| 1. |
- Allam, Venkata, et al.
(författare)
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Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma
- 2023
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Ingår i: Thorax. - : BMJ Publishing Group Ltd. - 0040-6376 .- 1468-3296. ; 78:7, s. 661-673
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Tidskriftsartikel (refereegranskat)abstract
- Background: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma.Methods: We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo.Results: MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity.Conclusion: Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic asthma.
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| 2. |
- Emamikia, Sharzad, et al.
(författare)
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Impact of remission and low disease activity on health-related quality of life in patients with systemic lupus erythematosus
- 2022
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Ingår i: Rheumatology. - : Oxford University Press. - 1462-0324 .- 1462-0332. ; 61:12, s. 4752-4762
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To investigate the impact of remission and lupus low disease activity state (LLDAS) on health-related quality of life (HRQoL) in systemic lupus erythematosus.METHODS: SF-36, EQ-5D-3L and FACIT-Fatigue data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials were used. Duration in remission/LLDAS required to reach a HRQoL benefit ≥ minimal clinically important differences (MCIDs) during and post-treatment was determined using quantile regression and generalised estimating equations.RESULTS: Patients (N = 1684) were assessed every 4th week (15 visits). Four cumulative (β = 0.60) or four consecutive (β = 0.66) visits in remission were required to achieve a benefit ≥MCID in SF-36 physical component summary (PCS) scores, and six cumulative (β = 0.44) or five consecutive (β = 0.49) for a benefit ≥MCID in mental component summary (MCS) scores. Eight cumulative (β = 0.30 for both) or eight consecutive (β = 0.32 for both) visits in LLDAS were required for a benefit in PCS/MCS ≥MCID, respectively.For EQ-5D-3L index scores ≥MCID, six cumulative (β = 0.007) or five consecutive (β = 0.008) visits in remission were required, and eight cumulative (β = 0.005) or six consecutive (β = 0.006) visits in LLDAS. For FACIT-Fatigue scores ≥MCID, 12 cumulative (β = 0.34) or 10 consecutive (β = 0.39) visits in remission were required, and 17 cumulative (β = 0.24) or 16 consecutive (β = 0.25) visits in LLDAS.CONCLUSION: Remission and LLDAS contribute to a HRQoL benefit in a time-dependent manner. Shorter time in remission than in LLDAS was required for a clinically important benefit in HRQoL, and longer time in remission for a benefit in mental compared with physical HRQoL aspects. When remission/LLDAS was sustained, the same benefit was achieved in a shorter time.
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| 3. |
- Emamikia, Sharzad, et al.
(författare)
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The Impact of Remission and Low Disease Activity Attainment on Health-related Quality of Life in Two Phase III Clinical Trials of Belimumab in Systemic Lupus Erythematosus
- 2021
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Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 73:Suppl. 9, s. 2604-2606
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background/Purpose: Health- related quality of life (HRQoL) is considered one of the most important outcomes in clinical trials of systemic lupus erythematosus (SLE), along with reduction in disease activity and safety. We studied the duration and consecutiveness of remission or low disease activity throughout a 52- week long period on standard therapy plus belimumab or placebo in relation to HRQoL outcome.Methods: We analysed pooled 52- week data from the BLISS- 52 (N=865) and BLISS- 76 (N=819) phase III trials. We determined remission using the prevailing Definitions of Remission in SLE (DORIS) definition (1) and low disease activity using the Lupus Low Disease Activity State (LLDAS) (2). Remission required clinical (c)SLEDAI- 2K=0, PhGA (0– 3) <0.5, and prednisone ≤5 mg/day. LLDAS required SLEDAI- 2K ≤4, PhGA (0– 3) ≤1, and prednisone ≤7.5 mg/day. HRQoL was measured with the SF- 36 physical and mental component summary (PCS and MCS), and EQ- 5D- 3L. Minimal clinically important difference (MCID) at week 52 for PCS and MCS was set to 2.5, and for EQ- 5D- 3L utility index to 0.040. Associations were assessed using quantile regression analysis. Adjustments for demographics, disease duration, organ damage and baseline status were incorporated.Results: The minimum cumulative attainment of remission to achieve a benefit in PCS ≥MCID at week 52 was four visits (corresponding to 16 weeks) (β=0.63), while 7 visits (28 weeks) were required for MCS differences ≥MCID (β=0.37). Correspondingly, 9 visits in LLDAS (36 weeks) were required for achieving differences ≥MCID in both PCS (b=0.28) and MCS (β=0.29). Table 1 shows 95% confidence intervals and p values. When analysing the impact of sustained remission and LLDAS, four consecutive visits in remission (16 weeks) were required for PCS ≥MCID (b=0.70), whereas six visits (24 weeks) were required for MCS ≥MCID (b=0.46). Sustained LLDAS for nine consecutive visits (36 weeks) was needed for PCS and MCS ≥MCID (b=0.31 and 0.31, respectively). For EQ- 5D ≥MCID to be reached, a cumulative total of seven visits (28 weeks) in remission (b=0.006), or eight visits (32 weeks) in LLDAS (b=0.005) was required, whereas if sustained, remission for six visits (24 weeks; b=0.008) or LLDAS for seven visits (28 weeks; b=0.006) were sufficient.Conclusion: Attainment of remission or LLDAS in the BLISS- 52 and BLISS- 76 trials of belimumab was associated with improved HRQoL. Less time was required in remission than in LLDAS to achieve clinically important differences in multiple HRQoL aspects. Clinically important differences in HRQoL required shorter total time if the remission or LLDAS was sustained. Clinically important differences in mental aspects of HRQoL required longer time in remission than physical aspects. The impact of cumulative and sustained remission or LLDAS on HRQoL adds evidence on the clinical importance of these treat- to- target endpoints.References:1) van Vollenhoven R. et al. Ann Rheum Dis. 20172) Franklyn K. et al. Ann Rheum Dis. 2016
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| 4. |
- Fanouriakis, Antonis, et al.
(författare)
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EULAR recommendations for the management of systemic lupus erythematosus : 2023 update
- 2024
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Ingår i: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 83:1, s. 15-29
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 5. |
- Nielsen, Wils, et al.
(författare)
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OMERACT 2023 Systemic Lupus Erythematosus Special Interest Group : Winnowing and Binning Preliminary Candidate Domains for the Core Outcome Set
- 2024
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Ingår i: Seminars in Arthritis & Rheumatism. - : Elsevier. - 0049-0172 .- 1532-866X. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Outcome Measures in Rheumatology (OMERACT) Systemic Lupus Erythematosus (SLE) Working Group held a Special Interest Group (SIG) at the OMERACT 2023 conference in Colorado Springs where SLE collaborators reviewed domain sub-themes generated through qualitative research and literature review.OBJECTIVE: The objective of the SIG and the subsequent meetings of the SLE Working Group was to begin the winnowing and binning of candidate domain sub-themes into a preliminary list of candidate domains that will proceed to the consensus Delphi exercise for the SLE COS.METHODS: Four breakout groups at the SLE SIG in Colorado Springs winnowed and binned 132 domain sub-themes into candidate domains, which was continued with a series of virtual meetings by an advisory group of SLE patient research partners (PRPs), members of the OMERACT SLE Working Group Steering Committee, and other collaborators.RESULTS: The 132 domain sub-themes were reduced to a preliminary list of 20 candidate domains based on their clinical and research relevance for clinical trials and research studies.CONCLUSION: A meaningful and substantial winnowing and binning of candidate domains for the SLE COS was achieved resulting in a preliminary list of 20 candidate domains.
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| 6. |
- Ugarte-Gil, Manuel Francisco, et al.
(författare)
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Impact of glucocorticoids on the incidence of lupus-related major organ damage : A systematic literature review and meta-regression analysis of longitudinal observational studies
- 2021
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Ingår i: Lupus Science and Medicine. - : BMJ. - 2053-8790. ; 8:1
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Forskningsöversikt (refereegranskat)abstract
- Objective In systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ damage occurrence. Methods We conducted a literature search (PubMed (Medline), Embase and Cochrane January 1966-October 2021). We identified original longitudinal observational studies reporting GC exposure as the proportion of users and/or GC use with dose information as well as the occurrence of new major organ damage as defined in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Meta-regression analyses were performed. Reviews, case-reports and studies with <5 years of follow-up, <50 patients, different outcomes and special populations were excluded. Results We selected 49 articles including 16 224 patients, 14 755 (90.9%) female with a mean age and disease duration of 35.1 years and of 37.1 months. The mean follow-up time was 104.9 months. For individual damage items, the average daily GC dose was associated with the occurrence of overall cardiovascular events and with osteoporosis with fractures. A higher average cumulative dose adjusted (or not)/number of follow-up years and a higher proportion of patients on GC were associated with the occurrence of osteonecrosis. Conclusions We confirm associations of GC use with three specific damage items. In treating patients with SLE, our aim should be to maximise the efficacy of GC and to minimise their harms.
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