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The concept of an "immunological continuum model," introduced by McGonagle and McDermott in 2006, redefines the traditional dichotomy between autoimmunity and autoinflammation, proposing a spectrum where innate and adaptive immune dysregulation can co-occur, reflecting a more nuanced understanding of immune disorders. Systemic lupus erythematosus (SLE) exemplifies the complexity of this continuum, often displaying manifestations of autoimmunity, autoinflammation, and immunodeficiency. The interplay between genetic, epigenetic, hormonal, psychological, and environmental factors contributes to its distinctive immunopathological signatures. Historically recognized as a systemic disease with diverse clinical manifestations, SLE is primarily a polygenic autoimmune condition but can, however, present in monogenic forms. Examining SLE through the lens of the immunological continuum model allows for emphasis on the contributions of both innate and adaptive immunity. SLE and primary immunodeficiencies share genetic susceptibilities and clinical manifestations. Additionally, autoinflammatory mechanisms, such as inflammasome activation and interferonopathies, can play a role in SLE pathogenesis, illustrating the disease's position at the crossroads of immune dysregulation. Recognizing the diverse clinical expressions of SLE and its mimickers is critical for accurate diagnosis and targeted therapy. In conclusion, the immunological continuum model provides a comprehensive framework for understanding SLE, acknowledging its multifaceted nature and guiding future research and clinical practice toward more effective and individualized treatments. After the Mosaic of Autoimmunity, it is now the time to focus and attempt to solve the intricate mosaic of SLE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: To assess the choroidal status of Systemic Lupus Erythematosus (SLE) patients using Optical Coherence Tomography (OCT) and OCT-Angiography., Methods: SLE patients with disease duration < 10 years, no disease activity and no ocular involvement were recruited and cross-sectionally evaluated. A demographically similar cohort of healthy subjects was used for comparison. The main outcome is choroidal vascularity index (CVI). As secondary outcomes, choriocapillaris parameters and choroidal thickness (CT) were evaluated., Results: Forty eyes of 40 subjects (20 SLE patients and 20 healthy subjects) were studied with a mean ± SD age of 36.7 ± 9.9 years. In the SLE group, the mean ± SD duration of disease was 7.35 ± 2.21 years. Increased CVI was found in the SLE group (p = 0.022). Considering the choriocapillaris, SLE patients presented a lower number (p = 0.037) and a smaller total area (p = 0.041) of signal voids. No differences between groups were found in CT. For SLE patients, CT at subfoveal, temporal and inferior locations presented a negative moderate correlation with disease duration. A strong correlation between choriocapillaris parameters and age was demonstrated for both groups., Conclusions: This study provides evidence of subclinical choroidal changes in adult SLE patients with inactive disease and no overt ocular manifestation. Increased CVI and fewer and smaller flow voids in choriocapillaris with normal CT suggest increased choroidal vascularity in SLE., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Stress has been linked to worsening symptoms and increased disease activity in patients with Systemic lupus erythematosus (SLE). Life-events are individual stress points, and there is conflicting evidence regarding their role in SLE activity and disease perception., Methods: Adult SLE patients were recruited for the study. Clinical and laboratory features of SLE were recorded, and previous diagnosis of anxiety or depression were retrieved from patients' electronic charts. Flares were defined by the Systemic Lupus Erythematosus Disease Activity (SLEDAI) flare Index, and flares during the previous year were documented. During a routine visit, they completed validated Portuguese translations of the 10-item Perceived Stress Scale (PSS-10), Hospital Anxiety and Depression Scale (HADS) and Life Experience Survey (LES) for the previous year., Results: A total of 47 female SLE patients were recruited. Ten patients (21.3%) had experienced recent flares. Patients with recent flares reported fewer life events, with lower positive, negative, and total weightings sums compared to those without recent flares. Although 42.2% of patients perceived pathological levels of stress in the previous month, 48.9% had anxiety symptoms, and 34% were at high risk for an anxiety disorder, these psychometric measures did not differ significantly between the recent flare and no-flare groups., Conclusions: There is a high prevalence of pathological levels of stress among SLE patients. SLE patients with recent flares report less psychological impact from life events, both positive and negative, independent of other psychological or pharmacological factors., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and Sjögren's syndrome (SS) are heterogeneous autoimmune diseases. Severe manifestations and refractory/intolerance to conventional immunosuppressants demand other options, namely biological drugs, and small molecules. We aimed to define evidence and practice-based guidance for the off-label use of biologics in SLE, APS, and SS. Recommendations were made by an independent expert panel, following a comprehensive literature review and two consensus rounds. The panel included 17 internal medicine experts with recognized practice in autoimmune disease management. The literature review was systematic from 2014 until 2019 and later updated by cross-reference checking and experts' input until 2021. Preliminary recommendations were drafted by working groups for each disease. A revision meeting with all experts anticipated the consensus meeting held in June 2021. All experts voted (agree, disagree, neither agree nor disagree) during two rounds, and recommendations with at least 75% agreement were approved. A total of 32 final recommendations (20 for SLE treatment, 5 for APS, and 7 for SS) were approved by the experts. These recommendations consider organ involvement, manifestations, severity, and response to previous treatments. In these three autoimmune diseases, most recommendations refer to rituximab, which aligns with the higher number of studies and clinical experience with this biological agent. Belimumab sequential treatment after rituximab may also be used in severe cases of SLE and SS. Second-line therapy with baricitinib, bortezomib, eculizumab, secukinumab, or tocilizumab can be considered in SLE-specific manifestations. These evidence and practice-based recommendations may support treatment decision and, ultimately, improve the outcome of patients living with SLE, APS, or SS., Competing Interests: AM received consulting, speaker, and advisory board fees from AbbVie, Lilly, MSD, Novartis, Pfizer, and Roche, speaker fees from BMS and Janssen, consulting fees from Janssen and Takeda; and received support for attending meetings from AbbVie, Janssen, Novartis, and Pfizer. JDA received consulting, speaker, and advisory board fees from AbbVie, Lilly, and Novartis, and consulting fees from Pfizer. CV received advisory board fees from AstraZeneca, GSK, Janssen, Novartis, and Pfizer. MF is an employee of a contract research organization (CTI Clinical Trial & Consulting Services) that provides services to several pharmaceutical companies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marinho, Delgado Alves, Fortuna, Faria, Almeida, Alves, Araújo Correia, Campar, Brandão, Crespo, Marado, Matos-Costa, Oliveira, Salvador, Santos, Silva, Fernandes and Vasconcelos.)

Introduction: LupusQoL is a questionnaire specifically designed to assess health-related quality of life (HRQoL) in SLE patients. We report on the translation and cross-cultural adaptation of LupusQoL into European Portuguese., Methods: Translation and cultural adaptation were performed according to standard protocol described by the original developers. LupusQoL-PT was administered to patients during a routine visit from an outpatient clinic at a university hospital in Portugal. Content structure was validated using factorial analysis. Cronbach's alpha coefficient was computed for internal consistency. Sociodemographic were questioned during the visit and clinical data were collected during the visit and from the clinical files. Pearson's correlation, T-test, Mann-Whitney and one-way ANOVA were applied to test internal and external validation., Results: Seventy-nine SLE patients (78 woman: 1 man) were evaluated. Most had Low disease activity (mean SLEDAI-2k = 3.49; standard deviation 4.80), 19% had moderate to severe activity and 38% had damage accrual (mean SDI = 0.75; standard deviation 1.05). Cronbach's alpha coefficient was at least 0.812, confirming good internal consistency. Correlation coefficient and test-retest correlation between the eight domains of LupusQoL-PT were strong in almost every domain (p &lt; 0.01). External convergent analysis showed strong correlation between LupusQoL-PT and Medical Outcome Study Short Form 36-item version 2 and visual analogic scale. Current disease activity was negative correlated with "Body Image" domain. There was no correlation between other LupusQoL-PT domains and SLEDAI-2k on divergent validity. Patients with previous neuropsychiatric and DMARDs treatment had lower HRQoL in emotional domains, while patients with renal damage accrual had HRQoL impact in both physical and emotional domains. Portuguese SLE patients had lower HRQoL than French and Italian validation cohorts' patients, and higher than Spanish cohorts., Conclusion: LupusQoL-PT has shown adequate metric properties and should be considered an appropriate tool to evaluate HRQoL in Portuguese SLE patients.

Pregnancy in systemic lupus erythematosus (SLE) patients is associated with an increased risk of adverse outcomes. During pregnancy, SLE patients have a higher rate of miscarriage, stillbirth, preterm delivery, fetal growth restriction, or hypertensive disorders of pregnancy. To date, only a few case-control studies were published with the purpose to evaluate the magnitude of risk associated with pregnancy in lupus patients. The aim of our study was to evaluate the maternal and fetal outcomes in a cohort of Portuguese SLE patients and to compare it with a group of healthy pregnant women. We conducted a retrospective case-control study that included all pregnant women with SLE managed at a Portuguese tertiary center, between 2010 and 2019. Pregnancy outcomes were compared between SLE patients and a group of matched healthy pregnant women. Baseline maternal data was collected, and maternal-fetal and neonatal outcomes were evaluated. One hundred twenty-four SLE pregnancies were included. Of the patients, 95.2% were in remission at conception. In 13.7% of cases, a lupus flare was diagnosed during gestation and in 17.9% in the postpartum period. The live birth rate was 84.6%, and the incidence of adverse outcomes was 40.3% (OR 2.64, 95% CI 1.67-4.18). Considering only patients in remission at conception, the presence of adverse outcomes remained significantly higher (36.8% vs. 20.3%, P < 0.01). Miscarriage rate was 15.3% (OR 5.85, 95% CI 2.57-13.34) and preterm delivery occurred in 12.4% of the patients (OR 1.72, 95% CI 0.83-3.57). Preeclampsia prevalence was higher in SLE patients (OR 3.92, 95% CI 1.32-11.57). In the SLE group, the newborn admission to an intensive care unit rate was increased (OR 4.99, 95% CI 1.47-16.90). No neonatal or maternal deaths were reported. In our study, pregnancy with SLE was associated with an increased incidence of adverse outcomes, even in a population of SLE patients with well-controlled disease., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To achieve consensus on a definition of remission in SLE (DORIS)., Background: Remission is the stated goal for both patient and caregiver, but consensus on a definition of remission has been lacking. Previously, an international task force consisting of patient representatives and medical specialists published a framework for such a definition, without reaching a final recommendation., Methods: Several systematic literature reviews were performed and specific research questions examined in suitably chosen data sets. The findings were discussed, reformulated as recommendations and voted on., Results: Based on data from the literature and several SLE-specific data sets, a set of recommendations was endorsed. Ultimately, the DORIS Task Force recommended a single definition of remission in SLE, based on clinical systemic lupus erythematosus disease activitiy index (SLEDAI)=0, Evaluator's Global Assessment <0.5 (0-3), prednisolone 5 mg/day or less, and stable antimalarials, immunosuppressives, and biologics., Conclusion: The 2021 DORIS definition of remission in SLE is recommended for use in clinical care, education, and research including clinical trials and observational studies., Competing Interests: Competing interests: RFvV has received research and educational support (grants) from BMS, GSK, Lilly, Pfizer, Roche and UCB; and reimbursement for consultancy and/or speaking from AbbVie, AstraZeneca, Biogen, Biotest, BMS, Galapagos, Gilead, GSK, Janssen, Pfizer, Sanofi, Servier, UCB and Vielabio. RC—GSK, Alexion, Eli Lilly, AstraZeneca, Termo-Fisher and Rubió. BAP-E—GSK and Janssen. MFU-G received research grants from Janssen and Pfizer. LA acted as a consultant for Alexion, Amgen, AstraZeneca, BMS, GSK, Janssen-Cilag, LFB, Lilly, Menarini France, Medac, Novartis, Pfizer, Roche-Chugaï and UCB. CG—personal fees for honoraria from consultancy work from the Center for Disease Control, AstraZeneca, MGP, Sanofi and UCB; and personal fees for speaker’s bureau from UCB. HBo—unrestricted grants from Bristol-Myers Squibb and Roche; consultant for Bristol-Myers Squibb, Roche, Novartis, Medimmune and Union Chimique Belge; speaker for Bristol-Myers Squibb and Novartis; member of the advisory board of Bristol-Myers Squibb, Novartis and Sanofi. MI—consultations from GSK and Amgen. DJ—AstraZeneca, Aurinia, BMS, Boehringer-Ingelheim, Chemocentryx, Chugai, CSL, GSK, Infla-RX, Janssen, Novartis, Roche/Genentech, Takeda and Vifor. AK—honoraria from Bristol-Myers Squibb, KGaA, GlaxoSmithKline, Janssen Cilag and Lilly Deutschland. ML—receipts from GSK for advisory boards and sponsoring of investigator-initiated study. MN—research support from Actelion, AstraZeneca, BMS, GSK, Janssen and UCB; and honoraria from Actelion, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Pfizer and UCB. AT—consultation/speaker fees from UCB, GSK, Novartis and Janssen., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Systemic lupus erythematosus (SLE) is a life-threatening disorder that affects women at reproductive age. We evaluate the clinical impact of pregnancy in a cohort of Portuguese SLE patients and the risk factors associated with maternal and fetal adverse outcomes., Methods: A retrospective observational study that included all pregnant women with SLE managed at a Portuguese tertiary hospital, between January 1993 and December 2019. Baseline maternal information was collected, and maternal-fetal and neonatal outcomes were evaluated. Disease activity before and during pregnancy was assessed., Results: We included 215 pregnancies from 143 patients. Lupus nephritis was present in 20.0% and antiphospholipid syndrome (APS) in 21.9% of the cases. Preconception consultation was performed in 86.9% of the pregnancies, and 92.5% of the patients had no or low disease activity at conception. During gestation, 79.6% of the patients were under treatment, and hydroxychloroquine (HCQ) was the most commonly used drug (63.7%). Low-dose acetylsalicylic acid (ASA) was prescribed at conception in 87.9% of the patients. The live birth rate was 84.2%. An adverse pregnancy outcome (APO) occurred in 41.4% of the pregnancies. A miscarriage rate of 15.3% and a preterm delivery rate of 15.4% were found. Preeclampsia and fetal growth restriction complicated 13.1% and 14.0% of the gestations, respectively. Neonatal lupus occurred in 7.1% of the newborns, and there were 2 cases of congenital heart block. Significant risk factors for the development of AOP were disease activity at conception, lupus flare, hypocomplementemia, positivity for lupus anticoagulant, and APS. The use of ASA was significantly associated with a reduced incidence of miscarriage. An SLE flare was diagnosed in 16.3% of the cases. We identified as risk factors for lupus flares the presence of active disease at conception, a previous history of lupus nephritis, and the use of chronic medication. HCQ use during pregnancy was associated with a significant reduction of flare incidence during pregnancy and postpartum., Conclusions: Pregnancy in an SLE patient is associated with an increased incidence of adverse obstetric outcomes. Good disease control before pregnancy and adequate treatment, especially with HCQ, is crucial to achieving the best obstetric results.

Objective: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease with limited reliable diagnostic biomarkers. We investigated whether gene methylation could meet sensitivity and specificity criteria for a robust biomarker., Methods: IFI44L promoter methylation was examined using DNA samples from a discovery set including 377 patients with SLE, 358 healthy controls (HCs) and 353 patients with rheumatoid arthritis (RA). Two independent sets including 1144 patients with SLE, 1350 HCs, 429 patients with RA and 199 patients with primary Sjögren's syndrome (pSS) were used for validation., Results: Significant hypomethylation of two CpG sites within IFI44L promoter, Site1 (Chr1: 79 085 222) and Site2 (Chr1: 79 085 250; cg06872964), was identified in patients with SLE compared with HCs, patients with RA and patients with pSS. In a comparison between patients with SLE and HCs included in the first validation cohort, Site1 methylation had a sensitivity of 93.6% and a specificity of 96.8% at a cut-off methylation level of 75.5% and Site2 methylation had a sensitivity of 94.1% and a specificity of 98.2% at a cut-off methylation level of 25.5%. The IFI44L promoter methylation marker was also validated in an European-derived cohort. In addition, the methylation levels of Site1 and Site2 within IFI44L promoter were significantly lower in patients with SLE with renal damage than those without renal damage. Patients with SLE showed significantly increased methylation levels of Site1 and Site2 during remission compared with active stage., Conclusions: The methylation level of IFI44L promoter can distinguish patients with SLE from healthy persons and other autoimmune diseases, and is a highly sensitive and specific diagnostic marker for SLE., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)