Kikuchi-Fujimoto disease, simultaneously diagnosed with systemic lupus erythematosus in an Arabic female: an agonizing combination.

Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a rare, benign condition affecting young Oriental-Asian females. It is characterized by fever and tender cervical lymphadenopathy with an unclear aetiology, and in most longitudinal reviews, KFD occurs before systemic lupus erythematosus (SLE). Herein, the case of a 28-year-old Kuwaiti female without any relevant past medical history, who was simultaneously diagnosed with KFD and SLE following an Ebstein-Barr virus infection, is reported. The patient was treated with oral prednisolone, hydroxychloroquine, cyclosporin, and belimumab and her response was clinically and biochemically favourable. Although KFD is prevalent in Asian populations, it may affect all races. Early diagnosis of KFD is difficult, particularly when simultaneously diagnosed with SLE, but crucial to preventing inappropriate therapy. Clinicians need to know about this rare disease, especially when patients present with fever and swollen lymph nodes, due to a risk of misdiagnosis with tuberculosis or lymphoma, as these are more often thought to be the cause of such symptoms.

SF-36v2 and FACIT-Fatigue quality of life improvements with organ-specific SELENA-SLEDAI response and belimumab treatment in patients with systemic lupus erythematosus.

OBJECTIVE: Explore organ-specific SLE burden by assessing health-related quality of life (HRQoL) and fatigue changes associated with Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) organ system response (score improvement) and belimumab treatment. METHODS: Data from four phase III belimumab trials were pooled for post hoc analysis (GSK Study 217382): BLISS-52 (NCT00424476), BLISS-76 (NCT00410384), BLISS-SC (NCT01484496) and EMBRACE (NCT01632241). Patients with baseline organ system involvement were classed as organ system responders if SELENA-SLEDAI scores for that organ system decreased at any post-baseline visit. HRQoL (36-Item Short Form Health Survey version 2 (SF-36v2)) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)) changes over 52 weeks were compared between organ system responders and non-responders, and separately between belimumab versus placebo treatment arms among organ system responders. Group-level differences were compared using analysis of variance; differences were interpreted using published group-level minimal important difference (MID). RESULTS: In these post hoc analyses, musculoskeletal and mucocutaneous organ system responders had greater SF-36v2 improvements than non-responders across most SF-36v2 domains, but differences were largely MID), with FACIT-Fatigue also improving >MID for renal responders receiving belimumab. CONCLUSIONS: SLE disease burden differs with the organ system(s) involved. While these analyses are limited by mutual inclusivity of organ system groupings, differing patient numbers between groups and small numbers in some groups, they suggest that mucocutaneous and musculoskeletal organ system response improves SF-36v2 domain scores; cardiovascular and respiratory organ system response may meaningfully improve fatigue; and belimumab may offer additional HRQoL or fatigue benefits beyond standard therapy for musculoskeletal and renal responders.

Efficacy and safety study of targeted small-molecule drugs in the treatment of systemic lupus erythematosus.

BACKGROUND: Targeted small-molecule drugs in the treatment of systemic lupus erythematosus (SLE) have attracted increasing attention from clinical investigators. However, there is still a lack of evidence on the difference in the efficacy and safety of different targeted small-molecule drugs. Therefore, this study was conducted to assess the efficacy and safety of different targeted small-molecule drugs for SLE. METHODS: Randomized controlled trials (RCTs) on targeted small-molecule drugs in the treatment of SLE in PubMed, Web of Science, Embase, and Cochrane Library were systematically searched as of April 25, 2023. Risk of bias assessment was performed for included studies using the Cochrane's tool for evaluating the risk of bias. The primary outcome indicators were SRI-4 response, BICLA response, and adverse reaction. Because different doses and courses of treatment were used in the included studies, Bayesian network meta-regression was used to investigate the effect of different doses and courses of treatment on efficacy and safety. RESULTS: A total of 13 studies were included, involving 3,622 patients and 9 targeted small-molecule drugs. The results of network meta-analysis showed that, in terms of improving SRI-4, Deucravacitinib was significantly superior to that of Baricitinib (RR = 1.32, 95% CI (1.04, 1.68), P < 0.05). Deucravacitinib significantly outperformed the placebo in improving BICLA response (RR = 1.55, 95% CI (1.20, 2.02), P < 0.05). In terms of adverse reactions, targeted small-molecule drugs did not significantly increase the risk of adverse events as compared to placebo (P > 0.05). CONCLUSION: Based on the evidence obtained in this study, the differences in the efficacy of targeted small-molecule drugs were statistically significant as compared to placebo, but the difference in the safety was not statistically significant. The dose and the course of treatment had little impact on the effect of targeted small-molecule drugs. Deucravacitinib could significantly improve BICLA response and SRI-4 response without significantly increasing the risk of AEs. Therefore, Deucravacitinib is very likely to be the best intervention measure. Due to the small number of included studies, more high-quality clinical evidence is needed to further verify the efficacy and safety of targeted small-molecule drugs for SLE.

The STING inhibitor (ISD-017) reduces glomerulonephritis in 129.B6.Fcgr2b-deficient mice.

The absence of stimulator of interferon genes (STING) in 129.B6.Fcgr2b-deficient mice rescue lupus phenotypes. The administration of a STING inhibitor (ISD017) into the young 129.B6.Fcgr2b-deficient mice prevents lupus nephritis development. This study mainly aimed to evaluate the effects of STING inhibition (ISD107) on established SLE in mice to prove that ISD017 could be a good therapeutic drug to reverse the already set-up autoimmunity and kidney impairment. Twenty-four-week-old Fcgr2b-deficient mice were treated with cyclophosphamide (25 mg/kg, intraperitoneal, once per week), ISD017 (10 mg/kg, intraperitoneal, three times per week), or control vehicle for 8 weeks, and were analyzed for phenotypes. Both ISD017 and cyclophosphamide treatment increased long-term survival and reduced the severity of glomerulonephritis in Fcgr2b-deficient mice. While cyclophosphamide reduced activated B cells (B220+GL-7+), ISD017 decreased activated T cells (CD4+CD69+) and neutrophils (Ly6c+Ly6g+) in Fcgr2b-deficient mice. In addition, ISD017 reduced IL-1ß and interferon-inducible genes. In summary, ISD017 treatment in symptomatic 129.B6.Fcgr2b-deficient mice reduced the severity of glomerulonephritis and increased long-term survival. ISD017 worked comparably to cyclophosphamide for treating lupus nephritis in 129.B6.Fcgr2b-deficient mice. ISD017 reduced activated T cells and neutrophils, while cyclophosphamide targeted activated B cells. These results suggested that STING inhibitors can potentially be a new therapeutic drug for treating lupus.

Association of systemic lupus erythematosus standard of care immunosuppressants with glucocorticoid use and disease outcomes: a multicentre cohort study.

BACKGROUND: This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data. METHODS: The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes. RESULTS: Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual. CONCLUSIONS: This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus.

Non-thyroidal disease syndrome in patients with systemic lupus erythematosus: relation to disease inflammatory activity.

OBJECTIVE: To identify risk factors for the development of non-thyroidal illness syndrome (NTIS) in patients with systemic lupus erythematosus (SLE). METHODS: A retrospective analysis of 517 SLE patients and 1034 age-and sex-matched healthy population was conducted to compare the prevalence of NTIS in these two groups, and to analyze the laboratory and clinical characteristics of SLE patients with NTIS. Finally Logistic regression analysis was used to determine the risk factors for NTIS in SLE patients. RESULTS: The prevalence of NTIS in the SLE patients was significantly higher than that in controls (39.7% vs. 1.0%, P < 0.001). In SLE patients, compared with euthyroidism patients, NTIS patients exhibited higher levels of neutrophils, hepatic enzymes, kidney damage markers, inflammatory markers and SLE disease activity index (SLEDAI). They also had a higher incidence of organ insufficiency and positive antibodies such as anti-ds-DNA antibodies and anti-SSA antibodies. However, NTIS patients had lower levels of hemoglobin, lymphocytes, platelets, serum albumin, and complement. Additionally, NTIS patients had a shorter duration of lupus and lower utilization of disease-modifying antirheumatic drugs (DMARDs) (P < 0.05). Logistic regression analysis showed that elevated SLEDAI (OR = 1.060, 95%CI 1.022-1.099, P = 0.002), elevated systemic immune-inflammation index (SII) (OR = 1.003, 95%CI 1.001-1.007, P = 0.026), elevated erythrocyte sedimentation rate (ESR) (OR = 1.019, 95%CI 1.010-1.028, P < 0.001), and hepatic insufficiency (OR = 1.916, 95% CI 1.173-3.131, P = 0.009) were independent risk factors for the development of NTIS in SLE. DMARDs treatment (OR = 0.495, 95% CI 0.306-0.799, P < 0.001) was an independent protective factor for NTIS. CONCLUSIONS: Inflammatory activity in SLE patients is associated with the development of NTIS. Key Points • Inflammatory activity indexes such as SLEDAI, SII, and ESR are independent risk factors for NTIS in SLE patients.

Prednisone combined with Dihydroartemisinin attenuates systemic lupus erythematosus by regulating M1/M2 balance through the MAPK signaling pathway.

OBJECTIVE: Dihydroartemisinin (DHA) plays a very important role in various diseases. However, the precise involvement of DHA in systemic lupus erythematosus (SLE), relation to the equilibrium between M1 and M2 cells, remains uncertain. Therefore, we aimed to investigate the role of DHA in SLE and its effect on the M1/M2 cells balance. METHODS: SLE mice model was established by pristane induction. Flow cytometry was employed to measure the abundance of M1 and M2 cells within the peripheral blood of individuals diagnosed with SLE. The concentrations of various cytokines, namely TNF-α, IL-1ß, IL-4, IL-6, and IL-10, within the serum of SLE patients or SLE mice were assessed via ELISA. Immunofluorescence staining was utilized to detect the deposition of IgG and complement C3 in renal tissues of the mice. We conducted immunohistochemistry analysis to assess the expression levels of Collagen-I, a collagen protein, and α-SMA, a fibrosis marker protein, in the renal tissues of mice. Hematoxylin-eosin staining, Masson's trichrome staining, and Periodic acid Schiff staining were used to examine histological alterations. In this study, we employed qPCR and western blot techniques to assess the expression levels of key molecular markers, namely CD80 and CD86 for M1 cells, as well as CD206 and Arg-1 for M2 cells, within kidney tissue. Additionally, we investigated the involvement of the MAPK signaling pathway. The Venny 2.1 online software tool was employed to identify shared drug-disease targets, and subsequently, the Cytoscape 3.9.2 software was utilized to construct the "disease-target-ingredient" network diagram. Protein-protein interactions of the target proteins were analyzed using the String database, and the network proteins underwent enrichment analysis for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. RESULTS: The results showed that an increase in M1 cells and a decrease in M2 cells within the peripheral blood of individuals diagnosed with SLE. Further analysis revealed that prednisone (PDN) combined with DHA can alleviate kidney damage and regulate the balance of M1 and M2 cells in both glomerular mesangial cells (GMC) and kidney. The MAPK signaling pathway was found to be involved in SLE kidney damage and M1/M2 balance in the kidney. Furthermore, PDN and/or DHA were found to inhibit the MAPK signaling pathway in GMC and kidney. CONCLUSION: We demonstrated that PDN combined with DHA attenuates SLE by regulating M1/M2 balance through MAPK signaling pathway. These findings propose that the combination of PDN and DHA could serve as a promising therapeutic strategy for SLE, as it has the potential to mitigate kidney damage and reinstate the equilibrium of M1 and M2 cells.

Interpreting hydroxychloroquine blood levels for medication non-adherence: a pharmacokinetic study.

OBJECTIVE: Characterise the relationship between hydroxychloroquine (HCQ) blood levels and the number of missed doses, accounting for dosage, dose timing and the large variability in pharmacokinetics (PK) between patients. METHODS: We externally validated a published PK model and then conducted dosing simulations. We developed a virtual population of 1000 patients for each dosage across a range of body weights and PK variability. Using the model, 10 Monte Carlo simulations for each patient were conducted to derive predicted whole blood concentrations every hour over 24 hours (240 000 HCQ levels at steady state). To determine the impact of missed doses on levels, we randomly deleted a fixed proportion of doses. RESULTS: For patients receiving HCQ 400 mg daily, simulated random blood levels <200 ng/mL were exceedingly uncommon in fully adherent patients (<0.1%). In comparison, with 80% of doses missed, approximately 60% of concentrations were <200 ng/mL. However, this cut-off was highly insensitive and would miss many instances of severe non-adherence. Average levels quickly dropped to <200 ng/mL after 2-4 days of missed doses. Additionally, mean levels decreased by 29.9% between peak and trough measurements. CONCLUSIONS: We propose an algorithm to optimally interpret HCQ blood levels and approximate the number of missed doses, incorporating the impact of dosage, dose timing and pharmacokinetic variability. No single cut-off has adequate combinations of both sensitivity and specificity, and cut-offs are dependent on the degree of targeted non-adherence. Future studies should measure trough concentrations to better identify target HCQ levels for non-adherence and efficacy.

Systemic Lupus Erythematosus: A Review.

Importance: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by inflammation and immune-mediated injury to multiple organ systems, including the mucocutaneous, musculoskeletal, hematologic, and kidney systems. Approximately 3.4 million people worldwide have received a diagnosis of SLE. Observations: Approximately 90% of people with SLE are female. Although there are no uniformly accepted diagnostic criteria for SLE, the 2019 European Alliance of Associations for Rheumatology (formerly the European League Against Rheumatism)/American College of Rheumatology classification criteria developed for scientific study are an estimated 96.1% sensitive and 93.4% specific for SLE. These classification criteria include both clinical factors, such as fever, cytopenia, rash, arthritis, and proteinuria, which may be indicative of lupus nephritis; and immunologic measures, such as SLE-specific autoantibodies and low complement levels. Approximately 40% of people with SLE develop lupus nephritis, and an estimated 10% of people with lupus nephritis develop end-stage kidney disease after 10 years. The primary goal of treatment is to achieve disease remission or quiescence, defined by minimal symptoms, low levels of autoimmune inflammatory markers, and minimal systemic glucocorticoid requirement while the patient is treated with maintenance doses of immunomodulatory or immunosuppressive medications. Treatment goals include reducing disease exacerbations, hospitalizations, and organ damage due to the disease or treatment toxicity. Hydroxychloroquine is standard of care for SLE and has been associated with a significant reduction in mortality. Treatments in addition to hydroxychloroquine are individualized, with immunosuppressive agents, such as azathioprine, mycophenolate mofetil, and cyclophosphamide, typically used for treating moderate to severe disease. Three SLE medications were recently approved by the Food and Drug Administration: belimumab (for active SLE in 2011 and for lupus nephritis in 2020), voclosporin (for lupus nephritis), and anifrolumab (for active SLE). Conclusions and Relevance: Systemic lupus erythematosus is associated with immune-mediated damage to multiple organs and increased mortality. Hydroxychloroquine is first-line therapy and reduces disease activity, morbidity, and mortality. When needed, additional immunosuppressive and biologic therapies include azathioprine, mycophenolate mofetil, cyclophosphamide, belimumab, voclosporin, and anifrolumab.

Characterization of the patterns of care, access, and direct cost of systemic lupus erythematosus in Brazil: findings from the Macunaíma study.

BACKGROUND: A cost of illness (COI) study aims to evaluate the socioeconomic burden that an illness imposes on society as a whole. This study aimed to describe the resources used, patterns of care, direct cost, and loss of productivity due to systemic lupus erythematosus (SLE) in Brazil. METHODS: This 12-month, cross-sectional, COI study of patients with SLE (ACR 1997 Classification Criteria) collected data using patient interviews (questionnaires) and medical records, covering: SLE profile, resources used, morbidities, quality of life (12-Item Short Form Survey, SF-12), and loss of productivity. Patients were excluded if they were retired or on sick leave for another illness. Direct resources included health-related (consultations, tests, medications, hospitalization) or non-health-related (transportation, home adaptation, expenditure on caregivers) hospital resources.Costs were calculated using the unit value of each resource and the quantity consumed. A gamma regression model explored cost predictors for patients with SLE. RESULTS: Overall, 300 patients with SLE were included (92.3% female,mean [standard deviation (SD)] disease duration 11.8 [7.9] years), of which 100 patients (33.3%) were on SLE-related sick leave and 46 patients (15.3%) had stopped schooling. Mean (SD) travel time from home to a care facility was 4.4 (12.6) hours. Antimalarials were the most commonly used drugs (222 [74.0%]). A negative correlation was observed between SF-12 physical component and SLE Disease Activity Index (- 0.117, p = 0.042), Systemic Lupus International CollaboratingClinics/AmericanCollegeofRheumatology Damage Index (- 0.115, p = 0.046), medications/day for multiple co-morbidities (- 0.272, p < 0.001), SLE-specific drugs/day (- 0.113, p = 0.051), and lost productivity (- 0.570, p < 0.001). For the mental component, a negative correlation was observed with medications/day for multiple co-morbidities (- 0.272, p < 0.001), SLE-specific medications/day (- 0.113, p = 0.051), and missed appointments (- 0.232, p < 0.001). Mean total SLE cost was US$3,123.53/patient/year (median [interquartile range (IQR)] US$1,618.51 [$678.66, $4,601.29]). Main expenditure was medication, with a median (IQR) cost of US$910.62 ($460, $4,033.51). Mycophenolate increased costs by 3.664 times (p < 0.001), and inflammatory monitoring (erythrocyte sedimentation rate or C-reactive protein) reduced expenditure by 0.381 times (p < 0.001). CONCLUSION: These results allowed access to care patterns, the median cost for patients with SLE in Brazil, and the differences across regions driven by biological, social, and behavioral factors. The cost of SLE provides an updated setting to support the decision-making process across the country.

Emerging Molecular and Synaptic Targets for the Management of Chronic Pain Caused by Systemic Lupus Erythematosus.

Patients with systemic lupus erythematosus (SLE) frequently experience chronic pain due to the limited effectiveness and safety profiles of current analgesics. Understanding the molecular and synaptic mechanisms underlying abnormal neuronal activation along the pain signaling pathway is essential for developing new analgesics to address SLE-induced chronic pain. Recent studies, including those conducted by our team and others using the SLE animal model (MRL/lpr lupus-prone mice), have unveiled heightened excitability in nociceptive primary sensory neurons within the dorsal root ganglia and increased glutamatergic synaptic activity in spinal dorsal horn neurons, contributing to the development of chronic pain in mice with SLE. Nociceptive primary sensory neurons in lupus animals exhibit elevated resting membrane potentials, and reduced thresholds and rheobases of action potentials. These changes coincide with the elevated production of TNFα and IL-1ß, as well as increased ERK activity in the dorsal root ganglion, coupled with decreased AMPK activity in the same region. Dysregulated AMPK activity is linked to heightened excitability in nociceptive sensory neurons in lupus animals. Additionally, the increased glutamatergic synaptic activity in the spinal dorsal horn in lupus mice with chronic pain is characterized by enhanced presynaptic glutamate release and postsynaptic AMPA receptor activation, alongside the reduced activity of glial glutamate transporters. These alterations are caused by the elevated activities of IL-1ß, IL-18, CSF-1, and thrombin, and reduced AMPK activities in the dorsal horn. Furthermore, the pharmacological activation of spinal GPR109A receptors in microglia in lupus mice suppresses chronic pain by inhibiting p38 MAPK activity and the production of both IL-1ß and IL-18, as well as reducing glutamatergic synaptic activity in the spinal dorsal horn. These findings collectively unveil crucial signaling molecular and synaptic targets for modulating abnormal neuronal activation in both the periphery and spinal dorsal horn, offering insights into the development of analgesics for managing SLE-induced chronic pain.

[Jianpi Zishen granule inhibits podocyte autophagy in systemic lupus erythematosus: a network pharmacology and clinical study].

OBJECTIVE: To explore the therapeutic mechanism of Jianpi Zishen (JPZS) granules for systemic lupus erythematosus(SLE) in light of podocyte autophagy regulation. METHODS: TCMSP, GeneCards, OMIM, and TTD databases were used to obtain the targets of JPZS granules, SLE, and podocyte autophagy. The protein-protein interaction network was constructed using Cytoscape, and the key active ingredients and targets were screened for molecular docking. In the clinical study, 46 patients with SLE were randomized into two groups to receive baseline treatment with prednisone acetate and mycophenolate mofetil (control group) and additional treatment with JPZS granules (observation group) for 12 weeks, with 10 healthy volunteers as the healthy control group. Urinary levels of nephrin and synaptopodin of the patients were detected with ELISA. Western blotting was performed to determine peripheral blood levels of p-JAK1/JAK1, p-STAT1/STAT1, LC3II/LC3I, and p62 proteins of the participants. RESULTS: Four key active ingredients and 5 core target genes (STAT1, PIK3CG, MAPK1, PRKCA, and CJA1) were obtained, and enrichment analysis identified the potentially involved signaling pathways including AGE-RAGE, JAK/STAT, EGFR, and PI3K/Akt. Molecular docking analysis showed that STAT1 was the most promising target protein with the highest binding activity, suggesting its role as an important mediator for signal transduction after JPZS granule treatment. In the 43 SLE patients available for analysis, treatment with JPZS granule significantly reduced serum levels of p-JAK1/JAK1, p-STAT1/STAT1, and LC3II/LC3I (P < 0.05 or 0.01), increased the protein level of P62 (P < 0.05), and reduced urinary levels of nephrin and synaptopodin (P < 0.05). CONCLUSION: The therapeutic effect of JPZS granules on SLE is mediated probably by coordinated actions of quercetin, kaempferol, ß-sitosterol, and isorhamnetin on their target gene STAT1 to inhibit the JAK/STAT pathway, thus suppressing autophagy and alleviating podocyte injuries in SLE.

Analysis of belimumab prescription and outcomes in a 10-year monocentric cohort: is there an advantage with early use?

OBJECTIVE: The objective is to evaluate perscriptions of belimumab (BEL), how these have changed over the years and their impact on clinical outcomes in patients with systemic lupus erythematosus (SLE). METHODS: This is a retrospective analysis of prospectively collected data. We retrieved demographic and clinical data and concomitant therapies at BEL starting (baseline). Disease activity was assessed at baseline and after 6 and 12 months and organ damage at baseline and at the last visit. RESULTS: From 422 patients followed in the Pisa SLE cohort, 102 patients received BEL and were included and 22 (21.6%) were immunosuppressant (IS)-naïve. Lupus Low Disease Activity State (LLDAS) with a glucocorticoid (GC) dosage ≤5 mg/day (LLDAS5) and remission were achieved by 47% and 38% of patients at 6 months, and by 75% and 66% at 12 months. Comparing IS-naïve patients with those who received BEL after at least one conventional IS, we did not find significant differences in baseline characteristics and in the achievement of LLDAS5 and remission. Despite at baseline we did not observe significant differences in mean GC daily dosage, IS-naïve patients were taking a significantly lower GC daily dose at 6 and 12 months. Interestingly, IS-naïve patients were more common in the most recent years. CONCLUSIONS: Our data confirm that BEL is effective in controlling disease activity, and in recent years BEL has been considered as an earlier treatment option before other IS. Early introduction of BEL can be at least as effective as a step-up approach and can help to reduce the GC dosage.

De novo Connective Tissue Disorders as Immune-related Adverse Events.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment through blocking immunoregulatory pathways, resulting in augmented antitumor responses. However, ICIs can cause inflammatory autoimmune toxicities, known as immune-related adverse events (irAEs). Common rheumatic irAEs include inflammatory arthritis, polymyalgia rheumatica-like symptoms, and myositis. Fewer cases of de novo connective tissue disease as irAEs have been described and have mainly presented with cutaneous manifestations of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Treatments include glucocorticoids and steroid-sparing agents such as hydroxychloroquine, mycophenolate mofetil, and methotrexate with improvement of symptoms. In this review, the authors discuss immune-related SLE and SSc and their management.

[Low disease activity and remission status of systemic lupus erythematosus in a real-world study].

OBJECTIVE: To investigate the rates of low disease activity and clinical remission in patients with systemic lupus erythematosus (SLE) in a real-world setting, and to analyze the related factors of low disease activity and clinical remission. METHODS: One thousand patients with SLE were enrolled from 11 teaching hospitals. Demographic, clinical and laboratory data, as well as treatment regimes were collec-ted by self-completed questionnaire. The rates of low disease activity and remission were calculated based on the lupus low disease activity state (LLDAS) and definitions of remission in SLE (DORIS). Charac-teristics of patients with LLDAS and DORIS were analyzed. Multivariate Logistic regression analysis was used to evaluate the related factors of LLDAS and DORIS remission. RESULTS: 20.7% of patients met the criteria of LLDAS, while 10.4% of patients achieved remission defined by DORIS. Patients who met LLDAS or DORIS remission had significantly higher proportion of patients with high income and longer disease duration, compared with non-remission group. Moreover, the rates of anemia, creatinine elevation, increased erythrocyte sedimentation rate (ESR) and hypoalbuminemia was significantly lower in the LLDAS or DORIS group than in the non-remission group. Patients who received hydroxychloroquine for more than 12 months or immunosuppressant therapy for no less than 6 months earned higher rates of LLDAS and DORIS remission. The results of Logistic regression analysis showed that increased ESR, positive anti-dsDNA antibodies, low level of complement (C3 and C4), proteinuria, low household income were negatively related with LLDAS and DORIS remission. However, hydroxychloroquine usage for longer than 12 months were positively related with LLDAS and DORIS remission. CONCLUSION: LLDAS and DORIS remission of SLE patients remain to be improved. Treatment-to-target strategy and standar-dized application of hydroxychloroquine and immunosuppressants in SLE are recommended.

Novel and potential future therapeutic options in systemic autoimmune diseases.

Autoimmune inflammation is caused by the loss of tolerance to specific self-antigens and can result in organ-specific or systemic disorders. Systemic autoimmune diseases affect a significant portion of the population with an increasing rate of incidence, which means that is essential to have effective therapies to control these chronic disorders. Unfortunately, several patients with systemic autoimmune diseases do not respond at all or just partially respond to available conventional synthetic disease-modifying antirheumatic drugs and targeted therapies. However, during the past few years, some new medications have been approved and can be used in real-life clinical settings. Meanwhile, several new candidates appeared and can offer promising novel treatment options in the future. Here, we summarize the newly available medications and the most encouraging drug candidates in the treatment of systemic lupus erythematosus, rheumatoid arthritis, Sjögren's disease, systemic sclerosis, systemic vasculitis, and autoimmune myositis.

Effect of hydroxychloroquine blood concentration on the efficacy and ocular toxicity of systemic lupus erythematosus.

In the absence of evidence-based guidance on the impact of hydroxychloroquine (HCQ) blood concentration on efficacy and ocular toxicity in systemic lupus erythematosus (SLE), the clinical monitoring of HCQ blood concentration is not yet widely performed, which raised concerns about the necessity of conducting HCQ blood concentration monitoring. In this retrospective study, we consecutively enrolled 135 patients with SLE who received HCQ treatment for more than 6 months from July 2022 to December 2022. Ocular toxicity was evaluated by collecting relevant retinal parameters using optical coherence tomography angiography (OCTA). Therapeutic efficacy was evaluated using the SLE disease activity index (SLEDAI) and relevant clinical parameters. HCQ blood concentration was determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Spearman correlation analysis revealed that the cumulative dose of HCQ was positively correlated with the foveal avascular zone (FAZ) perimeter and FAZ area (r = 0.734, P < 0.001; r = 0.784, P < 0.001). Meanwhile, the treatment duration of HCQ was positively correlated with FAZ perimeter and FAZ area (r = 0.761, P < 0.001; r = 0.882, P < 0.001). The univariate and multivariate logistic regression analyses indicated that HCQ blood concentration was associated with the disease activity of patients with SLE (odds ratio 0.994, 95% CI 0.990-0.999). HCQ blood concentration may be an important factor in assessing the therapeutic effectiveness of SLE patients. The HCQ-related ocular toxicity was a long-term effect related to long term exposure, rather than the blood concentration of HCQ at the time of testing. More importantly, when addressing HCQ-related ocular toxicity, it may be crucial to pay attention to the cumulative dose and treatment duration of HCQ.

Disease evolution and organ damage accrual in patients with stable UCTD: a long-term monocentric inception cohort.

OBJECTIVES: Undifferentiated connective tissue diseases (UCTDs) are systemic autoimmune conditions that cannot be diagnosed nor classified as defined CTD; the majority maintains an undifferentiated profile (stable UCTD, sUCTD) over time. Data on long-term outcomes of sUCTD are lacking. METHODS: Retrospective longitudinal analysis of an inception cohort of 141 patients with sUCTD.Disease evolution and damage accrual were evaluated at 1, 5 and 10 years. Partial least square (PLS) regression was used to identify the basal variables contributing to damage accrual at 1, 5 and 10 years of follow-up. Trend of damage over time was compared with a cohort of age-matched and sex-matched patients with systemic lupus erythematosus (SLE) by means of Nelson-Aalen analysis. RESULTS: 11.3% of patients evolved to a definite CTD after a median 11 years (IQR 6-25) from the first symptom. At last visit, 10% were on glucocorticoids and 6% on immunosuppressive therapy. In 27.3%, at least one item of organ damage was recorded according to the SLICC/DI score (mean score 1.19±0.46). At PLS analysis, age at diagnosis and age at first symptoms were related to damage at 1 year, not taking antimalarials and taking immunosuppressants were associated with damage at 5 years.The mean survival without damage was 9.3 years in sUCTD and 8.4 years in SLE. The 10-year probability without damage was 62% and 23% in SLE and sUCTD, respectively (p=0.015). CONCLUSIONS: Although less significantly impacted than in patients with SLE, in the long-term UCTDs can accumulate organ damage and evolve into defined connective tissue diseases.