Challenges and opportunities in access to care for systemic lupus erythematosus patients across Europe and worldwide.

SLE presents significant challenges for patients and health-care professionals (HCPs), both across Europe and worldwide. Improving health-care outcomes for patients with SLE requires a comprehensive understanding of patient disease pathways. In particular, the geographical distance between SLE patients and specialized care centres, combined with the scarcity of rheumatologists, exacerbates delays in diagnosis and management. Also, the initial SLE symptoms can often be non-specific, and providing guidelines for primary HCPs and other non-specialists is extremely important. Improvement in access to treatment is also important, with several recently approved therapies for SLE not being available in several European countries and many low- and middle-income countries (LMICs). Furthermore, in the LMICs in which these treatments are available, they are not always covered by the health-care system, making their access almost impossible for those of lower socio-economic status. A number of provisions are already in place within the European Union, to improve access to care for patients with rare and complex diseases, including those with SLE. In particular, European Reference Networks (ERNs), such the ERN for Autoimmune Diseases ReCONNET, are virtual networks involving HCPs across Europe with the aim of improving the care of patients with rare and complex diseases that require highly specialized treatment and a concentration of knowledge and resources. In addition, lupus patient organizations such as Lupus Europe play a crucial role in raising awareness of SLE and advocating for improved access to care. Together, we can work towards a future where all people living with lupus receive the comprehensive and timely care they deserve.

Generalized lymphadenopathy in the presence of acute Epstein-Barr virus infection as the initial manifestation of systemic lupus erythematous: A case report.

Key Clinical Message: Clinicians should carefully consider generalized lymphadenopathy, particularly post viral infections, as one of the possible systemic lupus erythematous (SLE) first signs regarding unusual joint involvements such as sacroiliitis. Late diagnosis of this autoimmune inflammatory disease, could lead to irreversible morbidity and higher mortality. Abstract: Lymphadenopathy could represent various etiologies, including infections, malignancies, and rheumatologic diseases. SLE is known as the great mimicker which could be presented with different first manifestations. We report a 42-year-old woman in the acute phase of Epstein-Barr infection, admitted with polyarticular peripheral arthritis, sacroiliitis, and generalized lymphadenopathy. She had no similar history or taken unpasteurized dairy. Nodes were soft, mobile, and tender without skin change on top. During the process, she was diagnosed with SLE and discharged with prednisolone 30 mg/day and hydroxychloroquine 400 mg/day. After 2 weeks of follow-up, all lymphadenopathy and symptoms were diminished. This case underscores the thousand faces innate of SLE. Clinical awareness would lead to an accurate diagnosis and early intervention.

Unilateral Alveolar Hemorrhage: A Rare Pulmonary Complication in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that presents a broad spectrum of clinical manifestations. Alveolar hemorrhage in SLE is rare and has a poor prognosis. We present the case of a patient with a diagnosis of SLE and lupus nephropathy on hemodialysis who presented criteria for alveolar hemorrhage with unilateral involvement, with clinical improvement after the administration of steroid boluses. The uncommon presentation of unilateral pulmonary involvement and the importance of making an adequate protocol for ruling out differential diagnoses are highlighted.

Is systemic lupus erythematosus linked to Immunoglobulin G4 Autoantibodies?

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by a hyperactive immune system with multiple abnormalities in B-cell proliferation, antibody production, T-cell regulation, and immune complex (IC) formation. In humans, Immunoglobulin (Ig) G is found in four subclasses. IgG1-IgG4, which are distinguished by both structural and biological differences. Fab-arm Exchange (FAE), specific biases in the IgG4 response repertoire, and a decreased capacity to induce effector functions mediated by interactions in the fragment crystallizable (Fc) region are just a few of the distinctive characteristics of IgG4. The recent finding of the presence of double-stranded DNA (dsDNA) and antinuclear antibody (ANA)-IgG4 has raised attention to this IgG subclass and its possible role in SLE. IgG4 was previously believed to just have anti-inflammatory effects by inhibiting immune responses, but recent studies have shown that these antibodies can also play a role in the onset and development of some clinical disorders. To consider the clinical effects of IgG4 presence, it is necessary to discuss its characteristics, which could underlie the potential role it can play in SLE. Therefore, this study aimed to comprehensively review the role of IgG4 in SLE to elucidate the collective incidence of high IgG4 levels reported in some SLE patients.

Comparison of the Quantitative Values of Peripapillary, Macular and Choriocapillary Microvascular Structures According to the Presence of Lupus Nephritis in Patients with Systemic Lupus Erythematosus.

PURPOSE: To determine whether there are quantitative changes in macular, choriocapillary, and peripapillary microvascular structures using optical coherence tomography angiography (OCTA) due to the presence of lupus nephritis (LN) in patients with systemic lupus erythematosus (SLE) and to investigate the correlation between these quantitative values and disease duration. METHODS: Fifty -five patients followed up in the rheumatology clinic with an SLE diagnosis were evaluated. As the control group, 61 eyes of 61 age- and gender-matched healthy individuals were included. The patients with SLE were further divided into two groups: those with LN (29 eyes) and those without LN (26 eyes). Macular, choriocapillary, and peripapillary microvascular structures were quantitatively analyzed with OCTA and compared between the three study groups. A correlation analysis of the measured quantitative values and disease duration was also performed. RESULTS: In macular microvascular (MMV) analysis, the vessel densities (VDs) of the superficial capillary plexus (SCP) decreased in both SLE groups, while those of the deep capillary plexus (DCP) decreased only in the SLE group with LN. The foveal density significantly decreased in the SLE group with LN compared to the control group, there were no significant differences in terms of the radial peripapillary capillary VDs or the choriocapillaris flow area. Disease duration was not correlated with any of the quantitative parameters measured by OCTA in either SLE group. CONCLUSIONS: Identifying differences in retinal microvascular circulation in SLE patients with kidney damage helps predict possible nephropathy and therefore guides the treatment process of this patient.

Unraveling the diagnostic odyssey: stimulator of interferon gene-associated vasculopathy with onset in infancy in a 30-year-old female.

Stimulator of interferon gene (STING)-associated vasculopathy with onset in infancy (SAVI) is an extremely rare autoinflammatory disease. We present the case of a female Korean patient with early-onset interstitial lung disease who was initially suspected to have systemic lupus erythematosus (SLE) but was ultimately diagnosed with SAVI. The patient exhibited signs of interstitial lung disease and cutaneous manifestations before the age of 1 year and continued to have recurrent fever accompanied by pulmonary infiltrates. Based on positive findings for antibodies associated with SLE, such as antinuclear antibodies and anti-double-stranded DNA, the pulmonary involvement was considered a manifestation of SLE. Another significant symptom was recurrent skin ulceration, which led to partial spontaneous amputation of most of the toes due to inflammation. Given the early onset of interstitial lung disease, severe skin ulcers, and symptoms resembling SLE, autoinflammatory syndrome, especially SAVI was suspected. Following confirmation by genetic testing at age 29 years, the patient was started on tofacitinib, a Janus kinase inhibitor. Despite the prolonged use of multiple immunosuppressive therapies, the patient's lung condition continued to worsen, ultimately requiring lung transplantation. This observational report highlights the importance of considering SAVI as a potential diagnosis when manifestations of interstitial lung disease are observed during infancy. Early proactive treatment is crucial for lung involvement, as this can have long-term effects on patient's prognosis.

Clinical characteristics and prognostic value of autoantibody profile in children with monogenic lupus.

Objective: To report the frequency of selected autoantibodies and their associations with clinical features in Arab children with monogenic lupus. Methods: This study was retrospective single-center study of genetically confirmed monogenic lupus cases at childhood lupus clinic at King Faisal Specialist Hospital and Research Center, from June 1997 to July 2022. We excluded familial lupus without genetic testing and patients with insufficient data. Collected data comprised clinical and laboratory findings, including the autoantibody profile, which included the anti-double-stranded DNA (anti-dsDNA), anti-Smith, anti-Sjögren's-syndrome-related antigen A (anti-SSA), anti-Sjögren's-syndrome-related antigen B (anti-SSB), and antiphospholipid (APL) antibodies. Also, disease activity and accrual disease damage were collected at the last follow-up visit. Results: This study enrolled 27 Arab patients (14 males) with a median age of 11 years (interquartile range 8.0~16 years), with 63% having early-onset disease. The consanguinity rate and family history of lupus were high (74.1% and 55.6%, respectively). The most frequent clinical features were hematological (96.3%), fever (81.5%), mucocutaneous lesions (85.2%), and renal (66.7%). The frequency of the APL antibodies was 59.3%, anti-dsDNA was 55.6%, and anti-Smith and anti-SSA were 48.2% and 44.4%, respectively. Moreover, dsDNA antibodies were significantly associated with musculoskeletal complaints (p<0.05). Likewise, both anti-Smith and anti-SSA antibodies were linked to failure to thrive and recurrent infections in the univariate analysis (p<0.05). Conclusion: Our study reveals autoantibody frequencies and their association with clinical and prognostic in a substantial monogenic lupus cohort. Distinct clinical manifestations and prognosis association with certain autoantibodies support the idea that monogenic lupus is a distinctive form of lupus. Larger studies needed to validate these findings.

Cutaneous tuberculosis, different clinical spectrum of the same disease: the importance of pre-test probability.

This report presents three cases of cutaneous tuberculosis that were identified at the Calderon Hospital in Quito, Ecuador. The first case involved a 44-year-old man who had tuberculosis verrucosa cutis, characterized by circinate erythematous areas, ulcerated nodules, and verruciform plaques extending from the right lower limb to the hip. In the second case a 50-year-old woman with a 1-year history of pruritic dermatosis in the left ciliary area was diagnosed with lupus vulgaris. In the third case, a 23-year-old man with erythematous nodules draining caseous material at the neck, thorax, and axillary region was diagnosed with scrofuloderma. It was discovered that nearly every laboratory test that was accessible had drawbacks as a diagnostic technique. Correlating clinical and epidemiological features with the pretest probability is crucial for optimizing indicators and confirming or ruling out the diagnosis in immunocompromised and high-risk individuals with atypical lesions.

Restless leg syndrome in systemic lupus erythematosus: Associations with disease activity, quality of life and depression.

OBJECTIVES: The aim of this study was to determine the prevalence of restless leg syndrome (RLS) among patients with SLE, describe their clinical characteristics, examine its impact on health-related quality of life (HRQoL), and evaluate its association with depression. METHODS: A total of 124 SLE patients were recruited, with data on demographics, and clinical features collected. RLS diagnosis was based on the international RLS study group criteria, while depression was assessed by the patient health questionnaire. HRQoL was assessed by a disease-specific validated questionnaire, the LupusQoL, pain intensity was examined through the pain visual analogue scale, and disease activity was evaluated via the patient global assessment. These variables were compared between SLE patients with RLS and without RLS using t-tests or Wilcoxon and the chi-square test of independence for categorical variables. A p-value ≤0.05 was considered statistically significant. RESULTS: Among the SLE patients (mean age 48, 87.1 % women), 32 % had RLS. The SLE patients with RLS were found to have a longer delay in diagnosis (1 vs 0.5 years; p = 0.019) and were less likely to be employed (65 % vs 45 %, p = 0.040) compared to non-RLS patients. In addition, RLS patients were more likely to have coexisting Major Depressive Disorder (MDD) (p = 0.019), higher levels of pain (p = 0.006) and disease activity based on patient global assessment (p = 0.014). Further, most of the domains of LupusQoL were significantly lower in the RLS patients group suggesting a worse HRQoL. CONCLUSION: RLS was present in one-third of the SLE cohort, significantly impairing HRQoL and correlating with depression, higher pain, and increased disease activity. These findings underscore the importance of early RLS detection and management in SLE patients.

Measles in the vaccinated host.

A woman in her 40s known to have systemic lupus erythematosus presented with a maculopapular rash on her face, neck and chest following measles exposure. She had received a single-dose measles vaccine as a child in the 1970s and was therefore presumed to be immune, and thus not infectious. As a result, she was initially managed in an open bay. Measles virus IgM antibody in serum was undetectable; however, measles virus RNA was subsequently detected in throat swab by PCR, which is consistent with current infection. Measles is one of the most transmissible diseases in the world and cases are rising both in the UK and globally. Our case and literature review highlight the risk of vaccine failure in measles, especially in people who have not received two doses of the measles, mumps and rubella vaccine. It also highlights the challenges in diagnosing measles in previously vaccinated individuals.

Monoclonal antibodies targeting interleukins for systemic lupus erythematosus: updates in early clinical drug development.

INTRODUCTION: the advent of biological therapies has already revolutionized treatment strategies and disease course of several rheumatologic conditions, and monoclonal antibodies (mAbs) targeting cytokines and interleukins represent a considerable portion of this family of drugs. In Systemic Lupus Erythematosus (SLE) dysregulation of different cytokine and interleukin-related pathways have been linked to disease development and perpetration, offering palatable therapeutic targets addressable via such mAbs. AREAS COVERED: In this review, we provide an overview of the different biological therapies under development targeting cytokines and interleukins, with a focus on mAbs, while providing the rationale behind their choice as therapeutic targets and analyzing the scientific evidence linking them to SLE pathogenesis. EXPERT OPINION: an unprecedented number of clinical trials on biological drugs targeting different immunological pathways are ongoing in SLE. Their success might allow us to tackle present challenges of SLE management, including the overuse of glucocorticoids in daily clinical practice, as well as SLE heterogenicity in treatment response among different individuals, hopefully paving the way toward precision medicine.

Predictability of the Delta Neutrophil Index and Other Blood Parameters on Perinatal Outcomes in Pregnant Women With Systemic Lupus Erythematosus.

PROBLEM: This study aimed to evaluate the predictive value of delta neutrophil index (DNI), a peripheral blood parameter, on perinatal outcomes in pregnant women with systemic lupus erythematosus (SLE). METHOD OF STUDY: One hundred eighty-one participants, 78 pregnant women with SLE, and 103 healthy pregnant women were included in this retrospective study. Peripheral blood parameters including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and DNI taken in the first trimester were compared between groups. RESULTS: NLR, PLR, and DNI were significantly higher in the SLE group (p = 0.027, p = 0.007, p = 0.0001, respectively). The same parameters were not found to be significant in determining disease activity in pregnant women with SLE (p > 0.05). When the predictive value of DNI for SGA in pregnancies with SLE was evaluated by receiver operating characteristic curve (ROC), the area under the ROC curve (AUC) was 0.666 (95% CI; 0.544-0.788, p = 0.018) with 84.6% sensitivity, 53.8% specificity, 56.0% PPV, and 78.1% NPV at a cut-off value of 0.16. The predictive value of DNI according to ROC for stillbirth in pregnancies with SLE was AUC 0.731 (95% CI: 0.539-0.923, p = 0.019) with a cut-off value of 0.17, sensitivity of 90%, specificity of 51.5%, PPV of 58.5%, and NPV of 87.2%. CONCLUSIONS: Although DNI's prediction of SGA and stillbirth in pregnant women with SLE is encouraging, it needs more evidence from prospective studies with larger series.

The role of TNF-α as a potential marker for acute cutaneous lupus erythematosus in patients with systemic lupus erythematosus.

Acute cutaneous lupus erythematosus (ACLE) is closely associated with systemic symptoms in systemic lupus erythematosus (SLE). This study aimed to identify potential biomarkers for ACLE and explore their association with SLE to enable early prediction of ACLE and identify potential treatment targets for the future. In total, 185 SLE-diagnosed patients were enrolled and categorized into two groups: those with ACLE and those without cutaneous involvement. After conducting logistic regression analysis of the differentiating factors, we concluded that tumor necrosis factor-alpha (TNF-α) is an independent risk factor for ACLE. Analysis of the receiver operating characteristic revealed an area under the curve of 0.716 for TNF-α. Additionally, both TNF-α and ACLE are positively correlated with disease activity. TNF-α shows promise as a biomarker for ACLE, and in SLE patients, ACLE may serve as a clear indicator of moderate-to-severe disease activity.

Genetic polymorphisms in genes involved in the type I interferon system (STAT4 and IRF5): association with Asian SLE patients.

Systemic lupus erythematosus (SLE) is a common autoimmune disease with a polymorphic clinical presentation involving multisystem damages with significant differences in prevalence and disease severity among different ethnic groups. Although genetic, hormonal, and environmental factors have been demonstrated to contribute a lot to SLE, the pathogenesis of SLE is still unknown. Numerous evidence revealed that gene variants within the type I interferons (IFN) signaling pathway performed the great genetic associations with autoimmune diseases including SLE. To date, through genome-wide association studies (GWAS), genetic association studies showed that more than 100 susceptibility genes have been linked to the pathogenesis of SLE, among which TYK2, STAT1, STAT4, and IRF5 are important molecules directly connected to the type I interferon signaling system. The review summarized the genetic associations and the detailed risk loci of STAT4 and IRF5 with Asian SLE patients, explored the genotype distributions associated with the main clinical manifestations of SLE, and sorted out the potential reasons for the differences in susceptibility in Asia and Europe. Moreover, the therapies targeting STAT4 and IRF5 were also evaluated in order to propose more personalized and targeted treatment plans in SLE.

Kidney transplantation from a systemic lupus erythematosus donor and 1-year follow-up: A case report.

Systemic lupus erythematosus (SLE) is usually regarded as a relative contraindication for deceased kidney donation. The pathological variations because of the changes in the immune environment after kidney transplantation (KT) are unclear, and the recovery of renal function is poorly understood. We present a case of KT from a deceased donor with SLE who was followed-up for one year. Although SLE-related hemangioma developed during the perioperative period, it was cured after interventional treatment. A pre-planned biopsy was performed one year after KT, and it was found that most of the pathological changes and immunofluorescent markers of lupus had resolved. Renal function was stable, and urinary protein and occult blood levels reduced one year after KT.

A case report and literature review: Mycobacterium leprae infection diagnosed by metagenomic next-generation sequencing of cerebrospinal fluid.

BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae) that is responsible for deformities and irreversible peripheral nerve damage and has a broad spectrum of clinical and serological manifestations. Leprosy primarily affects the peripheral nerves and rarely presents with central nervous system involvement. Diagnosing leprosy can still be difficult in some cases, especially when the infection involves uncommon clinical manifestations and extracutaneous sites. Delayed diagnosis and treatment of leprosy may lead to irreversible damage and death. CASE PRESENTATION: We report a case of a 30-year-old female presenting with "repeated high fever with symptoms of headache for 14 days". On the day of admission, physical signs of lost eyebrows and scattered red induration patches all over her body were observed. The patient's diagnosis was based on the clinical characteristics using a combination of metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) and slit-skin smear. After confirming Listeria meningitis and multibacillary leprosy with erythema nodosum leprosum (ENL), a type 2 reaction, she was treated with ampicillin sodium, dapsone, rifampicin, clofazimine, methylprednisolone, and thalidomide. At the 1-year follow-up, the frequency and severity of headaches have significantly decreased and a good clinical response with improved skin lesions was found. CONCLUSION: This case highlights the importance of considering leprosy, which is a rare and underrecognized disease, in the differential diagnosis of skin rashes with rheumatic manifestations, even in areas where the disease is not endemic, and physicians should be alerted about the possibility of central nervous system infections. In addition, mNGS can be used as a complementary diagnostic tool to traditional diagnostic methods to enhance the diagnostic accuracy of leprosy.

Investigation of ferroptosis-associated molecular subtypes and immunological characteristics in lupus nephritis based on artificial neural network learning.

BACKGROUND: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) with poor treatment outcomes. The role and underlying mechanisms of ferroptosis in LN remain largely unknown. We aimed to explore ferroptosis-related molecular subtypes and assess their prognostic value in LN patients. METHODS: Molecular subtypes were classified on the basis of differentially expressed ferroptosis-related genes (FRGs) via the Consensus ClusterPlus package. The enriched functions and pathways, immune infiltrating levels, immune scores, and immune checkpoints were compared between the subgroups. A scoring algorithm based on the subtype-specific feature genes identified by artificial neural network machine learning, referred to as the NeuraLN, was established, and its immunological features, clinical value, and predictive value were evaluated in patients with LN. Finally, immunohistochemical analysis was performed to validate the expression and role of feature genes in glomerular tissues from LN patients and controls. RESULTS: A total of 10 differentially expressed FRGs were identified, most of which showed significant correlation. Based on the 10 FRGs, LN patients were classified into two ferroptosis subtypes, which exhibited significant differences in immune cell abundances, immune scores, and immune checkpoint expression. A NeuraLN-related protective model was established based on nine subtype-specific genes, and it exhibited a robustly predictive value in LN. The nomogram and calibration curves demonstrated the clinical benefits of the protective model. The high-NeuraLN group was closely associated with immune activation. Clinical specimens demonstrated the alterations of ALB, BHMT, GAMT, GSTA1, and HAO2 were in accordance with bioinformatics analysis results, GSTA1 and BHMT were negatively correlated with the severity of LN. CONCLUSION: The classification of ferroptosis subtypes and the establishment of a protective model may form a foundation for the personalized treatment of LN patients.

Healthcare Encounters and Outcomes of Filipino Patients with Systemic Lupus Erythematosus Managed at a Tertiary COVID-19 Referral Center.

Objective: The coronavirus disease 2019 (COVID-19) pandemic has limited healthcare delivery for patients with chronic diseases, including Systemic Lupus Erythematosus (SLE). This study aims to describe the outcomes of patients with SLE in a national COVID-19 referral center in the Philippines. Methods: A review of records of all adult patients with SLE seen in the University of the Philippines-Philippine General Hospital (UP-PGH) from March 2020 to December 2021 was done. Data about patient characteristics, health encounters, and outcomes before and after the first visit during the study period were extracted. Descriptive statistics were employed. Results: Our population of 403 patients was predominantly young (mean age 34.53 ± 11.14 years), female, and unemployed. This consisted of 370 known cases of SLE, 92 were diagnosed in institutions outside UP-PGH, and 33 new patients. Over the 22-month study period, there were 2,093 medical encounters, most of which were teleconsultations (81.70%). During an average gap of 53.6 ± 26.7 weeks between the last consultation and the first visit within the pandemic study period, 84 patients (22.70%) discontinued at least one of their SLE control medications, 68 (18.38%) patients developed a lupus flare, and 79 (21.35%) were hospitalized for various reasons. On their return to the rheumatology clinic during the pandemic, 37.47% were in lupus flare, 28.29% needed to be hospitalized, and 20 died. However, 86.75% of flares were controlled. During subsequent health encounters, 48 patients had a new flare (43 of these were controlled) and 20 died. The most common reason for hospitalization (n=160) was lupus disease flare and the most common cause of death (n=40) was pneumonia. Sixty patients acquired COVID-19 infection from which most recovered and four died. Conclusion: Audio teleconsultation was the most common method used by our lupus cohort to interact with their doctors during the pandemic. There was an average of a year-long interruption in medical care for 62.70%. More than a third developed a disease flare and 15% acquired COVID-19 but outcomes were good in more than 85%. Despite the challenges posed by the pandemic, the majority of our lupus cohort who were able to continue their treatment had favorable outcomes.

The relevance of antiphospholipid antibodies in obstetrics.

AIM AND METHODOLOGY: To provide a comprehensive review on new findings and current recommendations regarding antiphospholipid antibodies with particular emphasis on clinical impact on gestation. CONCLUSION: Antiphospholipid antibodies are an important risk factor for the development of a series of pregnancy-related complications. Early diagnosis and appropriate therapy can reduce the incidence of pregnancy loss and pregnancy-related complications.