favour of IFN-K (53% vs 30%, p=0.0022). A significant CS sparing effect of IFN-K was observed from W28 onwards, with a 24% prednisone daily dose reduction at W36 in IFN-K compared with PBO (p=0.0097). The safety profile of IFN-K was acceptable. CONCLUSIONS: IFN-K induced neutralising anti-IFN-α2b antibodies and significantly reduced the IFN gene signature with an acceptable safety profile. Although the clinical coprimary endpoint was not met, relevant secondary endpoints were achieved in the IFN-K group, including attainment of LLDAS and steroid tapering. TRIAL REGISTRATION NUMBER: NCT02665364.
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Factores Inmunológicos/administración & dosificación , Interferón-alfa/administración & dosificación , Lupus Eritematoso Sistémico/tratamiento farmacológico , Corticoesteroides/administración & dosificación , Adulto , Autoanticuerpos/sangre , Método Doble Ciego , Femenino , Humanos , Inyecciones Intramusculares , Interferón alfa-2 , Interferón-alfa/inmunología , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Privación de Tratamiento/estadística & datos numéricosRESUMEN
OBJECTIVE: To update the 2012 EULAR/ERA-EDTA recommendations for the management of lupus nephritis (LN). METHODS: Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements. RESULTS: The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5-0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2-3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3-0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin-angiotensin-aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease. CONCLUSIONS: We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.
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Inmunosupresores/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Sociedades Médicas , Antirreumáticos/uso terapéutico , Azatioprina/uso terapéutico , Inhibidores de la Calcineurina/uso terapéutico , Quimioterapia Combinada , Europa (Continente) , Tasa de Filtración Glomerular , Glucocorticoides/uso terapéutico , Humanos , Hidroxicloroquina/uso terapéutico , Fallo Renal Crónico/etiología , Fallo Renal Crónico/terapia , Nefritis Lúpica/complicaciones , Nefritis Lúpica/patología , Nefritis Lúpica/fisiopatología , Ácido Micofenólico/uso terapéutico , Proteinuria/etiología , Proteinuria/terapiaRESUMEN
RATIONALE & OBJECTIVE: Membranous nephropathy (MN) is characterized by the deposition of immune complexes along glomerular basement membranes. M-Type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), exostosin 1 and 2 (EXT1/2), and neural epidermal growth factor-like 1 protein (NELL-1) have been identified as established or potential podocyte antigens in MN. We investigated the association of podocyte antigen staining with MN clinical phenotype and outcomes. STUDY DESIGN: Multicenter retrospective cohort study. SETTING & PARTICIPANTS: 177 consecutive patients with MN unrelated to lupus erythematosus, identified after screening of 3,875 native kidney biopsies performed in the Belgian UCLouvain Kidney Disease Network from 2000 through 2018. PREDICTOR: Positive immunostaining for podocyte antigens on archived kidney biopsy samples. OUTCOMES: Association with different phenotypes (baseline characteristics of patients and pathologic findings on kidney biopsy), time to cancer and to kidney failure. ANALYTICAL APPROACH: Kaplan-Meier estimates and Cox regression analyses to assess time to cancer and kidney failure. RESULTS: 177 patients were followed up for a median of 4.0 (IQR, 1.3-8.0) years. Diagnosis of PLA2R-positive (PLA2R+), THSD7A+, and double-negative (PLA2R-/THSD7A-) MN was made in 117 (66.1%), 6 (3.4%), and 54 (30.5%) patients, respectively. Progression to kidney failure was similar in all groups. Although the number of patients with THSD7A+MN was small, they showed a higher incidence (50%) and increased risk for developing cancer during follow-up (adjusted HR, 5.0 [95% CI, 1.4-17.9]; P=0.01). 8% and 5% of patients with double-negative MN stained positively for EXT1/2 and NELL-1, respectively. Most patients with EXT1/2+MN were women, had features of systemic autoimmunity, and showed glomerular C1q deposits. LIMITATIONS: Retrospective design; small number of patients in the THSD7A group; lack of evaluation of immunoglobulin G subclasses deposition. CONCLUSIONS: Our real-world data describe the relative prevalence of subgroups of MN and support the hypothesis that a novel classification of MN based on podocyte antigen staining may be clinically relevant.
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Autoanticuerpos/inmunología , Glomerulonefritis Membranosa/inmunología , Podocitos/patología , Adulto , Anciano , Biopsia , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Glomerulonefritis Membranosa/patología , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Podocitos/inmunología , Estudios Retrospectivos , Coloración y Etiquetado/métodosRESUMEN
OBJECTIVES: In patients with LN, clinical and histological responses to treatment have been shown to be discordant. We investigated whether per-protocol repeat kidney biopsies are predictive of LN relapses and long-term renal function impairment. METHODS: Forty-two patients with incident biopsy-proven active proliferative (class III/IV±V) LN from the database of the UCLouvain were included in this retrospective study. Per-protocol repeat biopsies were performed after a median [interquartile range (IQR)] time of 24.3 (21.3-26.2) months. The National Institutes of Health activity index (AI) and chronicity index (CI) scores were assessed in all biopsies. RESULTS: Despite a moderate correlation between urinary protein/creatinine ratios (UPCR) and AI scores at repeat biopsy (r = 0.48; P = 0.001), 10 patients (23.8%) with UPCR < 1.0 g/g still had a high degree of histological activity (AI > 3). High AI scores (continuous) in repeat biopsies were associated with an increased probability and/or shorter time to renal relapse (n = 11) following the repeat biopsy [hazard ratio (HR) = 1.2, 95% CI: 1.1, 1.3; P = 0.007], independently of proteinuria levels. High CI scores (continuous) in repeat biopsies were associated with a sustained increase in serum creatinine levels corresponding to ≥120% of the baseline value (HR = 1.8, 95% CI: 1.1, 2.9; P = 0.016) through a median (IQR) follow-up time of 131.5 (73.8-178.2) months, being also the case for acute tubulointerstitial inflammation and interstitial fibrosis/tubular atrophy in repeat but not baseline biopsies. CONCLUSION: Our results highlight the usefulness of per-protocol repeat biopsies, herein performed after a median time of 24 months from baseline, as an integral part of the treatment evaluation, also in patients showing adequate clinical response.
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Riñón/patología , Nefritis Lúpica/patología , Adulto , Biopsia , Creatinina/orina , Ciclofosfamida/uso terapéutico , Progresión de la Enfermedad , Femenino , Glucocorticoides/uso terapéutico , Humanos , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Túbulos Renales/patología , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/orina , Masculino , Metilprednisolona/uso terapéutico , Ácido Micofenólico/uso terapéutico , Pronóstico , Modelos de Riesgos Proporcionales , Proteinuria/orina , Quimioterapia por Pulso , Recurrencia , Estudios Retrospectivos , Rituximab/uso terapéutico , Adulto JovenRESUMEN
OBJECTIVE: Type I IFNs play a well-known role in the pathogenesis of SLE, through activation of CD4 T and antigen-presenting cells. Here, we investigated the effects of IFN alpha (IFNα) on SLE B cell activation and differentiation. METHODS: Peripheral blood mononuclear cells (PBMCs) and purified total or naïve B cells were obtained from healthy controls and SLE patients. The effects of IFNα on B cell differentiation were studied by flow cytometry. The role of STAT3 in B cell responses to IFNα was studied using pharmacological inhibitors and PBMCs from STAT3-deficient individuals. RESULTS: Incubation of normal PBMCs with IFNα induces a B cell differentiation pattern as observed spontaneously in SLE PBMCs. IFNα displays direct stimulatory effects on purified naïve B cells from healthy individuals, as evidenced by a significant induction of cell surface CD38 and CD95 in the presence of the cytokine. In purified naïve B cells, IFNα also induces STAT3 phosphorylation. IFNα-induced naïve B cell differentiation in total PBMCs is significantly inhibited in the presence of STAT3 inhibitors, or in PBMCs from individuals with STAT3 loss of function mutations. Spontaneous levels of STAT3, but not STAT1, phosphorylation are significantly higher in total B cells from SLE patients compared with controls. Pharmacological STAT3 inhibition in SLE PBMCs inhibits naïve B cell activation and differentiation. CONCLUSION: IFNα displays direct stimulatory effects on B cell differentiation and activation in SLE. STAT3 phosphorylation mediates the effects of IFNα stimulation in naïve B cells, an observation that opens new therapeutic perspectives in SLE.
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Linfocitos B/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Interferón-alfa/farmacología , Lupus Eritematoso Sistémico/metabolismo , Factor de Transcripción STAT3/metabolismo , Linfocitos B/metabolismo , Citocinas/metabolismo , Citometría de Flujo , Humanos , Activación de Linfocitos/efectos de los fármacos , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVES: To compare the ability of the Disease Activity Score (DAS) and the Revised EUSTAR Activity Index (RAI) to detect diffuse cutaneous systemic sclerosis (dcSSc) patients requiring treatment intensification in a Belgian cohort. METHODS: We retrospectively compared the widely used DAS and the recently developed RAI in a longitudinal cohort (median follow-up of 42 months) of 62 dcSSc patients, of whom 30 with a disease duration ≤3 years at inclusion. Active disease was defined by a DAS ≥3/10 or a RAI ≥2.5/10. We chose a pragmatic definition to assess disease progression, namely any start or increase of glucocorticoids, immunosuppressants, anti-endothelin receptors or prostanoids. Sensitivity, specificity, negative and positive predictive values (NPV and PPV) of DAS and RAI for prediction of actual treatment changes were compared by ROC curves. RESULTS: According to RAI, 48% (of all dcSSc patients) and 55% (of ≤3 years dcSSc patients) were categorised as effectively active during follow-up while 34% and 43% according to DAS, respectively. The PPV and the NPV to detect disease progression, in ≤3 years dcSSc patients, were 59% and 89% for RAI vs 73% and 87% for DAS, respectively. The area under ROC curves were high for both scores (0.85 for RAI and 0.87 for DAS). CONCLUSIONS: Both scores are proven as predictive to detect disease activity, with a slightly better sensitivity for RAI. By contrast, RAI lacks specificity in predicting a real need for treatment intensification, thereby possibly leading to overtreatment.
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Esclerodermia Difusa , Esclerodermia Sistémica , Bélgica , Estudios de Cohortes , Humanos , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVES: TLR3 mediates skin solar injury by binding nuclear material released from apoptotic keratinocytes, resulting in the production of pro-inflammatory cytokines. Because the TLR3 gene is located in 4q35, a known systemic lupus erythematosus (SLE) susceptibility locus, we wondered whether TLR3 single nucleotide polymorphisms (SNPs) were associated with inflammatory mechanisms relevant to the development of SLE, and disease susceptibility. METHODS: Functional assays were carried out in TLR3-transfected HEK293 cells and in monocyte-derived dendritic cells (moDCs). TLR3 and IFNß immunofluorescence studies were performed in skin samples from 7 SLE patients and 3 controls. We performed a SNP association study in a discovery cohort of 153 patients and 105 controls, followed by a confirmation study in an independent cohort of 1,380 patients and 2,104 controls. RESULTS: TLR3 and IFNß are overexpressed in SLE skin lesions. TLR3 overexpression in HEK293 cells amplifies their sensitivity to a pro-apoptotic stimulus. Taking advantage of a naturally occurring polymorphic TLR3 variant (rs3775291) that weakly versus strongly responds to poly I:C stimulation, we found that TLR3 is associated with amplified apoptotic responses, production of the Ro/SSA autoantigen and increased maturation of myeloid-derived dendritic cells (moDC) after exposure to UV irradiation. However, TLR3 SNPs are not associated with susceptibility to SLE in a large population of patients and controls. CONCLUSIONS: TLR3 is overexpressed in SLE skin lesions and amplifies apoptotic and inflammatory responses to UV-irradiation in antigen-presenting cells in vitro. However, TLR3 SNPs do not impact susceptibility to the development of the disease.
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Lupus Eritematoso Sistémico , Receptor Toll-Like 3 , Células Presentadoras de Antígenos , Apoptosis , Predisposición Genética a la Enfermedad , Células HEK293 , Humanos , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 3/genéticaRESUMEN
Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007-12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.
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Lupus Eritematoso Sistémico/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Comorbilidad , Manejo de la Enfermedad , Medicina Basada en la Evidencia/métodos , Glucocorticoides/uso terapéutico , Humanos , Hidroxicloroquina/uso terapéutico , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/complicaciones , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Ubiquitination of proteins leads to their degradation by the proteasome, and is regulated by ubiquitin ligases and substrate-specific ubiquitin-specific peptidases (USPs). The ubiquitination process also plays important roles in the regulation of cell metabolism and cell cycle. Here, we found that the expression of several USPs is increased in SSc tenosynovial and skin biopsies, and we demonstrated that USP inhibition decreases TGF-ß signalling in primary fibroblast cell lines. METHODS: High-density transcriptomic studies were performed using total RNA obtained from SSc tenosynovial samples. Confirmatory immunostaining experiments were performed on tenosynovial and skin samples. In vitro experiments were conducted in order to study the influence of USP modulation on responses to TGF-ß stimulation. RESULTS: Tenosynovial biopsies from SSc patients overexpressed known disease-associated gene pathways: fibrosis, cytokines and chemokines, and Wnt/TGF-ß signalling, but also several USPs. Immunohistochemistry experiments confirmed the detection of USPs in the same samples, and in SSc skin biopsies. Exposure of primary fibroblast cell lines to TGF-ß induced USP gene expression. The use of a pan-USP inhibitor decreased SMAD3 phosphorylation, and expression of COL1A1, COL3A1 and fibronectin gene expression in TGF-ß-stimulated fibroblasts. The effect of the USP inhibitor resulted in increased SMAD3 ubiquitination, and was blocked by a proteasome inhibitor, thereby confirming the specificity of its action. CONCLUSION: Overexpression of several USPs, including USP15, amplifies fibrotic responses induced by TGF-ß, and is a potential therapeutic target in SSc.
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Fibroblastos/metabolismo , Esclerodermia Sistémica/enzimología , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Proteasas Ubiquitina-Específicas/metabolismo , Humanos , Esclerodermia Sistémica/tratamiento farmacológicoRESUMEN
OBJECTIVES: Chronic renal impairment remains a feared complication of lupus nephritis (LN). The present work aimed at identifying mechanisms and markers of disease severity in renal tissue samples from patients with LN. METHODS: We performed high-throughput transcriptomic studies (Illumina HumanHT-12 v4 Expression BeadChip) on archived kidney biopsies from 32 patients with LN and eight controls (pretransplant donors). Histological staging (glomerular and tubular scores) and immunohistochemistry experiments were performed on the same and on a replication set of 37 LN kidney biopsy samples. RESULTS: A group of LN samples was identified by unsupervised clustering studies based on their gene expression features, that is, the overexpression of transcripts involved in antigen presentation, T and B cell activation. These samples were characterised by a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (T0) compared with the other systemic lupus erythematosus samples. Yet, apparent disease duration at T0, double-stranded DNA antibody titres at T0 and other relevant characteristics (serum C3, proteinuria, histological scores, numbers of previous flares) were not different between groups.Immunohistochemistry studies confirmed the association between interstitial infiltration by adaptive immune effectors and decreased renal function in the same and in a replication group of LN kidney biopsies. This was associated with transcriptomic, histological and immunohistochemical evidence of renal tubular cell involvement. CONCLUSION: Interstitial infiltration of LN kidney biopsies by adaptive immune effectors is associated with impaired renal tubular cell function and decreased eGFR. These results open new perspectives in evaluating and treating patients with LN, focusing on intrarenal mechanisms of immune cell activation.
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Nefritis Lúpica/inmunología , Nefritis Lúpica/patología , Adulto , Femenino , Humanos , Túbulos Renales/patología , Masculino , Insuficiencia Renal/inmunología , Insuficiencia Renal/patología , TranscriptomaRESUMEN
PURPOSE: To compare the diagnostic accuracy of DWI and STIR sequences in Whole body (WB) MRI of SpA patients. MATERIALS AND METHODS: Twenty consecutive patients with confirmed active SpA and 20 controls were investigated with identical WB MRI protocols, including DWI and STIR images. Two observers recorded 'lesions' (high signal intensity foci on STIR and high b-value DWI) in 17 anatomical areas, making a 17-point 'area score' and a 40-point 'lesion score'. ROC performance, inter-observer agreement, correlation with clinical parameters and spine and sacro-iliac joints (SIJ) MRI scores were assessed. RESULTS: SpA patients had significantly higher lesion scores on DWI than on STIR (p<0.025). The lesion score area under the curve was significantly higher with DWI (99.9) than with STIR (95.8, p=0.02). DWI lesion score ≥5 had both sensitivity and specificity ≥85 %. With STIR the best threshold ≥3 yielded sensitivity ≥85 % and specificity ≥60 %. DWI area score ≥3 yielded sensitivity ≥85 % and specificity ≥80 %. With STIR the best threshold ≥4 yielded sensitivity ≥70 % and specificity ≥80 %. Inter-observer agreement was strong for both sequences. In patients, the lesion score was positively correlated with ASDAS-CRP, log(CRP), and local MRI scores. CONCLUSIONS: DWI is a promising alternative to STIR in WB MRI to detect active SpA lesions. KEY POINTS: ⢠DWI is a robust alternative to STIR in WBMRI in SpA. ⢠DWI might be superior in discriminating relevant inflammatory and degenerative changes. ⢠Positive correlations exist between WB MRI, clinical, biological, local MRI data. ⢠Distribution and frequency of abnormal MRI findings in SpA are highlighted.
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Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Espondiloartritis/diagnóstico por imagen , Imagen de Cuerpo Entero/métodos , Adulto , Anciano , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Articulación Sacroiliaca/diagnóstico por imagen , Articulación Sacroiliaca/patología , Sensibilidad y Especificidad , Columna Vertebral/diagnóstico por imagen , Columna Vertebral/patología , Adulto JovenRESUMEN
OBJECTIVES: Treat-to-target recommendations have identified 'remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE. METHODS: An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%. RESULTS: The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by . (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5â mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life. CONCLUSIONS: The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.