BackgroundBelimumab (BLM) is a recombinant human IgG-1λ monoclonal antibody that inhibits B-cell activating factor. It is commonly used for treatment of systemic lupus erythematosus (SLE) patients with inadequate control to first-line treatments and inability to taper GC daily dose to acceptable levels. More recently it has been approved for patients with active lupus nephritis.ObjectivesTo report baseline profile of SLE patients treated with BLM enrolled in a SLE Spanish registry.MethodsMulticenter retrospective and longitudinal cohort study including SLE patients treated with BLM in 18 Spanish rheumatology units. Demographic, clinical data and treatments were collected at baseline, 6, 12 months and in the last visit available. Patients starting BLM in different periods (2010-2015 and 2016-2021) were compared regarding the reason of prescription of the drug.Results324 patients (91% female, 84,8% caucasian) were enrolled. Mean (±SD) age at diagnosis: 31.8 years (±11.9); mean disease duration of 8.7 years (±9.07) and mean follow-up 3.8 (±2.7). A total of 319 (98.45%) subjects met SLE 1997 ACR or SLICC 2012 criteria; 217 (68.2%) were anti-dsDNA positive and 224 (69.8%) had low complement levels. At baseline, the mean SLEDAI-2K score was 10.4 (±5.25); 152 (47.5%) of patients had damage with a mean SDI score of 0.83 (±1.2). A total of 289 patients (89.2%) had received disease modifying anti-rheumatic drugs (DMARDs) before BLM: conventional (cDMARDS) in 282 patients (87%) and biologic DMARDs (bDMARDs) in 74 patients (22.8%); 164 (51.9%) had received more than one cDMARDs, methotrexate being the most frequently used (44.4%). Other cDMARDs used were: mycophenolate mofetil in 104 (37.01%), azathioprine in 91 (32.38%), leflunomide in 29 (10.32%), cyclophosphamide in 28 (9.92%) and calcineurin inhibitors in 13 (4.6%) of patients. The most frequent bDMARDs used was Rituximab in 80%. Most patients were receiving antimalarials (83,2%) and glucocorticoids (GC) (91.2%), with a mean dose of 12.3 mg/day. A total of 209 (67.9%) patients were receiving more than 5 mg/day and 180 (58.4%) more than 7.5 mg/day of prednisone.BLM was used in monotherapy in 99 (30.5%) subjects. It was initiated due to disease activity in 307 patients (95%) and/or as a GC sparing agent in 191 patients (59%). Most patients initiated BLM for several concurrent reason; only a few patients received BLM just for maintenance (4/322) or save GC (8/322). At baseline, only 6 patients (1.9%) were in DORIS-21-remission and LLDAS. The main reasons of prescription for ongoing activity were arthritis (65.4%), cutaneous (40.7 %) or both (81%). There were no statistically significant differences in any of the prescription reasons when comparing the periods 2010-2015 and 2016-2021.Table 1.Type and reasons of prescription of BelimumabN (%) or mean (± SD) (n = 324 patients)Age at prescription of Belimumab (years)42.3 (± 12.9)Intravenous Belimumab215 (66.35%)Subcutaneous Belimumab110 (33%)Reasons of prescription* (multiple response allowed)Disease activity307 (95%)Maintenance197 (61%)Glucocorticoid sparing191 (59 %)ActivityCutaneous132 (40.7 %)Articular212 (65.4%)Renal58 (17,9%)Hematological60 (18.5%)Serosal47 (14.5%)Other29 (8.82%)ConclusionIn the majority of patients, belimumab was prescribed after the use of other DMARDs and more than 50% of patients had received at least 2 DMARDs and were receiving GC at medium doses. One third of patients received BLM as monotherapy. It was prescribed due to active disease in the vast majority of patients and/or as GC sparing agent. Activity in articular and cutaneous domains were the main reasons of indication. No changes in prescription habits were identified over time.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
BackgroundBelimumab (BLM) is a recombinant human IgG-1λ monoclonal antibody that inhibits B-cell activating factor. It is approved for the treatment of systemic lupus erythematosus (SLE). It is effective in reducing disease activity, flares, damage prevention and also as a steroid-sparing agent. A treat to target (T2T) approach in the care of SLE patients is important in terms of improving short and long-term outcomes.ObjectivesTo evaluate belimumab (BLM) effectiveness in SLE patients from a Spanish multicenter registry.MethodsA longitudinal retrospective multicenter cohort including SLE patients treated with belimumab from 18 Spanish rheumatology departments. Demographic, clinical and serological data were collected at baseline, 6, 12 and in the last visit available. Changes in SLEDAI-2K; LLDAS and DORIS 2021 states and global response according to physician criteria were compared between visits, as well as changes in damage and glucocorticoids used. T-test was used for numerical variables and the Fisher’s test for categorical variables.Results324 patients were included: 295 (91%) females with a mean (±SD) age of 42.4 (±12.9) years. Mean follow-up was 3,8 (±2.7) years and mean time with BLM was 2.7 (±2.4) years. At baseline, mean SLEDAI-2K was 10.4 (±5.25), 68.2% had elevated anti-double-stranded DNA (anti-dsDNA) antibodies and 69.8% had complement consumption. BLM was initiated concomitant to other DMARD in 67.9% (n=220) of patients.Mean reduction in SLEDAI-2K score was 5.0 (± 5.1), 6.1 (±5.5) and 7.13 (±5.3) points at 6, 12 months and in the last visit, respectively (p<0.05 for all comparisons). Rates of achievement of LLDAS, DORIS and clinical response according to physician criteria, significantly increased from baseline to 6, 12 months, and to the last visit (Table 1). Anti-dsDNA antibodies and inflammatory markers (ESR, CRP), significantly decreased from baseline to 6, 12 months and in the last visit. Complements increased over the follow up but without statistical significance.A total of 107 (45,9%) patients discontinued GC. At 6 months, 58.9% (n=155) of patients reduced the dose of GC with respect to baseline and 72.8% (n=131) of patients did it at the last visit.Mean (±SD) prednisone dose was significantly reduce over the visits: 12.3 (±12.16); 7.42 (±5.36); 5.8 (±4.42) and 4.7 (±3.7) mg/day at baseline, 6 and 12 months and in the last visit, respectively. Median (IQR) SDI score at the end of the observation period did not change from baseline visit: 0 (0-1) and 0 (0-1), respectively (p=0.97). Neither were changes observed in the percentage of patients with damage between the beginning and the end of the observation period: at baseline 47.5% (n=152) patients presented damage and, in the last visit, 45.6% (n=99).Table 1.Clinical response and changes in GC dose.Disease activity Mean (±SD) or number (%); n=324Baseline6 months12 monthsLast visitSLEDAI reduction; mean (±SD)10 (± 5.25)5.0 (± 5.1) *6.1 (± 5.5) *7.13 (± 5.3) *LLDAS6 (1.9%)137(45.8%) *145 (62%) *177 (73.1%) *DORIS6 (1.9%)72 (24%) *85 (36.3%) *127 (52.5%) *Response according to physician212 (65.4%) *185 (57.1%) *165 (50.9%) *Number of swollen joints; mean (±SD)3.3 (±3.6)1.2 (±2.8) *0.69 (±1.95) *0.55 (±1.82) *Prednisone dose (mg/day); mean (±SD)12.3 (± 12.16) *7.4 (± 5,36) *5.8 (± 4,42) *4.75 (±3.74) *SLEDAI:Systemic Lupus Erythematosus Disease Activity Index. cSLEDAI: clinical SLEDAI; LLDAS:Lupus Low Disease Activity State. DORIS:Definition of remission in SLE. *p<0.05Figure 1.Rates of therapeutic targets attained by patients in treatment with Belimumab.6 months12 monthsLast visitDiscontinued4574130Ongoing279250194ConclusionReal-world data of SLE patients confirm belimumab efficacy in real world, reducing clinical and serological activity in the short and medium-term. Add-on therapy with BLM leads to high rates of LLDAS and DORIS at 6 months, that continue increasing over time. BLM has an important GC sparing effect and prevents organ damage accrual. All these data shows that BLM is useful to achieve the therapeutic goals of a T2T strategy.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
BackgroundOur group have recently shown that (Sema)phorin3B is reduced in RA patients and plays a protective role in an arthritis mouse model, through the reduction of inflammatory mediators and the synovial fibroblast invasiveness and was associated with a reduction of CD68 positive synovial macrophages (Igea, 2022). On the other hand, MerTK is a receptor protein kinase involved in the resolution of inflammation and plays a protective role in arthritis mice models (Waterborg, 2018). A recent study has shown that a population of synovial tissue macrophages characterized by the expression of MerTK are associated with remission maintenance and with an anti-inflammatory phenotype of RA FLS (Alivernini, 2020).ObjectivesThe aim of this study is to determine the role of Sema3B in the phenotypic characteristics of RA macrophages and the implication of MerTK.MethodsPeripheral blood monocytes from RA patients (n=10) were differentiated into macrophages by culturing in the presence of IFN-γ (10 ng/mL) for 6 days. Afterwards, macrophages were stimulated for 24 h with LPS (10 ng/mL), Sema3B (200 ng/mL) or the combination of both mediators. The expression of pro- and anti-inflammatory mediators was determined by quantitative PCR (qPCR) and ELISA. The expression of MerTK and macrophage surface markers was measured by flow cytometry.ResultsSema3B did not modulate the macrophage expression of pro-inflammatory mediatorsIL1B, IL6, IL12B, IL23, TNF, CCL2, CXCL10andCD86, but significantly reduced the LPS-induced expression of these mediators (Figure 1A), as well as the protein secretion of IL6, IL12p70 and TNF. In addition, Sema3B alone, but not in combination with LPS, significantly induced the gene and protein expression of MerTK and the secretion of Resolvin D1, a MerTK-mediated lipid involved in resolution of inflammation (Figure 1B). Moreover, Sema3B reduced the expression of the M1 marker CD64, while induced the expression of the M2 marker CD163.Figure 1.Sema3B enhances anti-inflammatory activity in macrophages of RA patients (n=6). (A) Significative reduction of the genetic expression of pro-inflammatory mediators. (B) Significative increase ofMERTKand ResolvinD1. Macrophages differentiated from monocytes of RA patients during 6 days (IFN-γ 10 ng/mL) and stimulated with Sema3B (200 ng/ml), LPS (10 ng/mL) and their combination for 24 hours. Symbols represent individual patients; bars show the mean ± SEM. *P < 0.05 and **P < 0.01.ConclusionOur data demonstrate that Sema3B modulates the macrophage phenotype of RA macrophages, inducing a skewing towards an anti-inflammatory/pro-resolving phenotype, likely in a MerTK-dependent manner. Therefore, here we identified a new mechanism involved in the protective role of Sema3B in RA pathogenesis.References[1] Alivernini, S.et al. Nat. Med.26, 1295–1306 (2020).[2] Igea, A.et al. Arthritis Rheumatol.74(6), 972–983(2022).[3] Waterborg CEJ, et al.Front. Immunol. 9:742 (2018).AcknowledgementsAll patients involved in this study.Disclosure of InterestsNone Declared.
BackgroundSeveral studies have shown that different semaphorin family members are involved in the pathogenesis of rheumatoid arthritis (RA). On one hand, our group has demonstrated that (Sema)phorin 3B and Sema3F are reduced in RA patients and play a protective role. On the other hand, Sema4A and Sema4D are increased in RA patients and are associated with inflammatory processes (Garcia, 2019; Igea, 2022).ObjectivesThe aim of this study is to determine the role of Sema4B in the pathogenesis of RA.MethodsGene expression of Sema4B was obtained from the gene expression array available in Gene Expression Omnibus-NCBI (GSE77298). Fibroblasts-like synoviocytes from RA patients (RA-FLS) (n=8) were stimulated 4 and 24 h with Sema4B (200ng/mL), TNF (10 ng/mL) or the combination of both. Peripheral blood monocytes from RA patients (n=12) were differentiated into M1 macrophages by culturing in the presence of IFN-γ (10 ng/mL) for 6 days. Afterwards, macrophages were stimulated 24 h with Sema4B (200ng/mL), LPS (10 ng/mL) or the combination of both. The expression of inflammatory mediators was determined by quantitative PCR (qPCR) and ELISA. Viability and migration of FLS were determined using calcein assays and wound closure assays, respectively.ResultsSema4B expression was significantly higher in the synovial tissue and FLS of RA patients compared to healthy controls (HC) and osteoarthritis patients (OA), respectively. A significantly higher expression ofSEMA4Bin the synovium and FLS of RA patients compared to, respectively, was found. Interestingly, TNF stimulation induced the expression ofSEMA4Bby RA-FLS. Functional studies showed that Sema4B did not affect the viability of FLS but increased their migratory capacity. Moreover, Sema4B alone did not induce the expression of inflammatory mediators (data non shown), but significantly enhanced the TNF-induced expression ofIL6, IL8, TNF, CCL2andMMP3(Figure 1A) and the secretion of TNF. Finally, Sema4B alone did not modulate the expression of inflammatory mediators in macrophages, but significantly enhanced the LPS-mediated expression ofTNF,CCL2, andMMP1(Figure 1B), as well as the TNF protein secretion.Figure 1.Sema4B enhances pro-inflammatory activity in FLS (n=6) and macrophages (n=10) of RA patients. (A) Significative increment of the genetic expression of pro-inflammatory mediators in RA-FLS stimulated with Sema4B (200 ng/ml), TNF (10 ng/mL) and their combination for 24 hours. (B) Significative increase of the genetic expression of pro-inflammatory mediators in M1 macrophages. Macrophages differentiated from monocytes of RA patients during 6 days (IFN-γ 10 ng/mL) and stimulated with Sema4B (200 ng/ml), LPS (10 ng/mL) and their combination for 24 hours. Symbols represent individual patients; bars show the mean ± SEM. *P < 0.05.ConclusionOur data demonstrate that, in an inflammatory context, Sema4B induces FLS migration and the production of inflammatory mediators by FLS and macrophages. These results suggest that Sema4B is involved in inflammatory processes observed in the RA synovium and might be a potential therapeutic target in the treatment of RA.References[1]Garcia S. Role of Semaphorins in Immunopathologies and Rheumatic Diseases.Int J Mol Sci. 2019;20(2):374. Published 2019 Jan 16. doi:10.3390/ijms20020374[2]Igea A, Carvalheiro T, Malvar-Fernández B, et al. Central Role of Semaphorin 3B in a Serum-Induced Arthritis Model and Reduced Levels in Patients With Rheumatoid Arthritis.Arthritis Rheumatol. 2022;74(6):972-983. doi:10.1002/art.42065AcknowledgementsAll patients involved in this study.Disclosure of InterestsNone Declared.
BackgroundThe prevalence of depression and associated factors in systemic lupus erythematosus (SLE) are not well known and there are no longitudinal studies addressing this relevant subject in SLE.ObjectivesWe aimed to evaluate the prevalence of self-perceived depression in patients with SLE and associated factors in a large, multicenter cohort (RELESSER-PROS).MethodsProspective longitudinal study of patients with SLE (1997 ACR criteria) answering positively to the depression question of the Lupus Impact Tracker (LIT) questionary (namely: “I was depressed” question number 7) (LITQ7), over 4 years of follow-up (5 annual visits, V1 to V5). Self-perceived depression was addressed as “depression any time” or “depression most of time”, according to the kind of answer to the LITQ7 (answers 1,2,3 or 4 and answers 3 or 4 respectively). Only patients with no missing values in the covariates, making possible run longitudinal models, were included in the multivariable analysis. The following covariates, with potential impact in depression, were considered: SLEDAI, age, duration of the disease, SLICC/AR DI (SDI), fibromyalgia, Charlson index, smoking, BMI, menopause, sedentary lifestyle, marital status, unemployment and glucocorticoid use.Friedman test was used to test if the change in repeated measures was significative. Generalized estimating equation (GEE) models with binomial response, were built exploring the associations of individual longitudinal determinants with longitudinal assessment of depression. The best model was selected using quasi-likelihood under the independence model information criterion (QIC)ResultsA total of 1463 were included. Mean age: 55 (DS±13.59) years, 90% were female. Mean duration of the disease: 14 (±8.59) years. Fibromyalgia was present in 5.7% (76/1343). Corticosteroids use ranged from 49.4% to 57%, depending on the visit. Median SLEDAI ranged from 0 to 2 and SDI ranged from 1 to 2.Prevalence of “depression any time” was 89.9% (1104/1228) and 34.6% (200/578) were in depression “most of time”. Up to 26.5% (153/578) answered to LITQ7 “depression most of time” in the five visits; 89.7% of the patients which perceived themselves as depressed at least in 2 out of 5 visits. Only 6.9% of the patients with previous diagnosis of depression answered “0” to the Q7 of LIT (“none of the time”).Only following covariates showed changes, statistically significative, during the follow up: SLEDAI, SDI, Charlson and glucocorticoids use (Friedman test).Patients with “depression any time” develop more damage at V5 than patients without depression (answer to LITQ7=0) (p = 0.00931, T-test). In the GEE binomial analysis considering all the predefined covariates, that included only patients with no missing values for any of them (namely, 155 patients),fibromyalgia (OR 2.79; 95%CI: 1.28-6.05), unemployment (OR 1.95; 95%CI 1.02 -3.73), and glucocorticoids use (OR 1.88; 95%CI 1.18-2.99) were significant associated with “depression any time”.The best model (according QIC) displayed a statistically significant association only with fibromyalgia (OR 2.90; 95%CI: 1.58-5.33) and glucocorticoids use (OR 1.85; 95%CI 1.17-2.93). Neither SDI nor unemployment reached significance here (Table 1). Without entering glucocorticoids, SLEDAI turns significant in the model, suggesting collinearity.ConclusionThe prevalence of self-perceived depression is high in SLE. Longitudinal data analysis suggests a causal relationship between glucocorticoids use, fibromyalgia and self-perceived depression.Table 1.best multivariable GEE modelORLower limitUpper limit(Intercept)0,1210,0280,529SLEDAI1,0660,9911,147SLICC/ACR DI1,1380,9621,346Age1,0220,9941,051Fibromyalgia2,8981,5765,328BMI1,4850,6853,219Unemployment1,860,9723,56Low incomes1,7260,893,347Glucocorticoids use1,8531,1732,928Single marital status1,2920,7662,179QICC: 1006.75SLICC/ACR DI: SLICC/ACR damage index; BMI: body mass indexAcknowledgementsResearch Unit of the Spanish Society of Rheumatology. Spanish Foundation of Rheumatology financial supporting, through the research intensification grants program. GSK financial supporting,Disclosure of InterestsNone Declared.
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