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| 2. |
- Parodis, I, et al.
(författare)
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Rituximab-mediated late-onset neutropenia in systemic lupus erythematosus - distinct roles of BAFF and APRIL
- 2018
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Ingår i: Lupus. - : SAGE Publications. - 1477-0962 .- 0961-2033. ; 27:9, s. 1470-1478
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Tidskriftsartikel (refereegranskat)abstract
- Rituximab-mediated late-onset neutropenia (LON) has been described in various diseases. We investigated its occurrence, consequences and contributing factors in patients with systemic lupus erythematosus (SLE). Methods Rituximab-treated patients from the Karolinska University Hospital ( n = 107) were surveyed. LON was defined as an absolute neutrophil count <1500 cells/μl, occurring four weeks to two years following rituximab treatment, or later during sustained B-cell depletion. Serum levels of B-cell-related cytokines and growth factors of the myeloid lineage were determined using enzyme-linked immunosorbent assay. Results Thirty-two patients (29.9%) developed LON after a median time of 201.5 days. Thirteen patients were admitted to the hospital; 10 due to fever. Three patients developed critical conditions. BAFF levels increased from baseline (median: 0.62 ng/ml) to the post-treatment evaluation (median: 1.16 ng/ml; p < 0.001); post-treatment levels were higher in the LON group ( p = 0.021). APRIL levels were higher in the LON group both at baseline (median: 1.54 versus 1.15 ng/ml; p = 0.027) and post-treatment (median: 2.39 versus 1.11 ng/ml; p = 0.011). IL-6 and GM-CSF levels decreased in the non-LON group ( p < 0.001), but not in LON patients. High baseline disease activity predicted LON development (OR: 4.1; 95% CI: 1.1–15.2 for SLEDAI-2K > 8). No association with neutropenia prior to rituximab treatment was documented. Conclusion Post-rituximab LON was a common complication. Although the phenomenon was predominantly self-limiting, several patients developed severe conditions. Distinct roles of BAFF and APRIL are implicated: BAFF may contribute to LON development, whereas high APRIL levels may be predictive. Rituximab-treated SLE patients should be monitored for neutrophil counts, fever and infections.
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| 9. |
- Faustini, F, et al.
(författare)
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Rituximab in Systemic Lupus Erythematosus: Transient Effects on Autoimmunity Associated Lymphocyte Phenotypes and Implications for Immunogenicity
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 13, s. 826152-
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Tidskriftsartikel (refereegranskat)abstract
- B cell abnormalities are common in systemic lupus erythematosus (SLE), and include expansion of double negative (DN) and age-associated-like B cells (ABC-like). We aimed to investigate rituximab (RTX) effects on DN and ABC-like B-cell subsets and, when possible, also secondary effects on T cells. Fifteen SLE patients, fulfilling the ACR 1982 criteria, starting RTX and followed longitudinally up to two years, were analyzed for B- and T- lymphocyte subsets using multicolor flow cytometry. DN were defined as IgD-CD27- and ABC-like as CD11c+CD21- within the DN gate. Additional phenotyping was performed adding CXCR5 in the B-cell panel. Cellular changes were further analyzed in the context of the generation of anti-drug antibodies (ADA) against RTX and clinical information. The SLE patients were mainly females (86.6%), of median age 36.7 (29.8-49.4) years and disease duration of 6.1 (1.6-11.8) years. Within the DN subset, ABC-like (IgD-CD27-CD11c+CD21-) B cell frequency reduced from baseline median level of 20.4% to 11.3% (p=0.03), at early follow-up. The DN B cells were further subdivided based on CXCR5 expression. Significant shifts were observed at the early follow-up in the DN2 sub-cluster (CD11c+CXCR5-), which reduced significantly (-15.4 percentage points, p=0.02) and in the recently described DN3 (CD11c-CXCR5-) which increased (+13 percentage points, p=0.03). SLE patients treated with RTX are at high risk of developing ADA. In our cohort, the presence of ADA at 6 months was associated with lower frequencies of DN cells and to a more pronounced expansion of plasmablasts at early follow-up. The frequency of follicular helper T cells (TFH, CD4+PD-1+CXCR5+) and of peripheral helper T cells (TPH, CD4+PD-1+CXCR5-) did not change after RTX. A sub-cluster of PD-1highCD4+ T cells showed a significant decrease at later follow-up compared to early follow-up (p=0.0039). It is well appreciated that RTX transiently influences B cells. Here, we extend these observations to cell phenotypes which are believed to directly contribute to autoimmunity in SLE. We show early transient effects of RTX on ABC-like memory B cells, later effects on PD-1high CD4+ cells, and possible implications for RTX immunogenicity. Further insight in such effects and their monitoring may be of clinical relevance.
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| 10. |
- Faustini, F, et al.
(författare)
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RITUXIMAB THERAPY IN SYSTEMIC LUPUS ERYTHEMATOSUS - TRANSIENT EFFECTS ON AGE ASSOCIATED B-CELLS
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 203-204
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Immune system’s abnormalities in SLE involve several subsets of the B-cell compartment, including double negative B-cells (DN) and CD11c+CD21- B cells (also referred to as ABC-age associated B cells), which are expanded in the disease. ABC cells are also known to interact with T helper cells, T follicular and peripheral helper cells (1). Rituximab, a chimeric anti- CD20 antibody, depleting B cells, is commonly used off-label as treatment for SLE patients, especially in lupus nephritis. Little is known on the impact of B-cell depletion on such B-cell subsets and on B-T-cell interactions.Objectives:to investigate the effects of rituximab (RTX) on the frequencies of double negative B-cell subsets and CD11c+CD21- ABC cells and as well as T follicular helper (TFH, CXCR5+ PD-1+) and T peripheral helper (TPH, PD-1high) CD4+ T-cell subsets.Methods:15 SLE patients, starting RTX and followed longitudinally up to two years, were analyzed for lymphocyte subsets using multicolor flow cytometry. Cryopreserved PBMC were thawed and stained at the same time together with one buffy coat. Around 1 x 106 PBMC for each panel were labeled and further stained with fluorescent antibodies for B and T-cell markers. For the B-cell panel, PBMC were stained with anti-CD3, CD14, CD16, CD19, IgD, CD27, CD38, CD11c, CD21 and in some samples with anti-CXCR5 antibodies. For the T-cell panel, PBMC were labeled with anti-CD16, CD14, CD19 and CD3, CD4, CD8, PD-1, CCR7, CXCR5, CD45RA antibodies. All patients fulfilled the ACR 1982 classification criteria for SLE. Cellular changes were analyzed in the context of clinical information.Results:in the present cohort, the SLE patients were mainly female (86.6%) and of median age of 36.7 (29.8-49.4) with a disease duration of 6.1(1.6-11.8) years, and active disease with SLEDAI-2K at baseline 12.0 (8.0-16.0). The frequency of age-associated B cells (ABCs; CD27-IgD-CD11c+ CD21-) decreased by 13% (p=0.03) in the first two to four months after rituximab start, while globally the DN (IgD-CD27-) B cells transiently increased by around 3% (p=0.15) at the first follow-up. This increase could not be attributed to the DN1 (CXCR5+CD11c-) or DN2 (CXCR5-CD11c+) subsets but to the CD11c-CXCR5- DN (DN3) B cells (increase= 6.7%, p=0.03). In parallel, T effector cells (CCR7- CD45RA+) and TEMRA (CD45RA+ CCR7-) frequencies increased after first follow up in both CD4+ and CD8+ T cells. The frequency of TFH (CXCR5+ PD-1+) cells did not change after rituximab, however a decrease of PD-1high CD4+ cells was observed in most patients, although not significant, after 2-4 month of treatment. In most patients the frequency of PD-1high CD4+ cells either reduce or stay the same after RTX treatment (reduction= 0.53, p=0.28). After 11-15 months of RTX treatment the frequency of PD-1high CD4+ T cell reduces by a -0.5% in comparison to 2-4 months (p=0.039). The SLEDAI at baseline did not correlate with the frequency of PD-1high CD4+ T cells (r=0.03, p=0.9).Conclusion:the importance of T cell - B cell interactions in SLE pathogenesis was recently strengthened by the identification of the lymphocyte subsets TFH/TPH and ABCs respectively. Here, in the context of rituximab treated SLE, we could detect a reduction in the frequencies of both ABCs and PD-1high T cells after treatment with rituximab, while the DN3 and effector memory T cells frequencies increased. Our data suggests that anti-CD20 mediated B-cell depletion affects both B-cell and T-cell subsets frequencies, and that monitoring these specific cell subsets may be clinically relevant.References:[1]Bocharnikov AV, Keegan J, Wacleche VS, Cao Y, Fonseka CY, Wang G, et al. PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21. JCI insight. 2019;4(20)Disclosure of Interests:Francesca Faustini Speakers bureau: More than two years ago and not in relation to any aspect of the present research, Natalie Sippl: None declared, Ragnhild Stålesen: None declared, Karine Chemin: None declared, Iva Gunnarsson: None declared, Vivianne Malmström: None declared.
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| 12. |
- Faustini, F, et al.
(författare)
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URINE-GALECTINE 3 BINDING PROTEIN (U-GAL3BP) IS A SENSITIVE MARKER OF KIDNEY INFLAMMATION AND RESPONSE TO TREATMENT IN LUPUS
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 305-306
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Lupus nephritis (LN) represents a serious manifestation of systemic lupus erythematosus (SLE) which requires timely diagnosis, treatment and monitoring. Kidney biopsy is the gold standard of diagnosis and is instrumental to treatment decisions, however it is not generally performed for monitoring and evaluation of response to treatment. To such purposes, accessible biomarkers, for instance urinary, might be highly advantageous.Objectives:To evaluate urine-Galectin 3 binding protein (uGAL3BP) as a novel biomarker in biopsy-proven active lupus nephritis (A-LN) in comparison to active non-renal SLE (ANR-SLE), inactive SLE (I-SLE), and in population-based controls (HC). Furthermore, we compared uGAL3BP with known markers of renal pathology including neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), kidney injury molecule 1 (KIM-1), and galectin 3 (GAL3).Methods:Urine samples from A-LN (n=86), ANR-SLE (n=63), I-SLE (n=73) and HC (n=48) were included. uGAL3BP was measured using a commercial ELISA kit and values, adjusted for u-creatinine levels, were expressed as ng/mmol. Other markers analyzed according to clinical routine at the Department of Clinical Chemistry at Uppsala University Hospital were also adjusted for u-creatinine levels. Renal biopsies were graded according to the ISN/RPS classification(1) and evaluated for activity and chronicity index. Ten A-LN patients were evaluated before and after induction treatment.Results:In the A-LN group, median (IQR) levels of u-GAL3BP were 15.8 (6.8-24.6) ng/mmol, while in ANR-SLE, I-SLE, HC were significantly lower 4.4 (2.0-9.0), 2.8 (1.7-4.7), 2.0 (0.9-4.8) respectively (Kruskal-Wallis p<0.0001). Similarly, u-NGAL was found at higher levels in A-LN patients, 3.3 (2.0-5.7) μg/mmol, with respect to the ANR-SLE 2.0 (0.9-4.5), I-SLE 1.6 (0.8-3.2), and HC 2.4 (1.2-5.3), (p=0.008). The highest levels of OPN were found in the group of I-SLE (190.6 (85.1-299.9) μg/mmol, compared to A-LN 72.98 (37.6-118.1), ANR-SLE 92.3 (58.5-129.7) and HC 76.5 (58.2-120.3), (p<0.0001). KIM-1 levels differed among groups with higher levels in the A-LN group (188.9 (113.7-309.7) ng/mmol), in comparison to ANR-SLE 131.4 (92.2-186.1), I-SLE 123.8 (70.3-200.2), and HC 78.2 (68.8-115.1), (p<0.0001). GAL3 showed comparable levels across groups.When exploring the biomarkers across histologic subgroups of LN, u-GAL3BP could discriminate between proliferative and mesangial forms (17.7(9.6-32.5) vs 6.7(5.1-16.1) ng/mmol, p=0.027), while it did not discriminate against membranous LN. U-NGAL was higher in proliferative LN 3.7(2.4-5.8) µg/mmol with respect to membranous 2.4 (1.1-3.8) (p=0.01), while mesangial LN showed comparable levels. OPN, KIM-1 and GAL3 were comparable across groups.In the ten patients with available samples after induction therapy (mycophenolate mofetil (MMF) in 4, rituximab (RTX) in one, cyclophosphamide in 5 (one combined with MMF and one with RTX), u-GAL3BP showed a significant decrease of median levels from 218.8 to 41.5 ng/mmol (Wilcoxon p=0.03). u-GAL3BP associated with renal activity in class III/IV LN (R=0.42, p=0.004).Conclusion:Among the tested markers, high uGal3BP adjusted for creatinine was found to be a promising marker of renal involvement in SLE patients and associated with renal activity in patients with proliferative forms (class III/IV) of LN. A decrease was further seen following therapy, suggesting that u GAL3-BP could be used to monitor renal activity.References:[1]Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241-50.[2]Houssiau FA, Vasconcelos C, D’Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum. 2002;46(8):2121-31.Disclosure of Interests:Francesca Faustini Speakers bureau: I have received speaking fees, last time more than two years ago, Helena Idborg: None declared, Elisabet Svenungsson: None declared, Sven Poetzsch Employee of: Merck Serono, Shinji Okitsu Employee of: Merck Serono, Anders Larsson: None declared, Iva Gunnarsson: None declared
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| 14. |
- Hetland, M. L., et al.
(författare)
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Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial
- 2020
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Ingår i: Bmj-British Medical Journal. - : BMJ. - 1756-1833. ; 371
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. DESIGN Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. SETTING Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. PARTICIPANTS Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. INTERVENTIONS Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intraarticular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. MAIN OUTCOME MEASURES The primary outcome was adjusted clinical disease activity index remission (CDAI <= 2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. RESULTS 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. CONCLUSIONS All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.
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| 17. |
- Kharlamova, N., et al.
(författare)
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False Positive Results in SARS-CoV-2 Serological Tests for Samples From Patients With Chronic Inflammatory Diseases
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Patients with chronic inflammatory diseases are often treated with immunosuppressants and therefore are of particular concern during the SARS-CoV-2 pandemic. Serological tests will improve our understanding of the infection and immunity in this population, unless they tests give false positive results. The aim of this study was to evaluate the specificity of SARS-Cov-2 serological assays using samples from patients with chronic inflammatory diseases collected prior to April 2019, thus defined as negative. Samples from patients with multiple sclerosis (MS, n=10), rheumatoid arthritis (RA, n=47) with or without rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibodies (anti-CCP2) and systemic lupus erythematosus (SLE, n=10) with or without RF, were analyzed for SARS-CoV-2 antibodies using 17 commercially available lateral flow assays (LFA), two ELISA kits and one in-house developed IgG multiplex bead-based assay. Six LFA and the in-house validated IgG assay correctly produced negative results for all samples. However, the majority of assays (n=13), gave false positive signal for samples from patients with RA and SLE. This was most notable in samples from RF positive RA patients. No false positive samples were detected in any assay using samples from patients with MS. Poor specificity of commercial serological assays could possibly be, at least partly, due to interfering antibodies in samples from patients with chronic inflammatory diseases. For these patients, the risk of false positivity should be considered when interpreting results of the SARS-CoV-2 serological assays.
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| 20. |
- Ostergaard, Mikkel, et al.
(författare)
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Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis : 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial
- 2023
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ PUBLISHING GROUP. - 0003-4967 .- 1468-2060. ; 82:10, s. 1286-1295
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Tidskriftsartikel (refereegranskat)abstract
- Background The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action. Methods Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naive early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI <= 2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025). Results Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences. Conclusions Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments.
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| 23. |
- Sippl, N., et al.
(författare)
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Arthritis in systemic lupus erythematosus is characterized by local IL-17A and IL-6 expression in synovial fluid
- 2021
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Ingår i: Clinical and Experimental Immunology. - : John Wiley & Sons. - 0009-9104 .- 1365-2249. ; 205:1, s. 44-52
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Tidskriftsartikel (refereegranskat)abstract
- Arthritis is a common clinical feature of systemic lupus erythematosus (SLE) and is usually non-erosive, as opposed to rheumatoid arthritis (RA). While RA synovial pathology has been extensively studied, little is known about the pathophysiology of lupus arthritis. Here, we aimed to explore the cytokine and cellular compartments in synovial fluids of SLE patients with arthritic manifestations. Acellular synovial fluid and paired serum samples from SLE patients (n = 17) were analyzed with cytokine bead array for T helper-associated cytokines. From two SLE patients, synovial fluid mononuclear cells (SFMC) could also be captured and were analyzed by multiparameter flow cytometry to dissect T cell, B cell, monocyte and dendritic cell phenotypes. SLE-derived SFMC were further stimulated in vitro to measure their capacity for producing interferon (IFN)-gamma and interleukin (IL)-17A. All patients fulfilled the ACR 1982 classification criteria for SLE. Clinical records were reviewed to exclude the presence of co-morbidities such as osteoarthritis or overlap with RA. IL-17A and IL-6 levels were high in SLE synovial fluid. A clear subset of the synovial CD4(+) T cells expressed CCR6(+), a marker associated with T helper type 17 (Th17) cells. IL-17A-production was validated among CD4(+)CCR6(+) T cells following in-vitro stimulation. Furthermore, a strong IFN-gamma production was observed in both CD4(+) and CD8(+) cells. Our study shows high IL-17A and IL-6 levels in synovial fluids of patients with lupus arthritis. The Th17 pathway has been implicated in several aspects of SLE disease pathogenesis and our data also point to Th17 involvement for lupus arthritis.
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