Systemic lupus erythematosus with chronic persistent intracranial hypertension: A case report.

OBJECTIVE: The aim is to investigate the clinical characteristics of systemic lupus erythematosus with intracranial hypertension. METHODS: The clinical characteristics of one case of systemic lupus erythematosus with chronic persistent intracranial hypertension were analyzed, and related literature was reviewed by searching Medline and Wanfang databases. RESULTS: Intracranial hypertension in SLE patients may occur at the onset or during the course of the disease. Our patient was diagnosed with IH 3 years after the onset of SLE. Headache and papilledema were the most common symptoms of intracranial hypertension, followed by nausea or vomiting, vision changes, and cerebral palsy. Our patient had a headache and cranial hypertension that lasted for years, but no papilledema was found. Corticosteroid is currently the mainstay of the treatment of IIH in patients with SLE, and immunosuppressive agents, acetazolamide, intravenous mannitol and furosemide are also used. However, our patient did not respond to these treatments and presents the characteristics of chronic persistent intracranial hypertension. CONCLUSION: Systemic lupus erythematosus with intracranial hypertension is a rare manifestation of SLE, which is not completely parallel to SLE activity. Headache and papilledema were the most common presenting symptoms. Different from previous reported cases, our patient had poor response to treatments, showing chronic and persistent characteristics.

Triple-combination therapy did not improve prognosis in anti-MDA5 positive dermatomyositis: a multicentre longitudinal cohort study.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM) is frequently linked with interstitial lung disease (ILD), especially the rapidly progressive ILD (RP-ILD). We conduct this research to evaluate the efficacy and safety of triple-combination (triple-combo) therapy consisting of high-dose corticosteroids, tacrolimus and intravenous cyclophosphamide in treating MDA5+ DM patients with ILD. METHODS: A multicentre longitudinal cohort study involving 115 MDA5+ DM patients from the Nanjing Medical University Myositis Associated ILD (NMMI) cohort was conducted between January 2019 and November 2022. Patients were categorised into triple-combo and non-triple therapy groups, and their outcomes were assessed. RESULTS: Contrary to expectations, triple-combo therapy did not improve the prognosis for MDA5+ DM patients but was linked to increased mortality rates, especially among those at high risk for RP-ILD. CONCLUSIONS: Our study suggests that triple-combo therapy might not be effective in improving prognosis in MDA5+ DM patients. Further research is needed to establish safer and more effective treatment modalities for this patient population.

Time-dependent changes in RPILD and mortality risk in anti-MDA5+ DM patients: a cohort study of 272 cases in China.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 positive (anti-MDA5+) DM has a close relationship with rapidly progressive interstitial lung disease (RPILD) and is associated with high mortality. However, data regarding the time-dependent risk of RPILD and deaths during disease progression are limited. We conducted this study to investigate whether the risk of RPILD and death were time-dependent or not in anti-MDA5+ DM. METHODS: We assessed a cohort of 272 patients with anti-MDA5+ DM. The clinical characteristics of patients with anti-MDA5+ were collected, and COX regression was used to analyse independent risk factors for RPILD and death. We also described changes in risk of RPILD and death over time and their potential clinical implications. RESULTS: There were 272 anti-MDA5+ DM patients enrolled in this study. According to the multivariate cox regression analysis, short disease course, high CRP level, anti-Ro52 positive and anti-MDA5 titre (++∼+++) were independent risk factors of RPILD. High creatine kinase level, high CRP level and RPILD were independent risk factors for death, and >90% RPILD and 84% mortality occurred in the first 6 months after disease onset. Notably, the first 3 months is a particularly high-risk period, with 50% of RPILD and 46% of deaths occurring. Hazards regarding RPILD and mortality diminished over time during a median follow-up of 12 months. CONCLUSION: These results suggest significant, time-dependent changes in RPILD and mortality risk in anti-MDA5+ DM patients, providing a cut-off time window to estimate disease progression and poor prognosis.

Systemic lupus erythematosus with diffuse intracranial calcification: A case report and review of literature.

OBJECTIVE: to investigate the clinical characteristics of systemic lupus erythematosus with diffuse intracranial calcification. METHODS: The clinical characteristics of one case of systemic lupus erythematosus with diffuse intracranial calcification were analyzed, and 12 cases in related literatures were reviewed by searching Medline and Wanfang database. RESULTS: Our case and 12 cases reviewed were all female. With the exception of one case, the course of SLE was more than 5 years. The clinical manifestations of the nervous system are diverse, including epilepsy, hemiplegia, cognitive impairment, and mental abnormalities. In the presence of neuropsychiatric manifestations, this case and six cases reviewed had SLE activity. Cerebrospinal fluid (CSF) examination was performed in seven patients, including four patients with CSF protein elevation, two patients with IL-6 elevation, and one patient with anti-ribosomal p antibody elevation. This case and 10 of 12 cases reviewed had bilateral basal ganglia calcification. Intracranial calcification was very high density on CT and showed high T1WI and low T2WI signal on MRI. CONCLUSION: Systemic lupus erythematosus with intracranial calcification is a rare and severe manifestation of SLE, which is not completely parallel to SLE activity. The clinical manifestations of the nervous system are diverse, and bilateral basal ganglia calcification is the most common in imaging. High T1WI signal and low T2WI signal may be used as one of the imaging features to identify intracranial calcification.

Leptin accelerates B cell dysfunctions via activating JAK/STAT3/5 and ERK1/2 pathways in patients with systemic lupus erythematosus.

OBJECTIVES: Our previous studies found that serum leptin was increased significantly in SLE, characterised by dysregulated autoreactive B cells producing excessive inflammatory cytokines and autoantibodies. The aim of this study was to explore the effects of leptin on B cell functions in SLE and clarify the key pathways in leptin dysregulated B cells. METHODS: Peripheral blood samples were obtained from 86 SLE patients and 28 normal controls. Purified B cells were stimulated with leptin or SLE serum and with or without anti-leptin antibody. The frequencies of CD19-CD138+ plasma cells and the expression of leptin receptor (LEPR) on B cells were determined with flow cytometry. The levels of antibodies and cytokines were assayed by ELISA. Classic signalling pathways were detected with western blotting method. RESULTS: Increased plasma cells and the levels of IgG and anti-dsDNA antibodies were positively correlated with serum leptin in SLE patients. LEPR+CD19+B cells were increased in SLE patients. Leptin up-regulated LEPR on B cells and activated B cells to produce higher levels of IL-6, IL-10 and TNF-α, and induced B cells to differentiated into plasma cells secreting more IgG and IgM. More importantly, anti-leptin neutralising antibody could partially restore increased cytokines, antibodies and plasma cells induced by SLE serum. Mechanistically, both leptin and SLE serum activated JAK/STAT3/5 and ERK1/2 signalling pathways in B cells, and the secretion-enhancing effects were restored by their inhibitors. CONCLUSIONS: Leptin may be a key factor leading to B cell dysfunction by activating JAK/STAT3/5 and ERK1/2 signalling pathways in SLE.

Determination of Anticyclic Citrullinated Peptide Based on Biotin-Streptavidin-Amplified Time-Resolved Fluoroimmunoassay.

BACKGROUND: A rapid and sensitive time-resolved fluoroimmunoassay (TRFIA) based on the biotin-streptavidin amplification system was developed for the determination of anticyclic citrullinated peptide (anti-CCP). METHODS: Europium-labeled streptavidin derivatives combined with europium and anhydride of diethylene triamine pentaacetic acid were used to label streptavidin, biotin was coupled with rabbit anti-human IgG to form a biotin-anti-human IgG bridge between streptavidin-europium and the anti-CCP antibody in the immunoassay. The anti-CCP assay was carried out by measuring the fluorescence of Eu(3+) -streptavidin at 615 nm. RESULTS: The presented method produced a wide linear range from 0.58 to 9,463 U/ml, while it was only 591.4-18.48 U/ml when using an ELISA kit, and featured a detection limit up to 0.5 U/ml for anti-CCP. The values determined by the biotin-streptavidin-TRFIA and ELISA correlated well (R(2) = 0.8927). The method was applied to determine anti-CCP in serum samples with satisfied recoveries of 96.45-104.63%. CONCLUSION: The assay results obtained by the present method showed that biotin-streptavidin-amplified TRFIA improve the traditional ELISA kit for anti-CCP detection. Therefore, it offers a better alternative immunoassay in rheumatoid arthritis management.

Gender differences in patients with anti-MDA5-positive dermatomyositis: a cohort study of 251 cases.

OBJECTIVE: To investigate the impact of sex differences on the clinical characteristics and prognosis of patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5+ DM). METHODS: We retrospectively analyzed a cohort of 251 patients with MDA5+ DM, including 71 in the male group and 180 in the female group. A multivariate logistic regression model was built to analyze independent risk factors for RPILD in each group. An ROC curve was drawn to evaluate the predictive value of independent risk factors. Kaplan‒Meier analysis was used to compare the cumulative survival rates, while the log-rank test was used to test for significant differences between the two groups. RESULTS: Patients in the male group had a significantly higher prevalence of heliotrope rash, V sign, severe interstitial lung disease (ILD), and rapidly progressive interstitial lung disease (RPILD) than those in the female group. Anti-Ro52 positivity, high CRP level and short disease were identified as independent risk factors for RPILD in both male and female groups by multivariate logistic regression analysis. The mortality rates of males and females were 33.8% and 22.0%, respectively, and the survival time of patients in the male group was shorter than that in the female group. CONCLUSION: Male patients with MDA5+ DM exhibit an increased risk of RPILD, elevated mortality rates and reduced overall survival time compared to their female counterparts, and anti-Ro52 positivity may be an unfavorable prognostic factor for these patients. Key Points • The prevalence of solar rash, V sign, severe interstitial lung disease (ILD) and rapidly progressive interstitial lung disease (RPILD) in anti-MDA5-positive female patients was significantly lower than that in male patients. • Positive Anti-Ro52, high CRP level, and short course of disease were independent risk factors for RPILD in both men and women. • Female patients exhibited a lower mortality rate than male patients (22.0% vs 33.8%) and demonstrated longer survival time.

Rapidly progressive interstitial lung disease risk prediction in anti-MDA5 positive dermatomyositis: the CROSS model.

Background: The prognosis of anti-melanoma differentiation-associated gene 5 positive dermatomyositis (anti-MDA5+DM) is poor and heterogeneous. Rapidly progressive interstitial lung disease (RP-ILD) is these patients' leading cause of death. We sought to develop prediction models for RP-ILD risk in anti-MDA5+DM patients. Methods: Patients with anti-MDA5+DM were enrolled in two cohorts: 170 patients from the southern region of Jiangsu province (discovery cohort) and 85 patients from the northern region of Jiangsu province (validation cohort). Cox proportional hazards models were used to identify risk factors of RP-ILD. RP-ILD risk prediction models were developed and validated by testing every independent prognostic risk factor derived from the Cox model. Results: There are no significant differences in baseline clinical parameters and prognosis between discovery and validation cohorts. Among all 255 anti-MDA5+DM patients, with a median follow-up of 12 months, the incidence of RP-ILD was 36.86%. Using the discovery cohort, four variables were included in the final risk prediction model for RP-ILD: C-reactive protein (CRP) levels, anti-Ro52 antibody positivity, short disease duration, and male sex. A point scoring system was used to classify anti-MDA5+DM patients into moderate, high, and very high risk of RP-ILD. After one-year follow-up, the incidence of RP-ILD in the very high risk group was 71.3% and 85.71%, significantly higher than those in the high-risk group (35.19%, 41.69%) and moderate-risk group (9.54%, 6.67%) in both cohorts. Conclusions: The CROSS model is an easy-to-use prediction classification system for RP-ILD risk in anti-MDA5+DM patients. It has great application prospect in disease management.

Fever in the initial stage of IIM patients: an early clinical warning sign for AE-ILD.

BACKGROUND: Fever is a common symptom of Idiopathic inflammatory myopathies (IIM). However, the exact correlation between fever and the prognosis of IIM is still unclear. This study aims to clarify if the IIM patients initiated with fever are associated with poorer outcomes. METHODS: This was a single-center retrospective cohort study. Data were collected from 79 newly diagnosed, treatment-naive IIM patients in the Affiliated Wuxi People's Hospital of Nanjing Medical University (Wuxi, Jiangsu, China) from November 2016 to June 2020. According to the presence or absence of fever at the onset, the IIM patients were divided into two groups(fever group n = 28, without fever group n = 51) Clinical characteristics, laboratory data, treatment, and outcomes were recorded. The Kaplan-Meier and log-rank tests were used to compare the all-cause mortality, relapse rate, and acute exacerbation of interstitial lung disease (AE-ILD) incidence. The association of fever with the outcomes was assessed in the unadjusted and adjusted forward logistic regression model. RESULTS: Compared with the non-fever group, the age at onset of the fever group was higher, and mechanic's hands (MH) and interstitial lung disease (ILD) were more common. Systemic inflammation (CRP and ESR) was significantly higher in the fever group, while the level of albumin(ALB) and muscle enzymes were lower. The fever group seemed to be received more aggressive treatment, with higher dose glucocorticoids and higher rates of intravenous immunoglobulins(IVIG) use. The all-cause mortality rate and the incidence rate of AE-ILD were higher in the fever group. Even adjusted for the age at onset and treatments, fever was significantly associated with AE-ILD and all-cause mortality. CONCLUSION: Our study has demonstrated that fever at initial diagnosis is associated with AE-ILD and mortality. Fever should serve as an early clinical warning sign for poor outcomes in IIM patients.

Assessing Myocardial Involvement in Systemic Lupus Erythematosus Patients without Cardiovascular Symptoms by Technetium-99m-sestamibi Myocardial Perfusion Imaging: A Correlation Study on NT-proBNP.

BACKGROUND: In patients with systemic lupus erythematosus (SLE), myocardial involvement is the third leading course of death after lupus nephropathy (LN) and infections. Previous autopsy studies have demonstrated a high incidence of cardiovascular abnormalities in the myocardium. However, the patients with typical symptoms are far much fewer than expected from post-mortem examinations. OBJECTIVES: The current study aimed to evaluate the technetium-99m-sestamibi (99mTc-MIBI) gated myocardial perfusion imaging (GMPI) characteristics of lupus patients without cardiovascular symptoms, and the relationships between GMPI characteristics and biochemical markers of myocardial injury, and to explore the role of GMPI in assessing myocardial involvement. METHODS: Thirty patients were studied with rest myocardial perfusion imaging, and summed rest score (SRS), summed motion score (SMS), and summed thickening score (STS) were calculated automatically. Biomarkers, including N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and creatine-kinase-MB (CK-MB), were detected simultaneously. GMPI parameters, LV functions and biomarkers were compared between two NT-proBNP groups. The relationships between these parameters were studied by correlation analysis. RESULTS: SMS, STS, and glomerular filtration rate (eGFR) were the main influencing factors of NTproBNP level (p = 0.001, <0.001, 0.042, respectively). Thirteen patients with an evaluated concentration of NT-proBNP had the lower left ventricular ejection fraction (LVEF), peak filling rate (PFR), eGFR and higher levels of CK-MB (in all comparisons, p < 0.05), and SRS was the only influencing factor of NT-proBNP (p = 0.007). Within thirteen patients with SRS≥2, there was a significant correlation between SRS and NT-proBNP (p < 0.001). CONCLUSION: 99mTc-MIBI GMPI could evaluate the left ventricular function and prompt the cardiomyocyte function at the cellular level. SMS and STS were the main influencers for plasma NT-proBNP, and SRS was the independent factor for elevated NT-proBNP. This radionuclide imaging method could provide additional diagnostic information on myocardial involvement in patients with SLE.

Deficient leptin receptor signaling in T cells of human SLE.

Background: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease mainly mediated by IgG autoantibody. While follicular helper T (Tfh) cells are crucial for supporting IgG autoantibody generation in human SLE, underlying mechanisms for Tfh cell mal-differentiation remain unclear. Methods: In total, 129 SLE patients and 37 healthy donors were recruited for this study. Circulating leptin was determined by ELISA from patients with SLE and healthy individuals. CD4 T cells isolated from SLE patients and healthy donors were activated with anti-CD3/CD28 beads under cytokine-unbiased conditions in the presence or absence of recombinant leptin protein, followed by detection for Tfh cell differentiation by quantifying intracellular transcription factor Bcl-6 and cytokine IL-21. AMPK activation was assessed by analyzing phosphor-AMPK using phosflow cytometry and immunoblots. Leptin receptor expression was determined using flow cytometry and its overexpression was achieved by transfection with an expression vector. Humanized SLE chimeras were induced by injecting patients' immune cells into immune-deficient NSG mice and used for translational studies. Results: Circulating leptin was elevated in patients with SLE, inversely associated with disease activity. In healthy individuals, leptin efficiently inhibited Tfh cell differentiation through inducing AMPK activation. Meanwhile, leptin receptor deficiency was a feature of CD4 T cells in SLE patients, impairing the inhibitory effect of leptin on the differentiation of Tfh cells. As a result, we observed the coexistence of high circulating leptin and increased Tfh cell frequencies in SLE patients. Accordingly, overexpression of leptin receptor in SLE CD4 T cells abrogated Tfh cell mal-differentiation and IgG anti-dsDNA generation in humanized lupus chimeras. Conclusion: Leptin receptor deficiency blocks the inhibitory effect of leptin on SLE Tfh cell differentiation, serving as a promising therapeutic target for lupus management.

Identification of Three Different Phenotypes in Anti-Melanoma Differentiation-Associated Gene 5 Antibody-Positive Dermatomyositis Patients: Implications for Prediction of Rapidly Progressive Interstitial Lung Disease.

OBJECTIVE: There is substantial heterogeneity among the phenotypes of patients with anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis (DM), hindering disease assessment and management. This study aimed to identify distinct phenotype groups in patients with anti-MDA5+ DM and to determine the utility of these phenotypes in predicting patient outcomes. METHODS: A total of 265 patients with anti-MDA5+ DM were retrospectively enrolled in the study. An unsupervised hierarchical cluster analysis was performed to characterize the different phenotypes. RESULTS: Patients were stratified into 3 clusters characterized by markedly different features and outcomes. Cluster 1 (n = 108 patients) was characterized by mild risk of rapidly progressive interstitial lung disease (RPILD), with the cumulative incidence of non-RPILD being 85.2%. Cluster 2 (n = 72 patients) was characterized by moderate risk of RPILD, with the cumulative incidence of non-RPILPD being 73.6%. Patients in cluster 3 (n = 85 patients), which was characterized by a high risk of RPILD and a cumulative non-RPILD incidence of 32.9%, were more likely than patients in the other 2 subgroups to have anti-Ro 52 antibodies in conjunction with high titers of anti-MDA5 antibodies. All-cause mortality rates of 60%, 9.7%, and 3.7% were determined for clusters 3, 2, and 1, respectively (P < 0.0001). Decision tree analysis led to the development of a simple algorithm for anti-MDA5+ DM patient classification that included the following 8 variables: age >50 years, disease course of <3 months, myasthenia (proximal muscle weakness), arthritis, C-reactive protein level, creatine kinase level, anti-Ro 52 antibody titer, and anti-MDA5 antibody titer. This algorithm placed patients in the appropriate cluster with 78.5% accuracy in the development cohort and 70.0% accuracy in the external validation cohort. CONCLUSION: Cluster analysis identified 3 distinct clinical patterns and outcomes in our large cohort of anti-MDA5+ DM patients. Classification of DM patients into phenotype subgroups with prognostic values may help physicians improve the efficacy of clinical decision-making.

Coexistence of Anti-Ro52 Antibodies in Anti-MDA5 Antibody-Positive Dermatomyositis Is Highly Associated With Rapidly Progressive Interstitial Lung Disease and Mortality Risk.

OBJECTIVE: Interstitial lung disease (ILD) is a common extramuscular complication contributing to significant morbidity and mortality in patients with dermatomyositis (DM) who are positive for antimelanoma differentiation-associated gene 5 antibody (anti-MDA5+). We conducted this study to investigate the association of anti-Ro52 antibodies with clinical characteristics and prognosis in patients with anti-MDA5+ DM. METHODS: We assessed a cohort of 246 patients with anti-MDA5+ DM. To calculate hazard ratios and 95% CIs for rapidly progressive ILD (RP-ILD) and death while controlling for potential confounders, variables selected by univariate Cox regression analysis were included in a multivariate Cox regression model with the stepwise forward-selection method. A 2-tailed analysis with P < 0.05 was considered to be statistically significant. RESULTS: A total of 246 patients with anti-MDA5+ DM were enrolled; 70 patients were male, and the patient group had an average age of 53.1 (12.4) years. Anti-Ro52 was present in 64.2% (158/246) patients. Patients with anti-MDA5+ DM who were positive for anti-Ro52 had a higher rate of RP-ILD (log-rank P < 0.001) and a higher mortality rate (log-rank P = 0.01). For patients with anti-MDA5+ DM who were positive for anti-Ro52, those with a short disease course and high inflammation were at increased risk of RP-ILD and death. The appearance of active rash was an independent protective factor of death. CONCLUSION: Anti-Ro52 antibodies were highly prevalent in patients with anti-MDA5+ DM, and their coexistence correlated with a higher rate of RP-ILD and mortality. Patients with a short disease course, with increased inflammation, and without rash were more likely to have a poor prognosis.

Systemic sclerosis associated with moyamoya syndrome: A case report and literature review.

Systemic sclerosis (SSc) associated with moyamoya syndrome (MMS) is a clinically rare disease. To further understand the clinical characteristics of SSc associated with MMS, we investigated and analyzed one case of SSc associated with MMS and conducted a literature review about this disease. Publications retrieved from MEDLINE and Wanfang databases were reviewed and discussed, and we found five well-described cases of SSc associated with MMS. The five patients had no family history of moyamoya disease, and the risk factors (cardiovascular disease) `were found in one of the five patients. The patients included in this study were more frequently female, and they often had limited or diffuse SSc. Unilateral involvement was frequently observed with clinical symptoms including hemiplegia, headache, loss of eyesight, and aphasia. The medical treatments included corticosteroids, immunosuppressive agents, antiplatelet agents, and anticoagulant therapy. The treatment with extra-intracranial revascularization was an effective treatment strategy for MMD and MMS. Unilateral MMD was more likely to be associated with SSc. The efficacy of corticosteroids and immunosuppressive agents was uncertain.

Fever in the initial stage of IIM patients: an early clinical warning sign for AE-ILD

Abstract Background Fever is a common symptom of Idiopathic inflammatory myopathies (IIM). However, the exact correlation between fever and the prognosis of IIM is still unclear. This study aims to clarify if the IIM patients initiated with fever are associated with poorer outcomes. Methods This was a single-center retrospective cohort study. Data were collected from 79 newly diagnosed, treatment-naive IIM patients in the Affiliated Wuxi People's Hospital of Nanjing Medical University (Wuxi, Jiangsu, China) from November 2016 to June 2020. According to the presence or absence of fever at the onset, the IIM patients were divided into two groups(fever group n = 28, without fever group n = 51) Clinical characteristics, laboratory data, treatment, and outcomes were recorded. The Kaplan-Meier and log-rank tests were used to compare the all-cause mortality, relapse rate, and acute exacerbation of interstitial lung disease (AE-ILD) incidence. The association of fever with the outcomes was assessed in the unadjusted and adjusted forward logistic regression model. Results Compared with the non-fever group, the age at onset of the fever group was higher, and mechanic's hands (MH) and interstitial lung disease (ILD) were more common. Systemic inflammation (CRP and ESR) was significantly higher in the fever group, while the level of albumin(ALB) and muscle enzymes were lower. The fever group seemed to be received more aggressive treatment, with higher dose glucocorticoids and higher rates of intravenous immunoglobulins(IVIG) use. The all-cause mortality rate and the incidence rate of AE-ILD were higher in the fever group. Even adjusted for the age at onset and treatments, fever was significantly associated with AE-ILD and all-cause mortality. Conclusion Our study has demonstrated that fever at initial diagnosis is associated with AE-ILD and mortality. Fever should serve as an early clinical warning sign for poor outcomes in IIM patients.