Application of blinatumomab, a bispecific anti-CD3/CD19 T-cell engager, in treating severe systemic sclerosis: A case study.

Systemic sclerosis, a severe inflammatory autoimmune disease, shares a common thread with cancer through the underlying mechanism of inflammation. This inflammatory milieu not only drives the immune dysregulation characteristic of autoimmune diseases but also plays a pivotal role in the pathogenesis of cancer. Among the cellular components involved, B cells have emerged as key players in hematologic tumor and autoimmune disease, contributing to immune dysregulation and persistent tissue fibrosis in systemic sclerosis, as well as tumor progression and immune evasion in cancer. Consequently, novel therapeutic strategies targeting B cells hold promise in both conditions. Recent exploration of CD19 CAR T cells in severe systemic sclerosis patients has shown great potential, but also introduced possible risks and drawbacks associated with viral vectors, prolonged CAR T cell persistence, lengthy production timelines, high costs, and the necessity of conditioning patients with organotoxic and fertility-damaging chemotherapy. Given these challenges, alternative CD19-depleting approaches are of high interest for managing severe systemic autoimmune diseases. Here, we present the pioneering use of blinatumomab, a bispecific anti-CD3/anti-CD19 T cell engager in a patient with progressive, severe systemic sclerosis, offering a promising alternative for such challenging cases.

The Impact of Removing the 10-Minute Bout Requirement and of Different Survey Administration Methods on National Physical Activity Estimates in Austria.

BACKGROUND: Monitoring survey methods, as well as movement recommendations, evolves over time. These changes can make trend observations over time difficult. The aim of this study was to examine the differences between 2 computer-assisted survey administration methods and the effect of the omission of the 10-minute minimum bout requirement in physical activity (PA) questions on PA outcomes. METHODS: We used data from the second Austrian PA Surveillance System for 2998 adults (18-64 y), applying computer-assisted personal interviewing and computer-assisted web interviewing. Within the computer-assisted web interviewing sample only, we added PA questions without the 10-minute requirement. Quantile and logistic regressions were applied. RESULTS: Between computer-assisted web interviewing and computer-assisted personal interviewing, within the computer-assisted personal interviewing sample, we found lower PA estimates in the leisure domain and work and household domain, but not in the travel domain, and no significant difference in the proportion of people meeting the PA recommendations. In all 3 PA domains, the median minutes did not differ when assessed with or without the 10-minute requirement. However, the percentage participation in the travel domain and work and household domain performing >0 minutes per week PA was higher when there was no 10-minute requirement. The proportion of people meeting the Austrian aerobic recommendation for adults when computed with or without the 10-minute requirement did not differ. CONCLUSION: Our findings suggest that the omission of the 10-minute requirement does not seem to result in marked differences in PA estimates or the proportion of adults meeting the recommendations.

UNC93B1 variants underlie TLR7-dependent autoimmunity.

UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.

From Health-in-All-Policies to Climate-in-All-Policies: Using the Synergies between Health Promotion and Climate Protection to Take Action.

The climate crisis is developing into a life-changing event on a global level. Health promotion with the aim to increase the health status of individuals, independent of the present health status, has been developed on a scientific basis at least for the last eight decades. There are some basic principles which are prerequisites for both health promotion and climate protection. Those principles include (1) sustainability, (2) orientation on determinants, and (3) requirement of individual as well as community approaches. People are generally aiming to protect their lifestyle habits (e.g., traveling and consumer habits) and personal property (e.g., car and house) with easy solutions and as little effort as possible, and this can affect both health and climate. To reduce the emission of greenhouse gases and to protect our environment, changes towards a sustainable lifestyle have to be embedded into everybody's mind. Examples for domains that need to be addressed in health promotion as well as in climate protection include (health and climate) literacy, physical activity and active mobility, and nutrition and dietary habits. If health promotion fails to tackle those domains, this will continue to drive the climate crisis. And climate change, in turn, will affect health. On the other hand, developing and promoting health resources in the domains mentioned could help to mitigate the health-damaging effects of climate change. Success in the joint efforts to promote health and protect the climate would improve the One Health approach, the health of people and the environment.

2023 International Consensus Guidance for the use of Tripterygium Wilfordii Hook F in the treatment of active rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects the joints and produces pain, swelling, and stiffness. It has a lifetime prevalence of up to 1% worldwide. An extract of Tripterygium wilfordii Hook F (TwHF), a member of the Celastraceae herbal family widely available in south China, has been used for treatment of RA since 1960s. METHODS: The current consensus practice guidance (CPG) aims to offer guidance on the application of TwHF in the clinical management of active RA. The CPG followed World Health Organisation (WHO)'s recommended process, carried out three systematic reviews to synthesize data from 19 randomised controlled trials (RCT) involving 1795 participants. We utilized Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to evaluate certainty of evidence and derive recommendations. We rigorously followed The Appraisal of Guidelines for Research and Evaluation II (AGREE II) as conduct guides to minimise bias and promote transparency. RESULTS: There was no obvious difference between TwHF monotherapy and methotrexate (MTX) monotherapy on ACR20 (RCT = 2, N = 390, RR = 1.06, 95%CI 0.90-1.26, moderate certainty), ACR50 (RCT = 3, N = 419, RR = 1.03, 95%CI 0.80-1.34, moderate certainty), ACR70 (RCT = 2, N = 390, RR = 1.12, 95%CI 0.69-1.79, low certainty). TwHF monotherapy may be better than salicylazosulfapyridine monotherapy on ACR20 and the effect may be similar on ACR50 and ACR70. Seven RCTs compared MTX combined with TwHF versus MTX monotherapy, and the meta-analysis results favoured combination therapy group on ACR20 (RCT = 3, N = 470, RR = 1.44, 95%CI 1.28-1.62, moderate certainty), ACR50 (RCT = 4, N = 500, RR = 1.88, 95%CI 1.56-2.28, moderate certainty) and ACR70 (RCT = 2, N = 390, RR = 2.12, 95%CI 1.40-3.19, low certainty). We found no obvious difference between groups on critical safety outcomes, including infection (RCT = 3, N = 493, RR = 1.37, 95%CI 0.84-2.23), liver dysfunction (RCT = 5, N = 643, RR = 1.14, 95%CI 0.71-1.85), renal damage (RCT = 3, N = 450, RR = 2.20, 95%CI 0.50-9.72). CONCLUSION: Upon full review of the evidence, the guidance panel reached consensus on recommendations for the use of TwHF in people with active RA, either as monotherapy or as combination therapy with MTX.

Cellular Immunobiology and Molecular Mechanisms in Alloimmunity-Pathways of Immunosuppression.

Current maintenance immunosuppression commonly comprises a synergistic combination of tacrolimus as calcineurin inhibitor (CNI), mycophenolic acid, and glucocorticoids. Therapy is often individualized by steroid withdrawal or addition of belatacept or inhibitors of the mechanistic target of rapamycin. This review provides a comprehensive overview of their mode of action, focusing on the cellular immune system. The main pharmacological action of CNIs is suppression of the interleukin-2 pathway that leads to inhibition of T cell activation. Mycophenolic acid inhibits the purine pathway and subsequently diminishes T and B cell proliferation but also exerts a variety of effects on almost all immune cells, including inhibition of plasma cell activity. Glucocorticoids exert complex regulation via genomic and nongenomic mechanisms, acting mainly by downregulating proinflammatory cytokine signatures and cell signaling. Belatacept is potent in inhibiting B/T cell interaction, preventing formation of antibodies; however, it lacks the potency of CNIs in preventing T cell-mediated rejections. Mechanistic target of rapamycin inhibitors have strong antiproliferative activity on all cell types interfering with multiple metabolic pathways, partly explaining poor tolerability, whereas their superior effector T cell function might explain their benefits in the case of viral infections. Over the past decades, clinical and experimental studies provided a good overview on the underlying mechanisms of immunosuppressants. However, more data are needed to delineate the interaction between innate and adaptive immunity to better achieve tolerance and control of rejection. A better and more comprehensive understanding of the mechanistic reasons for failure of immunosuppressants, including individual risk/benefit assessments, may permit improved patient stratification.

EULAR recommendations for the management of systemic lupus erythematosus: 2023 update.

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.

Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjögren's syndrome: results from a randomised, double-blind, placebo-controlled phase 2 trial.

OBJECTIVES: To evaluate the safety and efficacy of remibrutinib in patients with moderate-to-severe Sjögren's syndrome (SjS) in a phase 2 randomised, double-blind trial (NCT04035668; LOUiSSE (LOU064 in Sjögren's Syndrome) study). METHODS: Eligible patients fulfilling 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) criteria for SjS, positive for anti-Ro/Sjögren's syndrome-related antigen A antibodies, with moderate-to-severe disease activity (EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) (based on weighted score) ≥ 5, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) ≥ 5) received remibrutinib (100 mg) either one or two times a day, or placebo for the 24-week study treatment period. The primary endpoint was change from baseline in ESSDAI at week 24. Key secondary endpoints included change from baseline in ESSDAI over time, change from baseline in ESSPRI over time and safety of remibrutinib in SjS. Key exploratory endpoints included changes to the salivary flow rate, soluble biomarkers, blood transcriptomic and serum proteomic profiles. RESULTS: Remibrutinib significantly improved ESSDAI score in patients with SjS over 24 weeks compared with placebo (ΔESSDAI -2.86, p=0.003). No treatment effect was observed in ESSPRI score (ΔESSPRI 0.17, p=0.663). There was a trend towards improvement of unstimulated salivary flow with remibrutinib compared with placebo over 24 weeks. Remibrutinib had a favourable safety profile in patients with SjS over 24 weeks. Remibrutinib induced significant changes in gene expression in blood, and serum protein abundance compared with placebo. CONCLUSIONS: These data show preliminary efficacy and favourable safety of remibrutinib in a phase 2 trial for SjS.

Transcriptional profiling upon T cell stimulation reveals down-regulation of inflammatory pathways in T and B cells in SLE versus Sjögren's syndrome.

Systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) share clinical as well as pathogenic similarities. Although previous studies suggest various abnormalities in different immune cell compartments, dedicated cell-type specific transcriptomic signatures are often masked by patient heterogeneity. Here, we performed transcriptional profiling of isolated CD4, CD8, CD16 and CD19 lymphocytes from pSS and SLE patients upon T cell stimulation, in addition to a steady-state condition directly after blood drawing, in total comprising 581 sequencing samples. T cell stimulation, which induced a pronounced inflammatory response in all four cell types, gave rise to substantial re-modulation of lymphocyte subsets in the two autoimmune diseases compared to healthy controls, far exceeding the transcriptomic differences detected at steady-state. In particular, we detected cell-type and disease-specific down-regulation of a range of pro-inflammatory cytokine and chemokine pathways. Such differences between SLE and pSS patients are instrumental for selective immune targeting by future therapies.

Cross-regulation of antibody responses against the SARS-CoV-2 Spike protein and commensal microbiota via molecular mimicry.

The commensal microflora provides a repertoire of antigens that illicit mucosal antibodies. In some cases, these antibodies can cross-react with host proteins, inducing autoimmunity, or with other microbial antigens. We demonstrate that the oral microbiota can induce salivary anti-SARS-CoV-2 Spike IgG antibodies via molecular mimicry. Anti-Spike IgG antibodies in the saliva correlated with enhanced abundance of Streptococcus salivarius 1 month after anti-SARS-CoV-2 vaccination. Several human commensal bacteria, including S. salivarius, were recognized by SARS-CoV-2-neutralizing monoclonal antibodies and induced cross-reactive anti-Spike antibodies in mice, facilitating SARS-CoV-2 clearance. A specific S. salivarius protein, RSSL-01370, contains regions with homology to the Spike receptor-binding domain, and immunization of mice with RSSL-01370 elicited anti-Spike IgG antibodies in the serum. Additionally, oral S. salivarius supplementation enhanced salivary anti-Spike antibodies in vaccinated individuals. Altogether, these data show that distinct species of the human microbiota can express molecular mimics of SARS-CoV-2 Spike protein, potentially enhancing protective immunity.

Translational implications of newly characterized pathogenic pathways in systemic lupus erythematosus.

Improved characterization of relevant pathogenic pathways in systemic lupus erythematosus (SLE) has been further delineated over the last decades. This led to the development of targeted treatments including belimumab and anifrolumab, which recently became available in clinics. Therapeutic targets in SLE encompass interferon (IFN) signaling, B-T costimulation including immune checkpoints, and increasing modalities of B lineage targeting, such as chimeric antigen receptor (CAR) T cells directed against CD19 or sequential anti-B cell targeting. Patient profiling based on characterization of underlying molecular abnormalities, often performed through comprehensive omics analyses, has recently been shown to better predict patients' treatment responses and also holds promise to unravel key molecular mechanisms driving SLE. SLE carries two key signatures, namely the IFN and B lineage/plasma cell signatures. Recent advances in SLE treatments clearly indicate that targeting innate and adaptive immunity is successful in such a complex autoimmune disease. Although those signatures may interact at the molecular level and provide the basis for the first selective treatments in SLE, it remains to be clarified whether these distinct treatments show different treatment responses among certain patient subsets. In fact, notwithstanding the remarkable amount of novel clues for innovative SLE treatment, harmonization of big data within tailored treatment strategies will be instrumental to better understand and treat this challenging autoimmune disorder. This review will provide an overview of recent improvements in SLE pathogenesis, related insights by analyses of big data and machine learning as well as technical improvements in conducting clinical trials with the ultimate goal that translational research results in improved patient outcomes.

Safety profile of baricitinib in patients with systemic lupus erythematosus: an integrated analysis.

OBJECTIVES: To assess the safety of the oral Janus kinase inhibitor baricitinib in adult patients with systemic lupus erythematosus (SLE) receiving stable background therapy. Topics of special interest included infections and cardiovascular and thromboembolic events. METHODS: This analysis included integrated safety data from three randomised, placebo-controlled studies (one phase 2 and two phase 3) and one long-term extension study. Data are reported in three data sets: placebo-controlled, extended exposure and all-baricitinib. Outcomes include treatment-emergent adverse events (AEs), AEs of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates (IRs) were calculated. RESULTS: A total of 1655 patients received baricitinib for up to 3.5 years (median duration 473 days). With baricitinib 4 mg, baricitinib 2 mg and placebo, respectively, 50.8%, 50.7% and 49.0% of patients reported at least one infection and 4.4%, 3.4% and 1.9% of patients had a serious infection. The most common treatment-emergent infections included urinary tract infection, COVID-19, upper respiratory tract infection and nasopharyngitis. Herpes zoster was more common with baricitinib 4 mg (4.7%) vs baricitinib 2 mg (2.7%) and placebo (2.8%). Among baricitinib-4 mg, 2 mg and placebo-treated patients, respectively, 4 (IR=0.9), 1 (IR=0.2) and 0 experienced at least one positively adjudicated major adverse cardiovascular event, and 0, 3 (IR=0.6) and 2 (IR=0.4) reported at least one positively adjudicated venous thromboembolism. CONCLUSIONS: The results of this integrated safety analysis in patients with SLE are not substantially different to the established safety profile of baricitinib. No increased venous thromboembolism was found.

Unequally Unequal? Contextual-level status inequality and social cohesion moderating the association between individual-level socioeconomic position and systemic chronic inflammation.

BACKGROUND: Status inequality is hypothesised to increase socioeconomic inequalities in health by creating an environment in which social cohesion erodes and social comparisons intensify. Such an environment may cause systemic chronic inflammation. Although these are often-used explanations in social epidemiology, empirical tests remain rare. METHODS: We analysed data from the West of Scotland Twenty-07 Study. Our sample consisted of 1977 participants in 499 small residential areas. Systemic chronic inflammation was measured by high-sensitivity C-reactive protein (hs-CRP; <10 mg/L). An area-level measurement of status inequality was created using census data and contextual-level social cohesion was measured applying ecometrics. We estimated linear multilevel models with cross-level interactions between socioeconomic position (SEP), status inequality, and social cohesion adjusted for age and gender. Our main analysis on postcode sector-level was re-estimated on three smaller spatial levels. RESULTS: The difference in hs-CRP between disadvantaged and advantaged SEPs (0.806 mg/L; p = 0.063; [95%CI: -0.044; 1.656]) was highest among participants living in areas where most residents were in advantaged SEPs. In these status distributions, high social cohesion was associated with a shallower socioeconomic gradient in hs-CRP and low social cohesion was associated with a steeper gradient. In areas with an equal mix of SEPs or most residents in disadvantaged SEPs, the estimated difference in hs-CRP between disadvantaged and advantaged SEPs was -0.039 mg/L (p = 0.898; [95%CI: 0.644; 0.566]) and -0.257 mg/L (p = 0.568; [95%CI: 1.139; 0.625]) respectively. In these status distributions, the gradient in hs-CRP appeared steeper when social cohesion was high and potentially reversed when social cohesion was low. Results were broadly consistent when using area-levels smaller than postcode sectors. CONCLUSIONS: Inequalities in hs-CRP were greatest among participants living in areas wherein a majority of residents were in advantaged SEPs and social cohesion was low. In other combinations of these contextual characteristics, inequalities in systemic chronic inflammation were not detectable or potentially even reversed.

[Practicable diagnostics of Sjögren's syndrome in interstitial lung disease-A discussion article]. / Praktikable Sjögren-Diagnostik bei interstitieller Lungenerkrankung ­ ein Diskussionsbeitrag.

Sjögren's syndrome (SjS) is a possible autoimmune cause of interstitial lung disease. The diagnostic pathway for SjS, however, is largely undefined in comparison to other systemic autoimmune diseases. Subjective sicca symptoms, anti-SS-A/Ro antibodies and even ANA as screening tests all have relevant limitations in sensitivity and/or specificity. Against this background, in an interdisciplinary discussion we have developed a consensus for the clarification of SjS, which is presented here for broader discussion. In addition to ANA and anti-SS-A/Ro antibodies, antibodies against alpha-fodrin should be included. Objective measures of dryness, such a Schirmer and Saxon tests are important, as is a salivary gland biopsy in the absence of typical autoantibodies.

People Living with HIV and AIDS: Experiences towards Antiretroviral Therapy, Paradigm Changes, Coping, Stigma, and Discrimination-A Grounded Theory Study.

BACKGROUND: The experiences in coping with HIV/AIDS from people living with HIV (PLWH) in Austria, Munich, and Berlin regarding adherence, antiretroviral therapy (ART), stigmatization, and discrimination were the main focus of this study. Therapy adherence is the cornerstone for PLWH to reduce disease progression and increase life expectancy combined with a high quality of life. The experience of stigmatization and discrimination in different life situations and settings is still experienced today. AIMS: We aimed to examine the subjective perspective of PLWH concerning living with, coping with, and managing HIV/AIDS in daily life. METHODS: Grounded Theory Methodology (GTM) was used. Data collection was conducted with semi-structured face-to-face interviews with 25 participants. Data analysis was performed in three steps, open, axial, and selective coding. RESULTS: Five categories emerged, which included the following: (1) fast coping with diagnosis, (2) psychosocial burden due to HIV, (3) ART as a necessity, (4) building trust in HIV disclosure, (5) stigmatization and discrimination are still existing. CONCLUSION: In conclusion, it can be said that it is not the disease itself that causes the greatest stress, but the process of coping with the diagnosis. Therapy, as well as lifelong adherence, is hardly worth mentioning today. Much more significant is currently still the burden of discrimination and stigmatization.

Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-I).

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.

Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-II).

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. In this Article, we report the evaluation of efficacy and safety of baricitinib in patients with SLE in a 52-week phase 3 study. METHODS: In this phase 3 double-blind, randomised, placebo-controlled study, SLE-BRAVE-II, patients (aged ≥18 years) with active SLE receiving stable background therapy were randomly assigned 1:1:1 to baricitinib 4 mg, baricitinib 2 mg, or placebo once daily for 52 weeks. The primary endpoint was the proportion of patients with an SLE Responder Index (SRI)-4 response at week 52 in the baricitinib 4 mg treatment group compared with placebo. Glucocorticoid tapering was encouraged but not required per protocol. 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 an intention-to-treat population, comprising all participants who were randomly assigned and 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. Safety analyses were done on all randomly assigned participants who received at least one dose of investigational product and who did not discontinue. This study is registered with ClinicalTrials.gov, NCT03616964, and is complete. FINDINGS: A total of 775 patients were randomly assigned and received at least one dose of baricitinib 4 mg (n=258), baricitinib 2 mg (n=261), or placebo (n=256). There was no difference in the primary efficacy outcome of the proportion of SRI-4 responders at week 52 between participants who received baricitinib 4mg (121 [47%]; odds ratio 1·07 [95% CI 0·75 to 1·53]; difference with placebo 1·5 [95% CI -7·1 to 10·2]), 2 mg (120 [46%]; 1·05 [0·73 to 1·50]; 0·8 [-7·9 to 9·4]) and placebo (116 [46%]). None of the major secondary endpoints, including glucocorticoid tapering and time to first severe flare, were met. Serious adverse events were observed in 29 (11%) participants in the baricitinib 4 mg group, 35 (13%) in the baricitinib 2 mg group, and 22 (9%) in the placebo group. The safety profile of baricitinib in patients with SLE was consistent with the known baricitinib safety profile. INTERPRETATION: Although phase 2 data suggested baricitinib as a potential treatment for patients with SLE, which was supported in SLE-BRAVE-I, this result was not replicated in SLE-BRAVE-II. No new safety signals were observed. FUNDING: Eli Lilly and Company.

Integrated Care as a Model for Interprofessional Disease Management and the Benefits for People Living with HIV/AIDS.

INTRODUCTION: Today, antiretroviral therapy (ART) is effectively used as a lifelong therapy to treat people living with HIV (PLWH) to suppress viral replication. Moreover, PLWH need an adequate care strategy in an interprofessional, networked setting of health care professionals from different disciplines. HIV/AIDS poses challenges to both patients and health care professionals within the framework of care due to frequent visits to physicians, avoidable hospitalizations, comorbidities, complications, and the resulting polypharmacy. The concepts of integrated care (IC) represent sustainable approaches to solving the complex care situation of PLWH. AIMS: This study aimed to describe the national and international models of integrated care and their benefits regarding PLWH as complex, chronically ill patients in the health care system. METHODS: We conducted a narrative review of the current national and international innovative models and approaches to integrated care for people with HIV/AIDS. The literature search covered the period between March and November 2022 and was conducted in the databases Cinahl, Cochrane, and Pubmed. Quantitative and qualitative studies, meta-analyses, and reviews were included. RESULTS: The main findings are the benefits of integrated care (IC) as an interconnected, guideline- and pathway-based multiprofessional, multidisciplinary, patient-centered treatment for PLWH with complex chronic HIV/AIDS. This includes the evidence-based continuity of care with decreased hospitalization, reductions in costly and burdensome duplicate testing, and the saving of overall health care costs. Furthermore, it includes motivation for adherence, the prevention of HIV transmission through unrestricted access to ART, the reduction and timely treatment of comorbidities, the reduction of multimorbidity and polypharmacy, palliative care, and the treatment of chronic pain. IC is initiated, implemented, and financed by health policy in the form of integrated health care, managed care, case and care management, primary care, and general practitioner-centered concepts for the care of PLWH. Integrated care was originally founded in the United States of America. The complexity of HIV/AIDS intensifies as the disease progresses. CONCLUSIONS: Integrated care focuses on the holistic view of PLWH, considering medical, nursing, psychosocial, and psychiatric needs, as well as the various interactions among them. A comprehensive expansion of integrated care in primary health care settings will not only relieve the burden on hospitals but also significantly improve the patient situation and the outcome of treatment.

Multi-omics approaches for precision obesity management : Potentials and limitations of omics in precision prevention, treatment and risk reduction of obesity.

INTRODUCTION: Obesity is a multifactorial chronic disease that cannot be addressed by simply promoting better diets and more physical activity. To date, not a single country has successfully been able to curb the accumulating burden of obesity. One explanation for the lack of progress is that lifestyle intervention programs are traditionally implemented without a comprehensive evaluation of an individual's diagnostic biomarkers. Evidence from genome-wide association studies highlight the importance of genetic and epigenetic factors in the development of obesity and how they in turn affect the transcriptome, metabolites, microbiomes, and proteomes. OBJECTIVE: The purpose of this review is to provide an overview of the different types of omics data: genomics, epigenomics, transcriptomics, proteomics, metabolomics and illustrate how a multi-omics approach can be fundamental for the implementation of precision obesity management. RESULTS: The different types of omics designs are grouped into two categories, the genotype approach and the phenotype approach. When applied to obesity prevention and management, each omics type could potentially help to detect specific biomarkers in people with risk profiles and guide healthcare professionals and decision makers in developing individualized treatment plans according to the needs of the individual before the onset of obesity. CONCLUSION: Integrating multi-omics approaches will enable a paradigm shift from the one size fits all approach towards precision obesity management, i.e. (1) precision prevention of the onset of obesity, (2) precision medicine and tailored treatment of obesity, and (3) precision risk reduction and prevention of secondary diseases related to obesity.