Precise Targeting of Autoantigen-Specific B Cells in Lupus Nephritis with Chimeric Autoantibody Receptor T Cells.

Despite conventional therapy, lupus nephritis (LN) remains a significant contributor to short- and long-term morbidity and mortality. B cell abnormalities and the production of autoantibodies against nuclear complexes like anti-dsDNA are recognised as key players in the pathogenesis of LN. To address the challenges of chronic immunosuppression associated with current therapies, we have engineered T cells to express chimeric autoantibody receptors (DNA-CAART) for the precise targeting of B cells expressing anti-dsDNA autoantibodies. T cells from LN patients were transduced using six different CAAR vectors based on their antigen specificity, including alpha-actinin, histone-1, heparan sulphate, or C1q. The cytotoxicity, cytokine production, and cell-cell contact of DNA-CAART were thoroughly investigated in co-culture experiments with B cells isolated from patients, both with and without anti-dsDNA positivity. The therapeutic effects were further evaluated using an in vitro immune kidney LN organoid. Among the six proposed DNA-CAART, DNA4 and DNA6 demonstrated superior selectively cytotoxic activity against anti-dsDNA+ B cells. Notably, DNA4-CAART exhibited improvements in organoid morphology, apoptosis, and the inflammatory process in the presence of IFNα-stimulated anti-dsDNA+ B cells. Based on these findings, DNA4-CAART emerge as promising candidates for modulating autoimmunity and represent a novel approach for the treatment of LN.

Satisfaction and effectiveness of switching from intravenous to subcutaneous belimumab treatment in daily clinical practice.

BACKGROUND: In 2017, belimumab (BEL) was approved in subcutaneous (SQ) administration. The effectiveness after switching from intravenous (IV) to SQ and patient satisfaction in daily clinical practice has not been studied. During the pandemic, patient follow-up and treatment were significantly affected, and some patients need a change from IV to SQ. Our aim was to evaluate daily clinical practice satisfaction to SQ BEL therapy in patients previously treated IV BEL. We hypothesized that SQ BEL in SLE patients previously treated with IV BEL was similar in effectiveness and conferred higher satisfaction. METHODS: Observational, multicenter study, conducted in 7 reference centers in Catalonia. We included stable SLE patients (EULAR/ACR 2019) on treatment with SQ BEL and previous use of IV BEL (at least 3 months on IV BEL before switching). Since there are no well-validated tools for SQ BEL treatment satisfaction, we used RASQ-SQ, validated in patients with lymphoma who switched from IV Rituximab to SQ treatment, and modified for BEL treatment. RESULTS: Twenty-seven patients were included. The more prevalent clinical manifestations observed were related to the skin and joints and the patients had a mean baseline SLEDAI of 2.96 (SD 2.4) and SLICC score of 0.67 (SD 0.88). The median time from treatment with IV BEL before switching to SQ was 21 months (range). 84% of patients reported confidence in SQ BEL. 85.2% felt that treatment with SQ BEL was convenient or very convenient. 85% felt they had gained time with the change. 89% would recommend the SQ injection to other patients. Disease activity (mean SLEDAI) and remission rates remain stable after switching. No major new adverse effects were reported. CONCLUSIONS: Overall satisfaction, satisfaction with via of administration, and satisfaction with the time taken to receive BEL were higher for SQ BEL treatment. A switching SQ strategy is a reasonable alternative for BEL patients.

Thorough assessment of the effectiveness of belimumab in a large Spanish multicenter cohort of systemic lupus erythematosus patients.

OBJECTIVES: To provide an overview on the current use of belimumab (BLM) in SLE patients in clinical practice and to examine its efficacy in terms of standardized outcomes, drug survival, as well as patient and safety profiles. METHODS: A longitudinal retrospective multicentre cohort including SLE patients treated with BLM at 18 Spanish centers. Data was collected upon initiation of BLM, at 6 and 12 months after initiation, and at the last recorded visit. Changes in SLEDAI-2K, the proportion of patients who achieved LLDAS and DORIS 2021, and number of flares were compared between visits. Changes in damage, glucocorticoids use and employment status pre-BLM and post-BLM were also assessed. RESULTS: A total of 324 patients were included with a mean follow-up of 3.8 (±2.7) years. LLDAS was attained by 45.8%, 62% and 71% of patients, and DORIS by 24%, 36.2% and 52.5% on successive visits, respectively. Twenty-seven-point two percent of patients were in DORIS ≥ 50% of the visits and a 46% in LLDAS-50. Flares and number of flares were significantly lower one year after treatment with BLM and no changes in damage accrual were observed. Mean (±SD) prednisone dose was significantly reduced over time, with 70 (24%) patients discontinuing GC. CONCLUSION: Our study not only demonstrates belimumab´s efficacy in attaining treat-to-target goals in SLE patients, but also confirms its GC-sparing effect, and its prevention of flares and organ damage accrual.

Disease activity drives divergent epigenetic and transcriptomic reprogramming of monocyte subpopulations in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is characterised by systemic inflammation involving various immune cell types. Monocytes, pivotal in promoting and regulating inflammation in SLE, differentiate from classic monocytes into intermediate and non-classic monocytes, assuming diverse roles and changing their proportions in inflammation. In this study, we investigated the epigenetic and transcriptomic profiles of these and novel monocyte subsets in SLE in relation to activity and progression. METHODS: We obtained the DNA methylomes and transcriptomes of classic, intermediate, non-classic monocytes in patients with SLE (at first and follow-up visits) and healthy donors. We integrated these data with single-cell transcriptomics of SLE and healthy donors and interrogated their relationships with activity and progression. RESULTS: In addition to shared DNA methylation and transcriptomic alterations associated with a strong interferon signature, we identified monocyte subset-specific alterations, especially in DNA methylation, which reflect an impact of SLE on monocyte differentiation. SLE classic monocytes exhibited a proinflammatory profile and were primed for macrophage differentiation. SLE non-classic monocytes displayed a T cell differentiation-related phenotype, with Th17-regulating features. Changes in monocyte proportions, DNA methylation and expression occurred in relation to disease activity and involved the STAT pathway. Integration of bulk with single-cell RNA sequencing datasets revealed disease activity-dependent expansion of SLE-specific monocyte subsets, further supported the interferon signature for classic monocytes, and associated intermediate and non-classic populations with exacerbated complement activation. CONCLUSIONS: Disease activity in SLE drives a subversion of the epigenome and transcriptome programme in monocyte differentiation, impacting the function of different subsets and allowing to generate predictive methods for activity and progression.

VPS8D, a CORVET subunit, is required to maintain the contractile vacuole complex in Tetrahymena thermophila.

Contractile vacuole complexes (CVCs) are complex osmoregulatory organelles, with vesicular (bladder) and tubular (spongiome) subcompartments. The mechanisms that underlie their formation and maintenance within the eukaryotic endomembrane network are poorly understood. In the Ciliate Tetrahymena thermophila, six differentiated CORVETs (class C core vacuole/endosome tethering complexes), with Vps8 subunits designated A-F, are likely to direct endosomal trafficking. Vps8Dp localizes to both bladder and spongiome. We show by inducible knockdown that VPS8D is essential to CVC organization and function. VPS8D knockdown increased susceptibility to osmotic shock, tolerated in the wildtype but triggering irreversible lethal swelling in the mutant. The knockdown rapidly triggered contraction of the spongiome and lengthened the period of the bladder contractile cycle. More prolonged knockdown resulted in disassembly of both the spongiome and bladder, and dispersal of proteins associated with those compartments. In stressed cells where the normally singular bladder is replaced by numerous vesicles bearing bladder markers, Vps8Dp concentrated conspicuously at long-lived inter-vesicle contact sites, consistent with tethering activity. Similarly, Vps8Dp in cell-free preparations accumulated at junctions formed after vacuoles came into close contact. Also consistent with roles for Vps8Dp in tethering and/or fusion were the emergence in knockdown cells of multiple vacuole-related structures, replacing the single bladder.

Small-Extracellular-Vesicle-Derived miRNA Profile Identifies miR-483-3p and miR-326 as Regulators in the Pathogenesis of Antiphospholipid Syndrome (APS).

Primary antiphospholipid syndrome (PAPS) is a systemic autoimmune disease associated with recurrent thrombosis and/or obstetric morbidity with persistent antiphospholipid antibodies (aPL). Although these antibodies drive endothelial injury and thrombophilia, the underlying molecular mechanism is still unclear. Small extracellular vesicles (sEVs) contain miRNAs, key players in intercellular communication. To date, the effects of miRNA-derived sEVs in PAPS are not well understood. We characterised the quantity, cellular origin and miRNA profile of sEVs isolated from thrombotic APS patients (PAPS, n = 50), aPL-carrier patients (aPL, n = 30) and healthy donors (HD, n = 30). We found higher circulating sEVs mainly of activated platelet origin in PAPS and aPL patients compared to HD, that were highly engulfed by HUVECs and monocyte. Through miRNA-sequencing analysis, we identified miR-483-3p to be differentially upregulated in sEVs from patients with PAPS and aPL, and miR-326 to be downregulated only in PAPS sEVs. In vitro studies showed that miR-483-3p overexpression in endothelial cells induced an upregulation of the PI3K-AKT pathway that led to endothelial proliferation/dysfunction. MiR-326 downregulation induced NOTCH pathway activation in monocytes with the upregulation of NFKB1, tissue factor and cytokine production. These results provide evidence that miRNA-derived sEVs contribute to APS pathogenesis by producing endothelial cell proliferation, monocyte activation and adhesion/procoagulant factors.

Reduction of disease activity, corticosteroids use, and healthcare resource utilisation in patients with systemic lupus erythematosus treated with belimumab in clinical practice settings: OBSErve Spain multicentre study.

INTRODUCTION AND OBJECTIVES: This OBSErve Spain study, a part of the international OBSErve programme, evaluated belimumab real-world use and effectiveness following 6 months of treatment in patients with active systemic lupus erythematosus (SLE) in clinical practice in Spain. MATERIALS AND METHODS: In this retrospective, observational study (GSK Study 200883), eligible patients with SLE receiving intravenous belimumab (10mg/kg) had their disease activity (physician assessed), SELENA-SLEDAI scores, corticosteroid use, and healthcare resource utilisation (HCRU), assessed after 6 months of treatment versus index (belimumab initiation) or 6 months pre-index. RESULTS: Overall, 64 patients initiated belimumab, mainly due to ineffectiveness of previous treatments (78.1%) and to reduce corticosteroid use (57.8%). Following 6 months of treatment, 73.4% of patients achieved ≥20% overall clinical improvement, while only 3.1% of patients worsened. Mean (standard deviation, SD) SELENA-SLEDAI score decreased from 10.1 (6.2) at index to 4.5 (3.7) 6 months post-index. HCRU decreased from 6 months pre-index to 6 months post-index, with fewer hospitalisations (10.9% vs 4.7% patients) and ER visits (23.4% vs 9.4% patients). Mean (SD) corticosteroid dose decreased from 14.5 (12.5)mg/day at index to 6.4 (5.1)mg/day 6 months post-index. CONCLUSIONS: Patients with SLE receiving belimumab for 6 months in real-world clinical practice in Spain experienced clinical improvements and a reduction in HCRU and corticosteroid dose.

Hipertermia maligna / Malignant hyperthermia

Resumen: La hipertermia maligna es un raro desorden farmacogenético potencialmente mortal, que se presenta como una respuesta hipermetabólica a los anestésicos volátiles y relajantes musculares despolarizantes en individuos susceptibles. Esta susceptibilidad se asocia a mutaciones en tres genes: RYR1, CACNA1S y STAC3. Puede manifestarse con síntomas leves o como una crisis fulminante, con rabdomiólisis severa, fibrilación ventricular e insuficiencia renal y circulatoria aguda, por lo tanto, el pronóstico depende de qué tan pronto se sospeche del diagnóstico y qué tan rápido se inicie el tratamiento. El diagnóstico definitivo se basa en una prueba de sensibilidad en biopsia muscular fresca y en pruebas genéticas. La mejor manera de prevenir un evento es la detección precoz de los pacientes susceptibles así como contar con el equipo para responder ante una crisis en cada centro donde se administren anestésicos volátiles y la capacitación del personal. Esta revisión sintetiza los conceptos actuales clínicos y biomédicos para detección, prevención, diagnóstico y manejo de la hipertermia maligna.

Abstract: Malignant hyperthermia is a rare, life-threatening pharmacogenetic disorder which presents as a hypermetabolic response to volatile anesthetics and depolarizing muscle relaxants in susceptible individuals. This susceptibility is associated with mutations in three genes: RYR1, CACNA1S and STAC3. Can manifest with mild symptoms or as a fulminant crisis, with severe rhabdomyolysis, ventricular fibrillation and acute renal and circulatory failure, therefore the prognosis depends on how soon the diagnosis is suspected and how fast treatment is started. The definitive diagnosis is based on a fresh muscle biopsy sensitivity test and genetic testing. The best way to prevent an event is the early detection of susceptible, as well as have equipment to respond to a crisis in each center where volatile anesthetics are administered and the training of staff. This review synthesizes current clinical and biomedical concepts for detection, prevention, diagnosis and management of malignant hyperthermia.

Downregulation of miR-885-5p Promotes NF-κB Pathway Activation and Immune Recruitment in Cutaneous Lupus Erythematosus.

Cutaneous lupus erythematosus (CLE) has a specific microRNA expression profile. MiR-885-5p has been found to be downregulated in the epidermis of CLE lesions; however, its biological role in the disease has not been studied. In this study, we show that miR-885-5p is markedly reduced in CLE keratinocytes (KCs) with IFN-α and UVB being strong miR-885-5p regulators in vitro. Microarray expression profiling of anti‒miR-885-5p‒transfected KCs identified PSMB5 as a direct target. Specific inhibition of miR-885-5p increased epidermal proliferation by modulating keratin 16 gene K16, BIRC5, TP63, and CDK4 proliferative genes and promoted NF-κB signaling pathway in human primary KCs by increasing IκBα degradation. Silencing PSMB5 rescued the effect of miR-885-5p inhibition, indicating that miR-885-5p regulates proliferation and NF-κB activation by targeting PSMB5 in KCs. In addition, inhibition of miR-885-5p increased the ability of KCs to attract leukocytes in a PSMB5-independent manner. We identified TRAF1 as another direct target, and its silencing reduced leukocyte migration. Collectively, our findings suggest that UVB and IFN-ɑ downregulate miR-885-5p in CLE KCs, leading to epidermal inflammation by NF-κB activity enhancement and proliferation through PSMB5 and immune recruitment through TRAF1. Our data indicate that miR-885-5p is a potential therapeutic target in CLE.

Direct Oral Anticoagulants vs Vitamin K Antagonists in Patients With Antiphospholipid Syndromes: Meta-Analysis of Randomized Trials.

BACKGROUND: The efficacy and safety of direct oral anticoagulants (DOACs) for patients with thrombotic antiphospholipid syndrome remain controversial. OBJECTIVES: The authors performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists (VKAs). METHODS: We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials through April 9, 2022. The 2 main efficacy outcomes were a composite of arterial thrombotic events and venous thromboembolic events (VTEs). The main safety outcome was major bleeding. Random effects models with inverse variance were used. RESULTS: Our search retrieved 253 studies. Four open-label randomized controlled trials involving 472 patients were included (mean control-arm time-in-therapeutic-range 60%). All had proper random sequence generation and adequate allocation concealment. Overall, the use of DOACs compared with VKAs was associated with increased odds of subsequent arterial thrombotic events (OR: 5.43; 95% CI: 1.87-15.75; P < 0.001, I2 = 0%), especially stroke, and the composite of arterial thrombotic events or VTE (OR: 4.46; 95% CI: 1.12-17.84; P = 0.03, I2 = 0%). The odds of subsequent VTE (OR: 1.20; 95% CI: 0.31-4.55; P = 0.79, I2 = 0%), or major bleeding (OR: 1.02; 95% CI: 0.42-2.47; P = 0.97; I2 = 0%) were not significantly different between the 2 groups. Most findings were consistent within subgroups. CONCLUSIONS: Patients with thrombotic antiphospholipid syndrome randomized to DOACs compared with VKAs appear to have increased risk for arterial thrombosis. No significant differences were observed between patients randomized to DOACs vs VKAs in the risk of subsequent VTE or major bleeding.

Anafilaxia perioperatoria en el paciente pediátrico / Perioperative anaphylaxis in the pediatric patient

Resumen: Debido a la naturaleza de las reacciones alérgicas y a las dificultades en su diagnóstico en el entorno quirúrgico, hay pocas publicaciones sobre anafilaxia en la infancia y pese a ser adecuadamente investigadas, sólo una pequeña parte puede ser confirmada. Los agentes etiológicos principalmente relacionados con esta entidad en el período perioperatorio son los bloqueadores neuromusculares, el látex y los antibióticos. El diagnóstico puede ser complicado y si no se reconoce a tiempo, el tratamiento se retrasa o no se administra de manera adecuada, con consecuencias fatales. A continuación se hace una revisión de la literatura de la anafilaxia perioperatoria, entidad que permanece subestimada, poco reportada y con ello, también su diagnóstico y oportuno tratamiento.

Abstract: Due to the nature of allergic reactions and the difficulties in their diagnosis in the surgical setting, there are few publications on anaphylaxis in childhood and, when properly investigated, only a small part can be confirmed. The etiological agents mainly related to this entity in the perioperative period are neuromuscular blockers, latex and antibiotics. The diagnosis can be complicated and if it is not recognized in time, treatment is delayed or not administered properly, with fatal consequences. The following is a review of the literature on perioperative anaphylaxis, an entity that remains underestimated, underreported and thus also its diagnosis and timely treatment.

Humoral and cellular response in convalescent COVID-19 lupus patients.

In SLE, underlying immune dysregulation and immunosuppression may increase the susceptibility to COVID-19 and impair the humoral and adaptive response. We aimed to characterize COVID-19 infection, identifying susceptibility and severity risk factors, assessing the presence of SARS-CoV-2 IgG antibodies and analyzing the cellular response. We established a prospective cohort of lupus patients to estimate the COVID-19 incidence compared to the reference general population. Data were collected via telephone interviews and medical record review. SARS-CoV-2 IgG antibodies were measured cross-sectionally as part of routine surveillance. Longitudinal changes in antibody titers and immunological profile from convalescent COVID-19 patients were evaluated at 6, 12 and 24 week after symptom onset. From immunological studies, PBMCs from convalescent patients were extracted and analyzed by flow cytometry and gene expression analysis. We included 725 patients, identifying 29 with PCR-confirmed COVID-19 infection and 16 with COVID-19-like symptoms without PCR-testing. Of the 29 confirmed cases, 7 had severe disease, 8 required hospital admission (27.6%), 4 intensive care, and 1 died. COVID-19 accumulated incidence was higher in lupus patients. Health care workers and anti-SSA/Ro52 antibody positivity were risk factors for COVID-19 susceptibility, and hypocomplementemia for severity. SARS-CoV-2 IgG antibodies were detected in 8.33% of patients. Three fourths of confirmed COVID-19 cases developed antibodies. High prednisone doses were associated with lack of antibody response. Antibody titers declined over time (39%). Convalescent patients at week 12 after symptom onset displayed a CD8+T cell reduction and predominant Th17 with a mild Th2 response, more pronounced in severe COVID-19 disease. Longitudinal immune response analysis showed a progressive sustained increase in CD8+ T and B memory cells with a decrease of Th17 signaling. Lupus patients are at higher risk of COVID-19 infection and new susceptibility and severity risk factors were identified. Lupus patients were able to mount humoral and cellular responses despite immunosuppressive therapy.

Preventing organ damage in systemic lupus erythematosus: the impact of early biological treatment.

INTRODUCTION: One of the most important aims in the management of systemic lupus erythematosus (SLE) is to avoid or delay the accumulation of organ damage. The first five years after diagnosis are crucial for prognosis. AREAS COVERED: This manuscript reviews available data on organ damage accrual in SLE and early therapeutic intervention as a possible strategy to prevent its long-term accrual. EXPERT OPINION: Organ damage can be minimized by controlling disease activity and risk of flares, reducing the dose of glucocorticoids, and ensuring a proper therapeutic intervention with an early introduction of the right therapies. The current standard treatment cannot provide clinical remission in all patients with SLE. Therefore, there is a clinical need for introducing new therapeutic strategies able to achieve the main therapeutic objectives. The addition of biologic and other therapeutic agents to the standard of care is effective for controlling disease activity and for preventing severe flares, enabling a reduced use of glucocorticoids, and presumably reducing organ damage progression. Considering its efficacy and safety, early inclusion of biologic agents in the first lines of the treatment algorithm, at least in certain patients, could be considered as an innovative treatment approach to decrease disease burden in SLE patients.

What can we learn from DNA methylation studies in lupus?

During the past twenty years, a wide range of studies have established the existence of epigenetic alterations, particularly DNA methylation changes, in lupus. Epigenetic changes might have different contributions in children-onset versus adult-onset lupus. DNA methylation alterations have been identified and characterized in relation to disease activity and damage, different lupus subtypes and responses to drugs. However, to date there has been no practical application of these findings in the clinical milieu. In this article, we provide a review of key studies showing the relationship between DNA methylation and the many clinical aspects related to lupus. We also propose several options, in relation to the range of methodological developments and experimental design, that could optimize these findings and make them amenable for use in clinical practice.

Thalidomide Exerts Anti-Inflammatory Effects in Cutaneous Lupus by Inhibiting the IRF4/NF-Ò¡B and AMPK1/mTOR Pathways.

Thalidomide is effective in patients with refractory cutaneous lupus erythematosus (CLE). However, the mechanism of action is not completely understood, and its use is limited by its potential, severe side-effects. Immune cell subset analysis in thalidomide's CLE responder patients showed a reduction of circulating and tissue cytotoxic T-cells with an increase of iNKT cells and a shift towards a Th2 response. We conducted an RNA-sequencing study using CLE skin biopsies performing a Therapeutic Performance Mapping System (TMPS) analysis in order to generate a predictive model of its mechanism of action and to identify new potential therapeutic targets. Integrating RNA-seq data, public databases, and literature, TMPS analysis generated mathematical models which predicted that thalidomide acts via two CRBN-CRL4A- (CRL4CRBN) dependent pathways: IRF4/NF-Ò¡B and AMPK1/mTOR. Skin biopsies showed a significant reduction of IRF4 and mTOR in post-treatment samples by immunofluorescence. In vitro experiments confirmed the effect of thalidomide downregulating IRF4 in PBMCs and mTOR in keratinocytes, which converged in an NF-Ò¡B reduction that led to a resolution of the inflammatory lesion. These results emphasize the anti-inflammatory role of thalidomide in CLE treatment, providing novel molecular targets for the development of new therapies that could avoid thalidomide's side effects while maintaining its efficacy.

Phagocytic and pinocytic uptake of cholesterol in Tetrahymena thermophila impact differently on gene regulation for sterol homeostasis.

The ciliate Tetrahymena thermophila can either synthesize tetrahymanol or when available, assimilate and modify sterols from its diet. This metabolic shift is mainly driven by transcriptional regulation of genes for tetrahymanol synthesis (TS) and sterol bioconversion (SB). The mechanistic details of sterol uptake, intracellular trafficking and the associated gene expression changes are unknown. By following cholesterol incorporation over time in a conditional phagocytosis-deficient mutant, we found that although phagocytosis is the main sterol intake route, a secondary endocytic pathway exists. Different expression patterns for TS and SB genes were associated with these entry mechanisms. Squalene synthase was down-regulated by a massive cholesterol intake only attainable by phagocytosis-proficient cells, whereas C22-sterol desaturase required ten times less cholesterol and was up-regulated in both wild-type and mutant cells. These patterns are suggestive of at least two different signaling pathways. Sterol trafficking beyond phagosomes and esterification was impaired by the NPC1 inhibitor U18666A. NPC1 is a protein that mediates cholesterol export from late endosomes/lysosomes in mammalian cells. U18666A also produced a delay in the transcriptional response to cholesterol, suggesting that the regulatory signals are triggered between lysosomes and the endoplasmic reticulum. These findings could hint at partial conservation of sterol homeostasis between eukaryote lineages.

MicroRNAs in Several Cutaneous Autoimmune Diseases: Psoriasis, Cutaneous Lupus Erythematosus and Atopic Dermatitis.

MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that regulate the gene expression at a post-transcriptional level and participate in maintaining the correct cell homeostasis and functioning. Different specific profiles have been identified in lesional skin from autoimmune cutaneous diseases, and their deregulation cause aberrant control of biological pathways, contributing to pathogenic conditions. Detailed knowledge of microRNA-affected pathways is of crucial importance for understating their role in skin autoimmune diseases. They may be promising therapeutic targets with novel clinical implications. They are not only present in skin tissue, but they have also been found in other biological fluids, such as serum, plasma and urine from patients, and therefore, they are potential biomarkers for the diagnosis, prognosis and response to treatment. In this review, we discuss the current understanding of the role of described miRNAs in several cutaneous autoimmune diseases: psoriasis (Ps, 33 miRNAs), cutaneous lupus erythematosus (CLE, 2 miRNAs) and atopic dermatitis (AD, 8 miRNAs). We highlight their role as crucial elements implicated in disease pathogenesis and their applicability as biomarkers and as a novel therapeutic approach in the management of skin inflammatory diseases.

Real-World Effectiveness of Belimumab in the Treatment of Systemic Lupus Erythematosus: Pooled Analysis of Multi-Country Data from the OBSErve Studies.

INTRODUCTION: The real-world effectiveness of belimumab for systemic lupus erythematosus (SLE) in six countries was evaluated in the OBSErve program. The aim of this post hoc analysis (GSK study 206351) was to pool individual patient OBSErve data to further evaluate the effectiveness of belimumab in a large sample of patients with SLE. METHODS: OBSErve (Argentina, Canada, Germany, Spain, Switzerland, and the USA) enrolled adults ≥ 18 years of age with SLE, who were prescribed belimumab as part of standard therapy (index: date of belimumab initiation). Endpoints (month 6 vs. index) included physician-assessed overall clinical response to belimumab in the overall population (primary) and high disease activity subgroups (secondary; patients with a SLEDAI-2K/SELENA-SLEDAI score ≥ 10 or patients with high anti-dsDNA or low complement at index); other secondary endpoints included changes in glucocorticosteroid (GCS) use and changes in disease activity. Factors associated with physician-assessed overall clinical response were also evaluated. RESULTS: In total, 830 patients were included in the overall population (mean [standard deviation (SD)] age: 41.9 [12.57] years; female: 89.3%; 60.4% from the USA). Nearly half (48.1%) of belimumab-treated patients experienced a ≥ 50% physician-assessed improvement in their overall manifestations, and 13% achieved a near normalization of their condition (equal to ≥ 80% improvement). Initiating belimumab while on high-dose (> 7.5 mg/day) GCS use was associated with ≥ 50% clinical improvement at month 6 (OR: 1.9, p = 0.003). Most (78.1%; n = 518/663) patients were able to reduce or discontinue their oral GCS dose after 6 months of belimumab, with a mean (SD) change of - 8.5 (10.74) mg/day prednisone-equivalent. The mean (SD) change from belimumab initiation in disease activity score (SLEDAI-2K/SELENA-SLEDAI) was - 5.7 (4.5; n = 344). CONCLUSIONS: Belimumab improves clinical manifestations of SLE and is associated with GCS dose reductions in a real-world clinical setting, supporting the real-world effectiveness of belimumab for SLE.

Efficacy of Thalidomide in Discoid Lupus Erythematosus: Insights into the Molecular Mechanisms.

BACKGROUND: Thalidomide has been used successfully in a variety of chronic refractory inflammatory dermatological conditions with underlying autoimmune or infectious pathogenesis. It was first used for refractory discoid lupus erythematosus (DLE) in 1983 and has steadily grown since then. METHOD: In this review, we describe the therapeutic benefits of thalidomide for DLE treatment and its biological properties. We explain how new discoveries in DLE pathogenesis are relevant to understand thalidomide's mechanism of action and the need to find an alternative safe drug with similar therapeutic effects. SUMMARY: Thalidomide's efficacy in DLE patients is significant, with 80-90% reaching clinical remission according to different studies. However, thalidomide's use is still limited by serious adverse effects such as teratogenicity, neurotoxicity, and thrombosis. In addition, there is a frequent rate of relapse and many patients require a long-term low dose of thalidomide as maintenance. The achievement of clinical response within weeks is key to avoid irreversible DLE fibrotic sequelae, making it critical to introduce thalidomide earlier in the DLE treatment algorithm. Recently, microarray and miRNA screenings demonstrated a significant CD4+ T enrichment and T-helper 1 response predom-inance with a dysregulation of regulatory T cell (Treg) expression in DLE lesions that induced high levels of proinflammatory, chemotaxis, and apoptotic proteins that induce the chronic inflammation response. Thalidomide's anti-inflammatory, antiangiogenic, and T-cell co-stimulatory effects may be beneficial for DLE since it promotes cytokine inhibition, inhibits macrophage activation, regulates Treg responses, inhibits angiogenesis, modulates T cells, and promotes NK cell-mediated cytotoxicity.