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11 pages, 2316 KiB

Open AccessArticle

Renal Tissue Expression of BAFF and BAFF Receptors Is Associated with Proliferative Lupus Nephritis

by Miguel Marín-Rosales, Claudia Azucena Palafox-Sánchez, Ramón Antonio Franco-Topete, Francisco Josué Carrillo-Ballesteros, Alvaro Cruz, Diana Celeste Salazar-Camarena, José Francisco Muñoz-Valle and Francisco Ramos-Solano

J. Clin. Med. 2023, 12(1), 71; https://doi.org/10.3390/jcm12010071 - 22 Dec 2022

Cited by 5 | Viewed by 1859

Abstract

Background: The B-cell activating factor (BAFF) controls the maturation and survival of B cells. An imbalance in this cytokine has been associated with systemic autoimmunity in SLE and lupus nephritis (LN). However, few investigations have evaluated the tissular expression of BAFF in LN. [...] Read more.

Background: The B-cell activating factor (BAFF) controls the maturation and survival of B cells. An imbalance in this cytokine has been associated with systemic autoimmunity in SLE and lupus nephritis (LN). However, few investigations have evaluated the tissular expression of BAFF in LN. This study aimed to associate BAFF system expression at the tissular level with the proliferative LN classes. Methods: The analysis included eighteen kidney tissues, with sixteen LN (class III = 5, class IV = 6, class III/IV+V = 4, and class V = 1), and two controls. The tissular expression was evaluated with an immunochemistry assay. A Cytation5 imaging reader and ImageJ software were used to analyze the quantitative expression. A p-value < 0.05 was considered significant. Results: The expressions of BAFF, A proliferation-inducing ligand (APRIL), and their receptors were observed in glomerular, tubular, and interstitial zones, with BAFF being the most strongly expressed in the overall analysis. BAFF-Receptor (BR3), transmembrane activator and CALM interactor (TACI), and B-Cell maturation antigen (BCMA) displayed higher expressions in LN class IV in all zones analyzed (p < 0.05). Additionally, a positive correlation was found between APRIL, TACI, and BCMA at the glomerular level; BCMA and APRIL in the interstitial zone; and BR3, TACI, and BCMA in the tubule (p < 0.05). Conclusions: The expression of BAFF and BAFF receptors is mainly associated with LN class IV, emphasizing the participation of these receptors as an essential pathogenic factor in kidney involvement in SLE patients. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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15 pages, 1255 KiB

Open AccessArticle

Predictors of Early Response, Flares, and Long-Term Adverse Renal Outcomes in Proliferative Lupus Nephritis: A 100-Month Median Follow-Up of an Inception Cohort

by Eleni Kapsia, Smaragdi Marinaki, Ioannis Michelakis, George Liapis, Petros P. Sfikakis, John Boletis and Maria G. Tektonidou

J. Clin. Med. 2022, 11(17), 5017; https://doi.org/10.3390/jcm11175017 - 26 Aug 2022

Cited by 10 | Viewed by 2553

Abstract

Objective: To define predictors of response, time to response, flares, and long-term renal outcome in an inception cohort of proliferative lupus nephritis (PLN). Methods: We included 100 patients (80% female; mean age 31 ± 13 years) with biopsy-proven PLN (III, IV, III/IV + [...] Read more.

Objective: To define predictors of response, time to response, flares, and long-term renal outcome in an inception cohort of proliferative lupus nephritis (PLN). Methods: We included 100 patients (80% female; mean age 31 ± 13 years) with biopsy-proven PLN (III, IV, III/IV + V). Clinical, laboratory, histological and therapeutical parameters were recorded at baseline, 6, 9, 12, 18, 24, 36, 72 months, time of flare, and last follow-up visit. Logistic and Cox-regression models were applied. Results: After induction treatment (69% received cyclophosphamide (CYC) and 27% mycophenolic acid (MPA)), partial (PR) or complete (CR) response was achieved in 59% (26% CR, 33% PR) and 67% (43% CR, 24% PR) of patients at 3 and 6 months, respectively; median time to PR was 3 months (IQR 5) and median time to CR was 6 months (IQR 9). Baseline proteinuria <1.5 g/day correlated with a shorter time to CR (HR 1.77) and with CR at 3, 6, and 9 months (OR 9.4, OR 5.3 and OR 3.7, respectively). During 100-month median follow-up, 33% of patients had ≥1 renal flares (median time: 38 months). Proteinuria >0.8 g/day at 12 months was associated with a higher risk of flares (OR 4.12), while MPA and mixed classes with lower risk (OR 0.14 and OR 0.13, respectively). Baseline proteinuria >2 g/day and 12-month proteinuria >0.8 g/day correlated with a shorter time to flare (HR 2.56 and HR 2.57, respectively). At the end of follow-up, 10% developed stage 3–4 chronic kidney disease (CKD), and 12% end-stage renal disease (ESRD). Twelve-month proteinuria >0.8 g/day (OR 10.8) and interstitial fibrosis/tubular atrophy >25% (OR 7.7) predicted CKD or ESRD at last visit. Conclusions: Baseline proteinuria <1.5 g/day predicted time to CR. Twelve-month proteinuria >0.8 g/day correlated with flares (ever) and time to flare and, along with baseline interstitial fibrosis/tubular atrophy >25%, predicted CKD or ESRD at the last visit. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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15 pages, 1460 KiB

Open AccessArticle

Association of microRNA-34a rs2666433 (A/G) Variant with Systemic Lupus Erythematosus in Female Patients: A Case-Control Study

by Nesreen M. Ismail, Eman A. Toraih, Mai H. S. Mohammad, Eida M. Alshammari and Manal S. Fawzy

J. Clin. Med. 2021, 10(21), 5095; https://doi.org/10.3390/jcm10215095 - 30 Oct 2021

Cited by 3 | Viewed by 1898

Abstract

Several microRNAs (miRNAs) are associated with autoimmune disease susceptibility and phenotype, including systemic lupus erythematosus (SLE). We aimed to explore for the first time the role of the miRNA-34a gene (MIR34A) rs2666433A > G variant in SLE risk and severity. A total of [...] Read more.

Several microRNAs (miRNAs) are associated with autoimmune disease susceptibility and phenotype, including systemic lupus erythematosus (SLE). We aimed to explore for the first time the role of the miRNA-34a gene (MIR34A) rs2666433A > G variant in SLE risk and severity. A total of 163 adult patients with SLE and matched controls were recruited. Real-Time allelic discrimination PCR was applied for genotyping. Correlation with disease activity and clinic-laboratory data was done. The rs2666433 variant conferred protection against SLE development under heterozygous [A/G vs. G/G; OR = 0.57, 95%CI = 0.34–0.95], homozygous [A/A vs. G/G; OR = 0.52, 95%CI = 0.29–0.94], dominant [A/G + A/A vs. GG; OR = 0.55, 95%CI = 0.35–0.88], and log-additive [OR = 0.71, 95%CI = 0.53–0.95] models. Data stratification by sex revealed a significant association with SLE development in female participants under heterozygous/homozygous models (p-interaction = 0.004). There was no clear demarcation between SLE patients carrying different genotypes regarding the disease activity index or patients stratified according to lupus nephritis. Enrichment analysis confirmed the implication of MIR34A in the SLE pathway by targeting several genes related to SLE etiopathology. In conclusion, although the MIR34A rs2666433 variant conferred protection against developing SLE disease in the study population, it showed no association with disease activity. Replication studies in other populations are warranted. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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14 pages, 1230 KiB

Open AccessArticle

Lack of Association between Serum Interleukin-23 and Interleukin-27 Levels and Disease Activity in Patients with Active Systemic Lupus Erythematosus

by Katarzyna Pawlak-Buś, Wiktor Schmidt and Piotr Leszczyński

J. Clin. Med. 2021, 10(20), 4788; https://doi.org/10.3390/jcm10204788 - 19 Oct 2021

Cited by 2 | Viewed by 1825

Abstract

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of multiple autoantibodies, resulting in tissue and organ damage. Recent studies have revealed that interleukin-23 (IL-23) and interleukin-27 (IL-27) may be therapeutically relevant in selected SLE manifestations. This study [...] Read more.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of multiple autoantibodies, resulting in tissue and organ damage. Recent studies have revealed that interleukin-23 (IL-23) and interleukin-27 (IL-27) may be therapeutically relevant in selected SLE manifestations. This study aimed to identify associations between serum IL-27 and IL-23 levels and disease activity in Polish patients with different manifestations of SLE: neuropsychiatric lupus (NPSLE), and lupus nephritis (LN). Associations between interleukin levels and oligo-specific antibodies against double-stranded DNA (dsDNA), dose of glucocorticoids, and type of treatment were also analyzed. An enzyme-linked immunosorbent assay was used to assess anti-dsDNA antibodies and analyze the serum concentration of IL-27 and IL-23 from 72 patients aged 19–74 years with confirmed active SLE. Disease activity was measured using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2-K). No significant correlations between interleukin levels and SLEDAI score, anti-dsDNA, corticosteroid dose, or type of treatment were noted. Patients with NPSLE and LN presented the highest median scores of SLEDAI. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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16 pages, 2531 KiB

Open AccessArticle

Change of Renal Gallium Uptake Correlated with Change of Inflammation Activity in Renal Pathology in Lupus Nephritis Patients

by Tsu-Yi Hsieh, Yi-Ching Lin, Wei-Ting Hung, Yi-Ming Chen, Mei-Chin Wen, Hsin-Hua Chen, Wan-Yu Lin, Chia-Wei Hsieh, Ching-Tsai Lin, Kuo-Lung Lai, Kuo-Tung Tang, Chih-Wei Tseng, Wen-Nan Huang, Yi-Hsing Chen, Shih-Chuan Tsai and Yi-Da Wu

J. Clin. Med. 2021, 10(20), 4654; https://doi.org/10.3390/jcm10204654 - 11 Oct 2021

Cited by 1 | Viewed by 2229

Abstract

Background: Lupus nephritis (LN) often lead to end-stage renal disease in systemic lupus erythematosus patients. This study aimed to investigate the clinical application of renal gallium-67 scans for determining renal histological parameters in LN patients. Methods: Between 2006 and 2018, 237 biopsy-proven and [...] Read more.

Background: Lupus nephritis (LN) often lead to end-stage renal disease in systemic lupus erythematosus patients. This study aimed to investigate the clinical application of renal gallium-67 scans for determining renal histological parameters in LN patients. Methods: Between 2006 and 2018, 237 biopsy-proven and 35 repeat biopsies LN patients who underwent renal gallium scans before or after biopsy were included for analysis. The classification and scoring of LN were assessed according to the International Society of Nephrology/Renal Pathology Society. A delayed 48-h gallium scan was performed and interpreted by semiquantitative methods using left kidney/spine (K/S) ratio. The renal histological results were compared with gallium uptake. Results: Out of 237 participants, 180 (76%) had proliferative LN. Baseline gallium left K/S ratio was significantly higher in class IV LN as compared to class III (median (interquartile range, IQR): 1.16 (1.0–1.3), 0.95 (0.9–1.1), respectively, p < 0.001). Furthermore, changes in gallium uptake between two biopsies were positively correlated with changes activity index (r = 0.357, p = 0.035), endocapillary hypercellularity (r = 0.385, p = 0.032), and neutrophils infiltration (r = 0.390, p = 0.030) in renal pathology. Conclusions: Renal gallium uptake is associated with active inflammation in LN. Changes in renal gallium uptake positively correlated with changes in activity index in renal pathology. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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18 pages, 1167 KiB

Open AccessArticle

Mindfulness-Based Stress Reduction for Systemic Lupus Erythematosus: A Mixed-Methods Pilot Randomized Controlled Trial of an Adapted Protocol

by Renen Taub, Danny Horesh, Noa Rubin, Ittai Glick, Orit Reem, Gitit Shriqui and Nancy Agmon-Levin

J. Clin. Med. 2021, 10(19), 4450; https://doi.org/10.3390/jcm10194450 - 28 Sep 2021

Cited by 6 | Viewed by 3023

Abstract

Background: The psychological effects of systemic lupus erythematosus (SLE) are tremendous. This pilot mixed-methods randomized controlled trial aimed to evaluate the effects of a mindfulness-based stress reduction (MBSR) adapted protocol on psychological distress among SLE patients. Methods: 26 SLE patients were randomly assigned [...] Read more.

Background: The psychological effects of systemic lupus erythematosus (SLE) are tremendous. This pilot mixed-methods randomized controlled trial aimed to evaluate the effects of a mindfulness-based stress reduction (MBSR) adapted protocol on psychological distress among SLE patients. Methods: 26 SLE patients were randomly assigned to MBSR group therapy (n = 15) or a waitlist (WL) group (n = 11). An adapted MBSR protocol for SLE was employed. Three measurements were conducted: pre-intervention, post-intervention and 6-months follow up. A sub-sample (n = 12) also underwent qualitative interviews to assess their subjective experience of MBSR. Results: Compared to the WL, the MBSR group showed greater improvements in quality of life, psychological inflexibility in pain and SLE-related shame. Analysis among MBSR participants showed additional improvements in SLE symptoms and illness perception. Improvements in psychological inflexibility in pain and SLE-related shame remained stable over six months, and depression levels declined steadily from pre-treatment to follow-up. Qualitative analysis showed improvements in mindfulness components (e.g., less impulsivity, higher acceptance), as well as reduced stress following MBSR. Conclusions: These results reveal the significant therapeutic potential of MBSR for SLE patients. With its emphasis on acceptance of negative physical and emotional states, mindfulness practice is a promising treatment option for SLE, which needs to be further applied and studied. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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9 pages, 1329 KiB

Open AccessArticle

Cytomegalovirus-Associated Autoantibody against TAF9 Protein in Patients with Systemic Lupus Erythematosus

by Yen-Fu Chen, Ao-Ho Hsieh, Lian-Chin Wang, Kuang-Hui Yu and Chang-Fu Kuo

J. Clin. Med. 2021, 10(16), 3722; https://doi.org/10.3390/jcm10163722 - 21 Aug 2021

Viewed by 2373

Abstract

Background: Evidence indicates a causal link between cytomegalovirus (CMV) infection and the triggering of systemic lupus erythematosus (SLE). Animal studies have revealed that CMV phosphoprotein 65 (pp65) induces autoantibodies against nuclear materials and causes the autoantibody attack of glomeruli. IgG eluted from [...] Read more.

Background: Evidence indicates a causal link between cytomegalovirus (CMV) infection and the triggering of systemic lupus erythematosus (SLE). Animal studies have revealed that CMV phosphoprotein 65 (pp65) induces autoantibodies against nuclear materials and causes the autoantibody attack of glomeruli. IgG eluted from the glomeruli of CMVpp65-peptide-immunized mice exhibited cross-reactivity against dsDNA and TATA-box-binding protein associated factor 9 (TAF9). Whether the elevation of anti-TAF9 IgG is associated with anti-CMV reactivity in human lupus remains unclear. Methods: The sera from patients with rheumatic diseases, including ankylosing spondylitis (AS), gout, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren syndrome (SS) were examined using ELISA for antibodies of CMV, CMVpp65, and TAF9. Results: In total, 83.8% of the rheumatic patients had acquired CMV infections. The SLE patients had a high prevalence of anti-CMV IgM. The highest seropositivity rates for anti-HCMVpp65 and anti-TAF9 IgG were observed in the SLE patients. Purified anti-CMVpp65 IgG from CMVpp65/TAF9 dual-positive SLE sera reacted to both TAF9 and dsDNA. An increased prevalence of proteinuria and low hemoglobin levels were found in CMV IgG- and CMVpp65 IgG-positive SLE patients. Conclusions: This observation suggests that immunity to CMVpp65 is associated with cross-reactivity with TAF9 and dsDNA and that it is involved in the development of clinical manifestations in SLE. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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9 pages, 462 KiB

Open AccessArticle

Assessment of EULAR/ACR-2019, SLICC-2012 and ACR-1997 Classification Criteria in SLE with Longstanding Disease

by Berta Magallares, David Lobo-Prat, Ivan Castellví, Patricia Moya, Ignasi Gich, Laura Martinez-Martinez, Hye Park, Ana Milena Millán, Ana Laiz, César Díaz-Torné, Susana Fernandez and Hèctor Corominas

J. Clin. Med. 2021, 10(11), 2377; https://doi.org/10.3390/jcm10112377 - 28 May 2021

Cited by 10 | Viewed by 3357

Abstract

Background: Different classification criteria for systemic lupus erythematosus (SLE) have been launched over the years. Our aim was to evaluate the performance of the EULAR/ACR-2019, SLICC-2012 and ACR-1997 classification criteria in a cohort of SLE patients with longstanding disease. Methods: Descriptive observational study [...] Read more.

Background: Different classification criteria for systemic lupus erythematosus (SLE) have been launched over the years. Our aim was to evaluate the performance of the EULAR/ACR-2019, SLICC-2012 and ACR-1997 classification criteria in a cohort of SLE patients with longstanding disease. Methods: Descriptive observational study in 79 patients with established and longstanding SLE. The three classification criteria sets were applied to those patients. Results: Of the 79 patients, 70 were women (88.6%), with a mean age of 51.8 ± 14 years and a mean disease duration of 15.2 ± 11.5 years. The sensitivity of the different criteria were: 51.9%, 87.3% and 86.1% for ACR-1997, SLICC-2012 and EULAR/ACR-2019, respectively. In total, 68 out of 79 patients (53.7%) met all three classification criteria; 11.4% did not meet any classification criteria and were characterized by low SLEDAI (0.6 ± 0.9), low SLICC/ACR Damage Index (0.88 ± 0.56) and fulfilling only skin domains, antiphospholipid antibodies or hypocomplementemia. To fulfill EULAR/ACR-2019 criteria was associated with low complement levels (p < 0.04), high anti-dsDNA levels (p < 0.001), presence of lupus nephritis III-IV (p < 0.05) and arthritis (p < 0.001). Conclusion: The EULAR/ACR-2019 classification criteria showed high sensitivity, similar to SLICC-2012, in SLE patients with longstanding disease. Patients with serological, articular or renal involvement are more likely to fulfill SLICC-2012 or EULAR/ACR-2019 criteria. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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16 pages, 1118 KiB

Open AccessArticle

High Comorbidity Burden in Patients with SLE: Data from the Community-Based Lupus Registry of Crete

by Irini Gergianaki, Panagiotis Garantziotis, Christina Adamichou, Ioannis Saridakis, Georgios Spyrou, Prodromos Sidiropoulos and George Bertsias

J. Clin. Med. 2021, 10(5), 998; https://doi.org/10.3390/jcm10050998 - 02 Mar 2021

Cited by 25 | Viewed by 3014

Abstract

Comorbidities and multimorbidity, often complicating the disease course of patients with chronic inflammatory rheumatic diseases, may be influenced by disease-intrinsic and extrinsic determinants including regional and social factors. We analyzed the frequency and co-segregation of self-reported comorbid diseases in a community-based Mediterranean registry [...] Read more.

Comorbidities and multimorbidity, often complicating the disease course of patients with chronic inflammatory rheumatic diseases, may be influenced by disease-intrinsic and extrinsic determinants including regional and social factors. We analyzed the frequency and co-segregation of self-reported comorbid diseases in a community-based Mediterranean registry of patients (n = 399) with systemic lupus erythematosus (SLE). Predictors for multimorbidity were identified by multivariable logistic regression, strongly-associated pairs of comorbidities by the Cramer’s V-statistic, and comorbidities clusters by hierarchical agglomerative clustering. Among the most prevalent comorbidities were thyroid (45.6%) and metabolic disorders (hypertension: 24.6%, dyslipidemia: 33.3%, obesity: 35.3%), followed by osteoporosis (22.3%), cardiovascular (20.8%), and allergic (20.6%) disorders. Mental comorbidities were also common, particularly depression (26.7%) and generalized anxiety disorder (10.7%). Notably, 51.0% of patients had ≥3 physical and 33.1% had ≥2 mental comorbidities, with a large fraction (n = 86) displaying multimorbidity from both domains. Sociodemographic (education level, marital status) and clinical (disease severity, neurological involvement) were independently associated with physical or mental comorbidity. Patients were grouped into five distinct clusters of variably prevalent comorbid diseases from different organs and domains, which correlated with SLE severity patterns. Conclusively, our results suggest a high multimorbidity burden in patients with SLE at the community, advocating for integrated care to optimize outcomes. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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9 pages, 988 KiB

Open AccessArticle

Serum Levels of T Cell Immunoglobulin and Mucin-Domain Containing Molecule 3 in Patients with Systemic Lupus Erythematosus

by Tomoyuki Asano, Naoki Matsuoka, Yuya Fujita, Haruki Matsumoto, Jumpei Temmoku, Makiko Yashiro-Furuya, Shuzo Sato, Eiji Suzuki, Hiroko Kobayashi, Hiroshi Watanabe and Kiyoshi Migita

J. Clin. Med. 2020, 9(11), 3563; https://doi.org/10.3390/jcm9113563 - 05 Nov 2020

Cited by 10 | Viewed by 2025

Abstract

Objective: T cell immunoglobulin and mucin-domain-containing molecule 3 (TIM-3) is implicated in the development of various autoimmune diseases. We aimed to investigate the levels of soluble TIM-3 (sTIM-3) and their associations between clinical parameters in patients with systemic lupus erythematosus (SLE). Methods: Serum [...] Read more.

Objective: T cell immunoglobulin and mucin-domain-containing molecule 3 (TIM-3) is implicated in the development of various autoimmune diseases. We aimed to investigate the levels of soluble TIM-3 (sTIM-3) and their associations between clinical parameters in patients with systemic lupus erythematosus (SLE). Methods: Serum samples were collected from 65 patients with SLE and 35 age-matched healthy controls (HCs). The SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics (SLICC) damage index (SDI) were used to assess SLE disease activity and SLE-related organ damage. British Isles Lupus Assessment Group (BILAG)-2004 index was also used to assess SLE disease activity. Soluble TIM-3 (sTIM-3) in sera from patients with SLE and HCs were evaluated by enzyme-linked immunosorbent assay (ELISA). The results were compared with the clinical parameters of SLE including SLE disease activity. Results: Serum sTIM-3 levels in patients with SLE (median 2123 pg/mL (interquartile range (IQR), 229–7235)) were significantly higher than those in HCs (1363 pg/mL; IQR, 1097–1673; p = 0.0015). Serum levels of sTIM-3 were correlated with disease activity of SLE using the SLEDAI-2K score (p < 0.001, r = 0.53). The serum sTIM-3 levels in SLE patients with active renal disease (BILAG renal index A-B) were significantly higher than those without the active renal disease (BILAG renal index C–E). However, no significant difference was observed in serum sTIM-3 levels between SLE patients with and without active involvement in other organs (BILAG index). Serum sTIM-3 levels were significantly elevated in SLE patients with organ damage (2710 pg/mL; IQR, 256–7235) compared to those without organ damage (1532 pg/mL; IQR, 228–5274), as assessed by the SDI (p = 0.0102). Conclusions: Circulating sTIM-3 levels are elevated in SLE patients, and serum sTIM-3 levels are associated with SLE disease activity and SLE-related organ damage. The data indicate a possible link between the TIM-3/Gal-9 pathway and SLE clinical phenotypes, and further investigation of the TIM-3 pathway in SLE pathophysiology is warranted. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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17 pages, 2395 KiB

Open AccessArticle

Insights into the Procoagulant Profile of Patients with Systemic Lupus Erythematosus without Antiphospholipid Antibodies

by Elena Monzón Manzano, Ihosvany Fernández-Bello, Raúl Justo Sanz, Ángel Robles Marhuenda, Francisco Javier López-Longo, Paula Acuña, María Teresa Álvarez Román, Víctor Jiménez Yuste and Nora V. Butta

J. Clin. Med. 2020, 9(10), 3297; https://doi.org/10.3390/jcm9103297 - 14 Oct 2020

Cited by 9 | Viewed by 2619

Abstract

We aimed to identify the key players in the prothrombotic profile of patients with systemic lupus erythematosus (SLE) not mediated by antiphospholipid antibodies, as well as the potential utility of global coagulation tests to characterize hemostasis in these patients. Patients with SLE without [...] Read more.

We aimed to identify the key players in the prothrombotic profile of patients with systemic lupus erythematosus (SLE) not mediated by antiphospholipid antibodies, as well as the potential utility of global coagulation tests to characterize hemostasis in these patients. Patients with SLE without antiphospholipid antibodies and without signs of thrombosis were included. The kinetics of clot formation were determined by ROTEM^®. Platelet activation markers were determined by flow cytometry. Thrombin generation associated with Neutrophil Extracellular Traps (NETs) and microparticles (MPs) was measured by calibrated automated thrombogram (CAT). The plasma levels of PAI-1 were also determined. ROTEM^® showed a procoagulant profile in SLE patients. SLE patients had activated platelets and more leukocyte/platelet aggregates at basal conditions. The plasma PAI-1 and platelet aggregates correlated with several ROTEM^® parameters. The thrombin generation associated withthe tissue factor (TF) content of MPs and with NETs was increased. Our results suggest the utility of global tests for studying hemostasis in SLE patients because they detect their procoagulant profile, despite having had neither antiphospholipid antibodies nor any previous thrombotic event. A global appraisal of hemostasis should, if possible, be incorporated into clinical practice to detect the risk of a thrombotic event in patients with SLE and to consequently act to prevent its occurrence. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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14 pages, 541 KiB

Open AccessArticle

Adverse Pregnancy Outcomes after Multi-Professional Follow-Up of Women with Systemic Lupus Erythematosus: An Observational Study from a Single Centre in Sweden

by Muna Saleh, Christopher Sjöwall, Helena Strevens, Andreas Jönsen, Anders A. Bengtsson and Michele Compagno

J. Clin. Med. 2020, 9(8), 2598; https://doi.org/10.3390/jcm9082598 - 11 Aug 2020

Cited by 13 | Viewed by 2709

Abstract

While the management of pregnant patients with systemic lupus erythematosus (SLE) has improved over the last decades, the risk of maternal, foetal, and neonatal complications is still substantial. We evaluated the occurrence of adverse pregnancy outcomes (APO) occurring in 2002–2018 among patients with [...] Read more.

While the management of pregnant patients with systemic lupus erythematosus (SLE) has improved over the last decades, the risk of maternal, foetal, and neonatal complications is still substantial. We evaluated the occurrence of adverse pregnancy outcomes (APO) occurring in 2002–2018 among patients with SLE from the catchment area of the Department of Rheumatology in Lund, Sweden. Longitudinal clinical and laboratory data were collected and analysed. Results were stratified according to the sequence of conception. We investigated a total of 59 pregnancies in 28 patients. Prior lupus nephritis was the clinical feature that, in a multivariable regression analysis, displayed the strongest association with APO overall (OR 6.0, p = 0.02). SLE combined with antiphospholipid syndrome (APS) was associated with the risk of miscarriage (OR 3.3, p = 0.04). The positivity of multiple antiphospholipid antibodies (aPL) was associated with APO overall (OR 3.3, p = 0.05). IgG anti-cardiolipin during pregnancy resulted in a higher risk of preterm delivery (OR 6.8, p = 0.03). Hypocomplementaemia was associated with several APO, but only in the first pregnancies. We conclude that, despite the close follow-up provided, a majority of pregnancies resulted in ≥1 APO, but a few of them were severe. Our study confirms the importance of previous lupus nephritis as a main risk factor for APO in patients with SLE. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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16 pages, 877 KiB

Open AccessArticle

Use of Antimalarial Agents Is Associated with Favourable Physical Functioning in Patients with Systemic Lupus Erythematosus

by Alvaro Gomez, Sofia Soukka, Petter Johansson, Emil Åkerström, Sharzad Emamikia, Yvonne Enman, Katerina Chatzidionysiou and Ioannis Parodis

J. Clin. Med. 2020, 9(6), 1813; https://doi.org/10.3390/jcm9061813 - 10 Jun 2020

Cited by 8 | Viewed by 2317

Abstract

Impaired health-related quality of life (HRQoL) is a major problem in patients with systemic lupus erythematosus (SLE). Antimalarial agents (AMA) are the cornerstone of SLE therapy, but data on their impact on HRQoL are scarce. We investigated this impact using baseline data from [...] Read more.

Impaired health-related quality of life (HRQoL) is a major problem in patients with systemic lupus erythematosus (SLE). Antimalarial agents (AMA) are the cornerstone of SLE therapy, but data on their impact on HRQoL are scarce. We investigated this impact using baseline data from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials (n = 1684). HRQoL was self-reported using the Medical Outcomes Study short-form 36 (SF-36), functional assessment of chronic illness therapy (FACIT)-Fatigue and 3-level EuroQoL 5-Dimension (EQ-5D) questionnaires. Patients on AMA (n = 1098/1684) performed better with regard to SF-36 physical component summary, physical functioning, role physical, bodily pain, FACIT-Fatigue, EQ-5D utility index and EQ-5D visual analogue scale scores. The difference in SF-36 physical functioning (mean ± standard deviation (SD): 61.1 ± 24.9 versus 55.0 ± 26.5; p < 0.001) exceeded the minimal clinically important difference (≥5.0). This association remained significant after adjustment for potential confounding factors in linear regression models (standardised coefficient, β = 0.07; p = 0.002). Greater proportions of AMA users than non-users reported no problems in the mobility, self-care, usual activities and anxiety/depression EQ-5D dimensions. AMA use was particularly associated with favourable HRQoL in physical aspects among patients with active mucocutaneous and musculoskeletal disease, and mental aspects among patients with active renal SLE. These results provide support in motivating adherence to AMA therapy. Exploration of causality in the relationship between AMA use and favourable HRQoL in SLE has merit. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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Review

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16 pages, 4318 KiB

Open AccessReview

Urinary Biomarkers for Lupus Nephritis: A Systems Biology Approach

by Mohamed H. Omer, Areez Shafqat, Omar Ahmad, Juzer Nadri, Khaled AlKattan and Ahmed Yaqinuddin

J. Clin. Med. 2024, 13(8), 2339; https://doi.org/10.3390/jcm13082339 - 18 Apr 2024

Viewed by 298

Abstract

Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder. Kidney involvement, termed lupus nephritis (LN), is seen in 40–60% of patients with systemic lupus erythematosus (SLE). After the diagnosis, serial measurement of proteinuria is the most common method of monitoring treatment response [...] Read more.

Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disorder. Kidney involvement, termed lupus nephritis (LN), is seen in 40–60% of patients with systemic lupus erythematosus (SLE). After the diagnosis, serial measurement of proteinuria is the most common method of monitoring treatment response and progression. However, present treatments for LN—corticosteroids and immunosuppressants—target inflammation, not proteinuria. Furthermore, subclinical renal inflammation can persist despite improving proteinuria. Serial kidney biopsies—the gold standard for disease monitoring—are also not feasible due to their inherent risk of complications. Biomarkers that reflect the underlying renal inflammatory process and better predict LN progression and treatment response are urgently needed. Urinary biomarkers are particularly relevant as they can be measured non-invasively and may better reflect the compartmentalized renal response in LN, unlike serum studies that are non-specific to the kidney. The past decade has overseen a boom in applying cutting-edge technologies to dissect the pathogenesis of diseases at the molecular and cellular levels. Using these technologies in LN is beginning to reveal novel disease biomarkers and therapeutic targets for LN, potentially improving patient outcomes if successfully translated to clinical practice. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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15 pages, 1406 KiB

Open AccessReview

Biomarkers in Systemic Lupus Erythematosus along with Metabolic Syndrome

by Fernanda Isadora Corona-Meraz, Mónica Vázquez-Del Mercado, Flavio Sandoval-García, Jesus-Aureliano Robles-De Anda, Alvaro-Jovanny Tovar-Cuevas, Roberto-Carlos Rosales-Gómez, Milton-Omar Guzmán-Ornelas, Daniel González-Inostroz, Miguel Peña-Nava and Beatriz-Teresita Martín-Márquez

J. Clin. Med. 2024, 13(7), 1988; https://doi.org/10.3390/jcm13071988 - 29 Mar 2024

Viewed by 543

Abstract

Metabolic syndrome (MetS) is a group of physiological abnormalities characterized by obesity, insulin resistance (IR), and hypertriglyceridemia, which carry the risk of developing cardiovascular disease (CVD) and type 2 diabetes (T2D). Immune and metabolic alterations have been observed in MetS and are associated [...] Read more.

Metabolic syndrome (MetS) is a group of physiological abnormalities characterized by obesity, insulin resistance (IR), and hypertriglyceridemia, which carry the risk of developing cardiovascular disease (CVD) and type 2 diabetes (T2D). Immune and metabolic alterations have been observed in MetS and are associated with autoimmune development. Systemic lupus erythematosus (SLE) is an autoimmune disease caused by a complex interaction of environmental, hormonal, and genetic factors and hyperactivation of immune cells. Patients with SLE have a high prevalence of MetS, in which elevated CVD is observed. Among the efforts of multidisciplinary healthcare teams to make an early diagnosis, a wide variety of factors have been considered and associated with the generation of biomarkers. This review aimed to elucidate some primary biomarkers and propose a set of assessments to improve the projection of the diagnosis and evolution of patients. These biomarkers include metabolic profiles, cytokines, cardiovascular tests, and microRNAs (miRs), which have been observed to be dysregulated in these patients and associated with outcomes. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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16 pages, 1026 KiB

Open AccessReview

Progress in the Pathogenesis and Treatment of Neuropsychiatric Systemic Lupus Erythematosus

by Minhui Wang, Ziqian Wang, Shangzhu Zhang, Yang Wu, Li Zhang, Jiuliang Zhao, Qian Wang, Xinping Tian, Mengtao Li and Xiaofeng Zeng

J. Clin. Med. 2022, 11(17), 4955; https://doi.org/10.3390/jcm11174955 - 24 Aug 2022

Cited by 7 | Viewed by 3142

Abstract

Neuropsychiatric systemic lupus erythematosus (NPSLE) has a broad spectrum of subtypes with diverse severities and prognoses. Ischemic and inflammatory mechanisms, including autoantibodies and cytokine-mediated pathological processes, are key components of the pathogenesis of NPSLE. Additional brain-intrinsic elements (such as the brain barrier and [...] Read more.

Neuropsychiatric systemic lupus erythematosus (NPSLE) has a broad spectrum of subtypes with diverse severities and prognoses. Ischemic and inflammatory mechanisms, including autoantibodies and cytokine-mediated pathological processes, are key components of the pathogenesis of NPSLE. Additional brain-intrinsic elements (such as the brain barrier and resident microglia) are also important facilitators of NPSLE. An improving understanding of NPSLE may provide further options for managing this disease. The attenuation of neuropsychiatric disease in mouse models demonstrates the potential for novel targeted therapies. Conventional therapeutic algorithms include symptomatic, anti-thrombotic, and immunosuppressive agents that are only supported by observational cohort studies, therefore performing controlled clinical trials to guide further management is essential and urgent. In this review, we aimed to present the latest pathogenetic mechanisms of NPSLE and discuss the progress in its management. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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9 pages, 1255 KiB

Open AccessReview

Rapid Response of Refractory Systemic Lupus Erythematosus Skin Manifestations to Anifrolumab—A Case-Based Review of Clinical Trial Data Suggesting a Domain-Based Therapeutic Approach

by Marlene Plüß, Silvia Piantoni, Chris Wincup and Peter Korsten

J. Clin. Med. 2022, 11(12), 3449; https://doi.org/10.3390/jcm11123449 - 15 Jun 2022

Cited by 7 | Viewed by 5991

Abstract

Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease, and organ manifestations, such as lupus nephritis (LN) or skin disease, may be refractory to standard treatment. Therefore, new agents are required to allow for a more personalized therapeutic approach. Recently, several new [...] Read more.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease, and organ manifestations, such as lupus nephritis (LN) or skin disease, may be refractory to standard treatment. Therefore, new agents are required to allow for a more personalized therapeutic approach. Recently, several new therapies have been approved internationally, including voclosporine for LN and anifrolumab for moderately to severely active SLE. Here, we report a case of SLE with a predominant and refractory cutaneous manifestation despite combination treatment with glucocorticoids, hydroxychloroquine, mycophenolate mofetil, and belimumab, which had been present for more than 12 months. Belimumab was switched to anifrolumab, and the patient responded quickly after two infusions (eight weeks) with a reduction in the Cutaneous Lupus Assessment and Severity Index (CLASI) from 17 to 7. In addition, we review the available clinical trial data for anifrolumab with a focus on cutaneous outcomes. Based on phase II and III clinical trials investigating the intravenous administration, a consistent CLASI improvement was observed at 12 weeks. Interestingly, in a phase II trial of subcutaneous anifrolumab application, CLASI response was not different from placebo at 12 weeks but numerically different at 24 and 52 weeks, respectively. Thus, anifrolumab emerges as an attractive new therapeutic option suggesting a possible domain-based approach. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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7 pages, 600 KiB

Open AccessReview

Patient-Reported Outcomes in Systemic Lupus Erythematosus. Can Lupus Patients Take the Driver’s Seat in Their Disease Monitoring?

by Ioannis Parodis and Paul Studenic

J. Clin. Med. 2022, 11(2), 340; https://doi.org/10.3390/jcm11020340 - 11 Jan 2022

Cited by 11 | Viewed by 2041

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that has detrimental effects on patient’s health-related quality of life (HRQoL). Owing to its immense heterogeneity of symptoms and its complexity regarding comorbidity burden, management of SLE necessitates interdisciplinary care, with the goal being [...] Read more.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that has detrimental effects on patient’s health-related quality of life (HRQoL). Owing to its immense heterogeneity of symptoms and its complexity regarding comorbidity burden, management of SLE necessitates interdisciplinary care, with the goal being the best possible HRQoL and long-term outcomes. Current definitions of remission, low disease activity, and response to treatment do not incorporate self-reported patient evaluation, while it has been argued that the physician’s global assessment should capture the patient’s perspective. However, even the judgment of a very well-trained physician might not replace a patient-reported outcome measure (PROM), not only owing to the multidimensionality of self-perceived health experience but also since this notion would constitute a direct contradiction to the definition of PROMs. The proper use of PROMs is not only an important conceptual issue but also an opportunity to build bridges in the partnership between patients and physicians. These points of consideration adhere to the overall framework that there will seldom be one single best marker that helps interpret the activity, severity, and impact of SLE at the same time. For optimal outcomes, we not only stress the importance of the use of PROMs but also emphasize the urgency of adoption of the conception of forming alliances with patients and facilitating patient participation in surveillance and management processes. Nevertheless, this should not be misinterpreted as a transfer of responsibility from healthcare professionals to patients but rather a step towards shared decision-making. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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18 pages, 1089 KiB

Open AccessFeature PaperReview

Implications of Endogenous Retroelements in the Etiopathogenesis of Systemic Lupus Erythematosus

by Kennedy C. Ukadike and Tomas Mustelin

J. Clin. Med. 2021, 10(4), 856; https://doi.org/10.3390/jcm10040856 - 19 Feb 2021

Cited by 10 | Viewed by 3610

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A hypothesis that combines several of these factors proposes that genomic elements, the L1 [...] Read more.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A hypothesis that combines several of these factors proposes that genomic elements, the L1 retrotransposons, are instrumental in SLE pathogenesis. L1 retroelements are transcriptionally activated in SLE and produce two proteins, ORF1p and ORF2p, which are immunogenic and can drive type I interferon (IFN) production by producing DNA species that activate cytosolic DNA sensors. In addition, these two proteins reside in RNA-rich macromolecular assemblies that also contain well-known SLE autoantigens like Ro60. We surmise that cells expressing L1 will exhibit all the hallmarks of cells infected by a virus, resulting in a cellular and humoral immune response similar to those in chronic viral infections. However, unlike exogenous viruses, L1 retroelements cannot be eliminated from the host genome. Hence, dysregulated L1 will cause a chronic, but perhaps episodic, challenge for the immune system. The clinical and immunological features of SLE can be at least partly explained by this model. Here we review the support for, and the gaps in, this hypothesis of SLE and its potential for new diagnostic, prognostic, and therapeutic options in SLE. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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11 pages, 406 KiB

Open AccessReview

Management of Lupus Nephritis

by Farah Tamirou and Frédéric A. Houssiau

J. Clin. Med. 2021, 10(4), 670; https://doi.org/10.3390/jcm10040670 - 09 Feb 2021

Cited by 18 | Viewed by 8178

Abstract

Lupus nephritis (LN) is a frequent and severe manifestation of systemic lupus erythematosus. The main goal of the management of LN is to avoid chronic kidney disease (CKD). Current treatment strategies remain unsatisfactory in terms of complete renal response, prevention of relapses, CKD, [...] Read more.

Lupus nephritis (LN) is a frequent and severe manifestation of systemic lupus erythematosus. The main goal of the management of LN is to avoid chronic kidney disease (CKD). Current treatment strategies remain unsatisfactory in terms of complete renal response, prevention of relapses, CKD, and progression to end-stage kidney disease. To improve the prognosis of LN, recent data suggest that we should (i) modify our treat-to-target approach by including, in addition to a clinical target, a pathological target and (ii) switch from conventional sequential therapy to combination therapy. Here, we also review the results of recent controlled randomized trials. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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12 pages, 1219 KiB

Open AccessReview

The Main Challenges in Systemic Lupus Erythematosus: Where Do We Stand?

by Matteo Piga and Laurent Arnaud

J. Clin. Med. 2021, 10(2), 243; https://doi.org/10.3390/jcm10020243 - 11 Jan 2021

Cited by 42 | Viewed by 9140

Abstract

Systemic lupus erythematosus (SLE) is an immune-mediated multi-systemic disease characterized by a wide variability of clinical manifestations and a course frequently subject to unpredictable flares. Despite significant advances in the understanding of the pathophysiology and optimization of medical care, patients with SLE still [...] Read more.

Systemic lupus erythematosus (SLE) is an immune-mediated multi-systemic disease characterized by a wide variability of clinical manifestations and a course frequently subject to unpredictable flares. Despite significant advances in the understanding of the pathophysiology and optimization of medical care, patients with SLE still have significant mortality and carry a risk of progressive organ damage accrual and reduced health-related quality of life. New tools allow earlier classification of SLE, whereas tailored early intervention and treatment strategies targeted to clinical remission or low disease activity could offer the opportunity to reduce damage, thus improving long-term outcomes. Nevertheless, the early diagnosis of SLE is still an unmet need for many patients. Further disentangling the SLE susceptibility and complex pathogenesis will allow to identify more accurate biomarkers and implement new ways to measure disease activity. This could represent a major step forward to find new trials modalities for developing new drugs, optimizing the use of currently available therapeutics and minimizing glucocorticoids. Preventing and treating comorbidities in SLE, improving the management of hard-to-treat manifestations including management of SLE during pregnancy are among the remaining major unmet needs. This review provides insights and a research agenda for the main challenges in SLE. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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13 pages, 1332 KiB

Open AccessReview

Glucocorticoids in Systemic Lupus Erythematosus. Ten Questions and Some Issues

by Sabrina Porta, Alvaro Danza, Maira Arias Saavedra, Adriana Carlomagno, María Cecilia Goizueta, Florencia Vivero and Guillermo Ruiz-Irastorza

J. Clin. Med. 2020, 9(9), 2709; https://doi.org/10.3390/jcm9092709 - 21 Aug 2020

Cited by 53 | Viewed by 11986

Abstract

Since the discovery of glucocorticoids (GCs), their important anti-inflammatory effect, rapid mechanism of action, low cost, and accessibility have made them one of the mainstays of treatment for Systemic lupus erythematosus (SLE). Although their use has allowed controlling the disease and reducing acute [...] Read more.

Since the discovery of glucocorticoids (GCs), their important anti-inflammatory effect, rapid mechanism of action, low cost, and accessibility have made them one of the mainstays of treatment for Systemic lupus erythematosus (SLE). Although their use has allowed controlling the disease and reducing acute mortality in severe conditions, the implementation of a scheme based on high doses for long periods has inevitably been accompanied by an increase in adverse effects and infections, including long-term damage. The objective of this review is to answer some important questions that may arise from its use in daily clinical practice, and to propose a paradigm based on the use of methylprednisolone pulses followed by medium-low doses and a rapid decrease of prednisone. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Pathogenesis, Diagnosis and Treatment)

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