Low serum uric acid levels in patients with multiple sclerosis and neuromyelitis optica: An updated meta-analysis.
Wang Lijun,Hu Wei,Wang Jun,Qian Wenyi,Xiao Hang
Multiple sclerosis and related disorders
OBJECTIVES:To evaluate the association between serum uric acid (UA) levels and patients with MS and NMO. METHODS:The PubMed, Web of Science and Cochrane Library database were searched for relevant studies. Pooled standardized mean difference (SMD) and 95% confidence interval (CI) were used as effect size. Subgroup analysis was performed by gender, country, disease durations, scores of EDSS, detection method and clinical classification. RESULTS:A total of 10 case-control studies involving 1537 patients (1308 MS patients, 229 NMO patients) and 908 healthy controls were included. We found the serum UA levels of patients with MS and NMO were significantly lower compared to those of healthy controls (SMD=-0.52, 95%CI,-0.81 to -0.24). In the subgroup analysis, there was no significant difference between serum UA levels in patients and healthy controls in European subgroup (SMD=-0.32, 95%CI,-0.78 to 0.14). Additionally, we found that serum UA levels were higher in MS and NMO patients than in healthy controls in EDSS>3.5 subgroup (SMD=-0.38, 95%CI,-0.58 to -0.19), but not in EDSS≤3.5 subgroup (SMD=-0.35, 95%CI,-0.97 to 0.27). Patients of relapsing group had significant lower serum UA levels than patients of remitting group (SMD=0.70, 95%CI, 0.19-1.21). CONCLUSION:Patients with MS and NMO showed lower serum UA levels when compared with healthy controls. Serum UA might be a potential diagnostic biomarker for MS and NMO.
10.1016/j.msard.2016.05.008
Elevated cerebrospinal fluid uric acid during relapse of neuromyelitis optica spectrum disorders.
Shu Yaqing,Li Haiyan,Zhang Lei,Wang Yuge,Long Youming,Li Rui,Qiu Wei,Lu Zhengqi,Hu Xueqiang,Peng Fuhua
Brain and behavior
INTRODUCTION:Previous studies have shown that serum uric acid (UA) modulates outcomes of neurological diseases, although little is known about cerebrospinal fluid (CSF) UA levels in neuromyelitis optica spectrum disorders (NMOSDs). METHODS:Cerebrospinal fluid and serum UA levels were measured in samples from 68 patients, including NMOSDs during relapse (= 38) and controls with noninflammatory and non-neurodegenerative diseases (CTLs, = 30). Correlation analysis was performed between CSF UA and clinical characteristics, serum UA, and blood-brain barrier integrity in NMOSDs. RESULTS:Cerebrospinal fluid UA levels in NMOSDs were significantly higher than in CTLs (=.002), while serum UA differences between NMOSDs and CTLs were not statistically significant. In NMOSDs, CSF UA levels were significantly higher in patients with an impaired blood-brain barrier than in patients with an intact one (<.001), and significantly higher in longer disease duration than in shorter disease duration patients (=.002). CSF UA levels were also significantly higher in active patients upon MRI than in inactive patients (<.001), and significantly higher in patients with brain lesions than without brain lesions (=.024). CSF UA was significantly associated with the serum UA levels (= .454, =.002), disease duration (= .383, = .018), and blood-brain barrier index (= .805, <.001), but did not correlate with age, gender, annualized relapse rate, duration, or severity of NMOSD. Multiple regression analysis demonstrated that CSF UA was independent of the blood-brain barrier index (β = .765, <.001) and serum UA levels (β = .01, =.019) in NMOSDs. CONCLUSIONS:Cerebrospinal fluid UA levels were elevated in NMOSD patients during relapse, and were likely modified by serum UA levels and blood-brain barrier integrity.
10.1002/brb3.584
Hemorrhagic encephalitis in a patient with neuromyelitis optica: A case report.
Du Qin,Chen Hongxi,Shi Ziyan,Zhang Ying,Wang Jiancheng,Zhou Hongyu
The journal of spinal cord medicine
Neuromyelitis optica (NMO) is a severe, inflammatory, relapsing disease with a predilection for the optic nerves and spinal cord. The manifestations of brain involvement take various forms, but the occurrence of intracerebral hemorrhage is seldom observed. We report the case of a patient with NMO who presented with hemorrhagic encephalitis during the course of the disease. This case report is the first documented instance of hemorrhagic encephalitis identified in a patient with NMO. Among the manifestations of brain involvement in patients with NMO, hemorrhagic encephalitis is rare but can be observed.
10.1080/10790268.2019.1603435
Clinical features of transverse myelitis associated with systemic lupus erythematosus.
Zhang S,Wang Z,Zhao J,Wu D I,Li J,Wang Q,Su J,Xu D,Wang Y,Li M,Zeng X
Lupus
OBJECTIVE:This study aimed to identify the clinical characteristics and prognostic factors of systemic lupus erythematosus with transverse myelitis (SLE-TM) in a relatively large patient series. METHODS:This retrospective study considered 45 SLE-TM individuals treated as inpatients and outpatients at Peking Union Medical College Hospital between 1993 and 2018. SLE-TM patients were compared with 180 controls, and SLE-TM patients with neuromyelitis optica spectrum disorder (NMOSD) were compared to those without NMOSD. RESULTS:Compared to controls, the SLE-TM group frequently had a fever and had a significantly higher positive rate of anticardiolipin and lupus anticoagulant. Among the 45 patients, 22 met the NMOSD criteria. Compared to non-NMOSD patients, NMOSD patients had a lower incidence of rash ( = 0.023), serositis ( = 0.042) and renal disorder ( = 0.073); a lower prevalence of decreased complement ( = 0.083); and lower rates of positive anti-dsDNA ( = 0.074) and anti-Sm ( = 0.042). Among 22 SLE-TM patients with NMOSD, 18 underwent aquaporin 4 antibody testing, with 11 showing positive results. Out of the 45 patients, 39 were given methylprednisolone pulse treatment. After treatment, 32 patients had lower-limb muscle strength recovery (recovered group), whereas 13 had no change and persistent severe neurological deficits (non-recovered group). Compared to the recovered group, the non-recovered group were younger ( = 0.002), had a higher likelihood of having a fever ( = 0.020), initial severe myelitis ( < 0.001), long spinal segment involvement ( = 0.017) and higher C-reactive protein levels ( = 0.020). Methylprednisolone pulse given within two weeks of onset was more frequent in the recovered group than in the non-recovered group ( = 0.082). CONCLUSIONS:Disease characteristics differed between SLE-TM patients with and without NMOSD. SLE and NMOSD tended to be co-morbidities. Initial severe neurological impairment, extensive spinal cord lesions, hyper-inflammation and delayed steroid impulse treatment could be predictors of poor outcome for SLE-TM.
10.1177/0961203320905668
Coagulation Pathways in Neurological Diseases: Multiple Sclerosis.
Ziliotto Nicole,Bernardi Francesco,Jakimovski Dejan,Zivadinov Robert
Frontiers in neurology
Significant progress has been made in understanding the complex interactions between the coagulation system and inflammation and autoimmunity. Increased blood-brain-barrier (BBB) permeability, a key event in the pathophysiology of multiple sclerosis (MS), leads to the irruption into the central nervous system of blood components that include virtually all coagulation/hemostasis factors. Besides their cytotoxic deposition and role as a possible trigger of the coagulation cascade, hemostasis components cause inflammatory response and immune activation, sustaining neurodegenerative events in MS. Early studies showing the contribution of altered hemostasis in the complex pathophysiology of MS have been strengthened by recent studies using methodologies that permitted deeper investigation. Fibrin(ogen), an abundant protein in plasma, has been identified as a key contributor to neuroinflammation. Perturbed fibrinolysis was found to be a hallmark of progressive MS with abundant cortical fibrin(ogen) deposition. The immune-modulatory function of the intrinsic coagulation pathway still remains to be elucidated in MS. New molecular details in key hemostasis components participating in MS pathophysiology, and particularly involved in inflammatory and immune responses, could favor the development of novel therapeutic targets to ameliorate the evolution of MS. This review article introduces essential information on coagulation factors, inhibitors, and the fibrinolytic pathway, and highlights key aspects of their involvement in the immune system and inflammatory response. It discusses how hemostasis components are (dys)regulated in MS, and summarizes histopathological post-mortem human brain evidence, as well as cerebrospinal fluid, plasma, and serum studies of hemostasis and fibrinolytic pathways in MS. Studies of disease-modifying treatments as potential modifiers of coagulation factor levels, and case reports of autoimmunity affecting hemostasis in MS are also discussed.
10.3389/fneur.2019.00409
Complement in neurobiology.
Horstman Lawrence L,Jy Wenche,Ahn Yeon S,Maghzi Amir H,Etemadifar Masoud,Alexander J Steven,McGee Jeanie C,Minagar Alireza
Frontiers in bioscience (Landmark edition)
The complement (C) system is a vital arm of innate immunity with many roles, including control of inflammation. This article examines the (C) system with emphasis on recent developments on complement relevant to neurobiology, in particular regarding our understanding and treatment of immune-mediated diseases. We will briefly outline the C system, and provide an updated review of its many receptors and regulatory factors. This section concludes with a listing of important roles of the C system, from recruitment of neural stem/progenitor cells, to its' relation to coagulation and adaptive immunity, and its lesser-known but beneficial roles in physiology. We also review evidence for C-mediated diseases, which include multiple sclerosis and Alzheimer's disease. Therapeutic approaches for C-mediated diseases, considers emphasizing modulators of the C system including several less widely studied approaches such as heparinoids, vitamin D, and intravenous IgM. Finally, we summarize cutting-edge work on the role of C-mediated natural antibodies in autoimmunity and treatment strategies based on those findings, e.g., for remyelination and post-ischemic stroke repair. Improved understanding of the C system may hold great promise for the treatment of neurodegenerative diseases.
10.2741/3890
Coagulation/Complement Activation and Cerebral Hypoperfusion in Relapsing-Remitting Multiple Sclerosis.
Koudriavtseva Tatiana,Stefanile Annunziata,Fiorelli Marco,Lapucci Caterina,Lorenzano Svetlana,Zannino Silvana,Conti Laura,D'Agosto Giovanna,Pimpinelli Fulvia,Di Domenico Enea Gino,Mandoj Chiara,Giannarelli Diana,Donzelli Sara,Blandino Giovanni,Salvetti Marco,Inglese Matilde
Frontiers in immunology
Introduction:Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with an underlying immune-mediated and inflammatory pathogenesis. Innate immunity, in addition to the adaptive immune system, plays a relevant role in MS pathogenesis. It represents the immediate non-specific defense against infections through the intrinsic effector mechanism "immunothrombosis" linking inflammation and coagulation. Moreover, decreased cerebral blood volume (CBV), cerebral blood flow (CBF), and prolonged mean transit time (MTT) have been widely demonstrated by MRI in MS patients. We hypothesized that coagulation/complement and platelet activation during MS relapse, likely during viral infections, could be related to CBF decrease. Our specific aims are to evaluate whether there are differences in serum/plasma levels of coagulation/complement factors between relapsing-remitting (RR) MS patients (RRMS) in relapse and those in remission and healthy controls as well as to assess whether brain hemodynamic changes detected by MRI occur in relapse compared with remission. This will allow us to correlate coagulation status with perfusion and demographic/clinical features in MS patients. Materials and Methods:This is a multi-center, prospective, controlled study. RRMS patients (1° group: 30 patients in relapse; 2° group: 30 patients in remission) and age/sex-matched controls (3° group: 30 subjects) will be enrolled in the study. Patients and controls will be tested for either coagulation/complement (C3, C4, C4a, C9, PT, aPTT, fibrinogen, factor II, VIII, and X, D-dimer, antithrombin, protein C, protein S, von-Willebrand factor), soluble markers of endothelial damage (thrombomodulin, Endothelial Protein C Receptor), antiphospholipid antibodies, lupus anticoagulant, complete blood count, viral serological assays, or microRNA microarray. Patients will undergo dynamic susceptibility contrast-enhanced MRI using a 3.0-T scanner to evaluate CBF, CBV, MTT, lesion number, and volume. Statistical Analysis:ANOVA and unpaired t-tests will be used. The level of significance was set at p ≤ 0.05. Discussion:Identifying a link between activation of coagulation/complement system and cerebral hypoperfusion could improve the identification of novel molecular and/or imaging biomarkers and targets, leading to the development of new effective therapeutic strategies in MS. Clinical Trial Registration:Clinicaltrials.gov, identifier NCT04380220.
10.3389/fimmu.2020.548604
A Perspective of Coagulation Dysfunction in Multiple Sclerosis and in Experimental Allergic Encephalomyelitis.
Plantone Domenico,Inglese Matilde,Salvetti Marco,Koudriavtseva Tatiana
Frontiers in neurology
A key role of both coagulation and vascular thrombosis has been reported since the first descriptions of multiple sclerosis (MS). Subsequently, the observation of a close concordance between perivascular fibrin(ogen) deposition and the occurrence of clinical signs in experimental allergic encephalomyelitis (EAE), an animal model of MS, led to numerous investigations focused on the role of thrombin and fibrin(ogen). Indeed, the activation of microglia, resident innate immune cells, occurs early after fibrinogen leakage in the pre-demyelinating lesion stage of EAE and MS. Thrombin has both neuroprotective and pro-apoptotic effects according to its concentration. After exposure to high concentrations of thrombin, astrocytes become reactive and lose their neuroprotective and supportive functions, microglia proliferate, and produce reactive oxygen species, IL-1β, and TNFα. Heparin inhibits the thrombin generation and suppresses EAE. Platelets play an important role too. Indeed, in the acute phase of the disease, they begin the inflammatory response in the central nervous system by producing of IL-1alpha and triggering and amplifying the immune response. Their depletion, on the contrary, ameliorates the course of EAE. Finally, it has been proven that the use of several anticoagulant agents can successfully improve EAE. Altogether, these studies highlight the role of the coagulation pathway in the pathophysiology of MS and suggest possible therapeutic targets that may complement existing treatments.
10.3389/fneur.2018.01175
Pulmonary manifestations of systemic lupus erythematosus and Sjögren's syndrome.
Lopez Velazquez Marco,Highland Kristin B
Current opinion in rheumatology
PURPOSE OF REVIEW:Systemic lupus erythematosus (SLE) and Sjögren syndrome are chronic autoimmune inflammatory disorders that can present with multiorgan involvement including the lungs. This review will focus on recent literature pertaining to the epidemiology, pathogenesis, clinical presentation and diagnosis and management of SLE and Sjögren syndrome-associated pulmonary conditions. RECENT FINDINGS:Pulmonary manifestations of both disease entities have been well characterized and lung involvement can be observed during the course of the disease in most cases. Pulmonary manifestations of SLE and Sjögren syndrome can be classified based on anatomical site of involvement; and the large and small airways, lung parenchyma, lung vasculature, pleura and respiratory muscles can be involved. The pleura is most commonly involved in SLE, whereas the airways are most commonly involved in primary Sjögren's syndrome (pSS). Sleep disturbances have also been described in both entities. SUMMARY:Although further research into treatment strategies for the pulmonary complications seen in SLE and pSS is needed, the clinician should be aware of the risk factors and clinical presentation of the various pulmonary complications in SLE and pSS in order to identify patients who should be screened and/or have modifications in treatment strategies to mitigate the morbidity and mortality associated with these complications.
10.1097/BOR.0000000000000531
Complement, infection, and autoimmunity.
Conigliaro Paola,Triggianese Paola,Ballanti Eleonora,Perricone Carlo,Perricone Roberto,Chimenti Maria Sole
Current opinion in rheumatology
PURPOSE OF REVIEW:Complement system dysfunction in terms of upregulation, downregulation, or dysregulation can create an imbalance of both host defense and inflammatory response leading to autoimmunity. In this review, we aimed at describing the role of complement system in host defense to inflection and in autoimmunity starting from the evidence from primary and secondary complement system deficiencies. RECENT FINDINGS:Complement system has a determinant role in defense against infections: deficiencies of complement components are associated with increased susceptibility to infections. Primary complement system deficiencies are rare disorders that predispose to both infections and autoimmune diseases. Secondary complement system deficiencies are the result of the complement system activation with consumption. Complement system role in enhancing risk of infective diseases in secondary deficiencies has been demonstrated in patients affected by systemic autoimmune disorders, mainly systemic lupus erythematosus and vasculitis. SUMMARY:The relationship between the complement system and autoimmunity appears paradoxical as both the deficiency and the activation contribute to inducing autoimmune diseases. In these conditions, the presence of complement deposition in affected tissues, decreased levels of complement proteins, and high levels of complement activation fragments in the blood and vessels have been documented.
10.1097/BOR.0000000000000633
Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica.
Tradtrantip Lukmanee,Yao Xiaoming,Su Tao,Smith Alex J,Verkman Alan S
Acta neuropathologica
Neuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune inflammatory disease of the central nervous system in which immunoglobulin G antibodies against astrocyte water channel aquaporin-4 (AQP4-IgG) cause demyelination and neurological deficit. Injury to oligodendrocytes, which do not express AQP4, links the initiating pathogenic event of AQP4-IgG binding to astrocyte AQP4 to demyelination. Here, we report evidence for a complement 'bystander mechanism' to account for early oligodendrocyte injury in NMO in which activated, soluble complement proteins following AQP4-IgG binding to astrocyte AQP4 result in deposition of the complement membrane attack complex (MAC) on nearby oligodendrocytes. Primary cocultures of rat astrocytes and mature oligodendrocytes exposed to AQP4-IgG and complement showed early death of oligodendrocytes in close contact with astrocytes, which was not seen in pure oligodendrocyte cultures, in cocultures exposed to AQP4-IgG and C6-depleted serum, or when astrocytes were damaged by a complement-independent mechanism. Astrocyte-oligodendrocyte cocultures exposed to AQP4-IgG and complement showed prominent MAC deposition on oligodendrocytes in contact with astrocytes, whereas C1q, the initiating protein in the classical complement pathway, and C3d, a component of the alternative complement pathway, were deposited only on astrocytes. Early oligodendrocyte injury with MAC deposition was also found in rat brain following intracerebral injection of AQP4-IgG, complement and a fixable dead-cell stain. These results support a novel complement bystander mechanism for early oligodendrocyte injury and demyelination in NMO.
10.1007/s00401-017-1734-6
Complement-independent bystander injury in AQP4-IgG seropositive neuromyelitis optica produced by antibody-dependent cellular cytotoxicity.
Duan Tianjiao,Smith Alex J,Verkman Alan S
Acta neuropathologica communications
Cellular injury in AQP4-IgG seropositive neuromyelitis spectrum disorder (herein called NMO) involves AQP4-IgG binding to astrocytes, resulting in astrocyte injury by complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) mechanisms. The rapid disease progression, severe tissue damage, and abundant leukocyte infiltration seen in some NMO patients suggest a more direct mechanism for demyelination and neurologic deficit than secondary injury from astrocyte loss. Here, we report evidence for an 'ADCC bystander mechanism' in NMO involving injury to nearby cells by leukocytes following their activation by AQP4-bound AQP4-IgG on astrocytes. In model cocultures containing AQP4-expressing and null CHO cells, AQP4-IgG and complement killed bystander null cells to ~ 100 μm away from AQP4-expressing cells; AQP4-IgG and NK cells produced bystander killing to ~ 300 μm, with perforin deposition seen on injured null cells. Bystander cytotoxicity was also seen with neutrophil-mediated ADCC and in astrocyte-neuron cocultures. Mechanistic studies, including real-time imaging, suggested that leukocytes activated by an AQP4-dependent ADCC mechanism injure bystander cells by direct targeted exocytosis on neighboring cells and not by diffusion of soluble granule contents. In support of this conclusion, ADCC bystander injury was preferentially reduced by an RGDS peptide that inhibits integrin adhesion. Evidence for ADCC bystander injury to oligodendrocytes and neurons was also found in mice following intracerebral injection of AQP4-IgG and NK cells, which was inhibited by RGDS peptide. These results establish a novel cellular pathogenesis mechanism in AQP4-IgG seropositive NMO and provide evidence that inflammatory mechanisms can cause widespread tissue damage in NMO independently of the secondary effects from astrocyte loss.
10.1186/s40478-019-0766-7
Serum thyroid-stimulating hormone and anti-thyroglobulin antibody are independently associated with lesions in spinal cord in central nervous system demyelinating diseases.
Long Youming,Zheng Yangbo,Chen Mengyu,Zhang Bin,Gao Cong,Shan Fulan,Yang Ning,Fan Yongxiang
PloS one
Transverse myelitis (TM) is associated with neuromyelitis optica (NMO) and multiple sclerosis (MS). Early recognition of useful parameters may be helpful to distinguish their difference. This retrospective study analyzed thyroid parameters from 243 serum samples (relapse = 128; remission = 115) of 178 patients with demyelinating diseases (NMO, n = 25; TM, n = 48; MS, n = 105). The relationship between thyroid and clinical parameters was analyzed. Patients with NMO and TM had a higher frequency of abnormal thyroid-stimulating hormone (TSH), anti-thyroglobulin antibodies (TG-Ab), and antithyroid peroxidase antibody (TPO-Ab) than MS patients (p<0.05). The level of TSH and TG-Ab returned to normal levels after administration of high-dose intravenous methylprednisolone (p<0.05). In 96 patients (NMO, n = 19; TM, n = 25; MS, n = 52) without treatment, serum levels of TSH, TG-Ab and TPO-Ab were significantly different between patients with and without myelitis (p<0.01). Patients positive for aquaporin-4 (AQP4) antibodies showed higher abnormalities of TSH (p = 0.001), TG-Ab (p = 0.004) and TPO-Ab (p<0.0001) levels than AQP4 antibodies negative patients. Logistic regression analyses revealed independent relationships between TSH (odds ratio [OR] = 33.994; p<0.0001), TG-Ab (OR = 7.703; p = 0.017) and myelitis occurrence in 96 patients at the active stage. In 52 MS patients experiencing their first attack, MS patients with myelitis were associated with TSH abnormalities (OR = 42.778; p<0.0001). This study showed increased abnormalities of thyroid parameters in patients with NMO and TM than in MS patients. MS patients with myelitis also had greater TSH abnormality than in MS patients without myelitis. Abnormal TSH and TG-Ab were independently associated with myelitis occurrence in central nervous system demyelinating disorders.
10.1371/journal.pone.0100672
Relationship between serum bilirubin levels and optic neuritis.
Deng Juan,Liang Xue-Mei,Zhang Xiu-Lan,Ling Shi-Qi,Yang Ting-Ting,Li Min,Peng Fu-Hua
Chinese medical journal
BACKGROUND:Bilirubin is the end product of heme catabolism and has strong antioxidant properties. Serum bilirubin levels are reported to be reduced in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). The pathophysiology of optic neuritis (ON) resembles that of MS; however, the role of endogenous bilirubin in ON is unclear. The aim of this study is to measure serum bilirubin levels in patients with ON, and to investigate the correlation between ON and serum antioxidant status of bilirubin. METHODS:Serum levels of bilirubin were measured in 42 patients with ON, 50 patients with multiple sclerosis (MS), 48 patients with neuromyelitis optica (NMO) and 48 healthy control subjects. RESULTS:Serum total bilirubin (Tbil), direct bilirubin (Dbil) and indirect bilirubin (Ibil) levels in patients with ON were significantly lower than those in the healthy controls. However, no statistical significance was found between levels in the ON and MS, ON and NMO, and MS and NMO groups. In patients with ON, serum Tbil, Dbil, and Ibil levels were lower in those with recurrence or those with ON for a longer duration (≥ 1 year). Moreover, Tbil, Dbil, and Ibil concentrations were lower in patients with papillitis than in those with retrobulbar type ON, but the differences were not statistically significant. CONCLUSIONS:Low antioxidant status may exist in patients with ON. But serum levels of Tbil, Dbil, and Ibil did not correlate with clinical presentations, such as recurrence, duration of disease and subtypes of ON. Low antioxidant status already existed in MS or NMO patients before systemic symptoms appeared.
Low antioxidant status of serum uric acid, bilirubin and albumin in patients with neuromyelitis optica.
Peng F,Yang Y,Liu J,Jiang Y,Zhu C,Deng X,Hu X,Chen X,Zhong X
European journal of neurology
BACKGROUND:Oxidative stress plays a central role in neuropathology of multiple sclerosis (MS). The patients with MS have low antioxidant status. Antioxidant therapy may represent an attractive treatment of MS. However, the relationship between neuromyelitis optica (NMO), a distinct nosologic entity or a form of MS, and antioxidant status has not fully been investigated. OBJECTIVES:To investigate the correlation between NMO and serum antioxidant status of uric acid (UA), bilirubin and albumin. METHODS:The serum levels of antioxidant molecules UA, bilirubin (Tbil and Ibil) and albumin were measured in 236 individuals comprising healthy subjects and patients with NMO or MS. RESULTS:We found that serum levels of UA, Tbil, Ibil and albumin in patients with NMO were significantly lower than those in healthy control group. Moreover, these results were also observed when the male and female cohorts were investigated separately. Likewise, the serum levels of UA, Tbil, Ibil and albumin in patients with NMO were also lower than those of patients with MS. In all groups, women had lower serum UA, Tbil, Ibil and albumin levels than men. In UA groups, women had significantly lower serum UA levels than men. CONCLUSION:We concluded that there were reducing serum levels of UA, bilirubin and albumin in patients with NMO. The study showed patients with NMO had low antioxidant status. As a replacement therapy to patients, administration of albumin, bilirubin and UA or theirs precursors, such as inosine of UA precursor, may be beneficial to the patients with NMO.
10.1111/j.1468-1331.2011.03488.x
The role of complement system in adipose tissue-related inflammation.
Vlaicu Sonia I,Tatomir Alexandru,Boodhoo Dallas,Vesa Stefan,Mircea Petru A,Rus Horea
Immunologic research
As the common factor linking adipose tissue to the metabolic context of obesity, insulin resistance and atherosclerosis are associated with a low-grade chronic inflammatory status, to which the complement system is an important contributor. Adipose tissue synthesizes complement proteins and is a target of complement activation. C3a-desArg/acylation-stimulating protein stimulates lipogenesis and affects lipid metabolism. The C3a receptor and C5aR are involved in the development of adipocytes' insulin resistance through macrophage infiltration and the activation of adipose tissue. The terminal complement pathway has been found to be instrumental in promoting hyperglycemia-associated tissue damage, which is characteristic of the major vascular complications of diabetes mellitus and diabetic ketoacidosis. As a mediator of the effects of the terminal complement complex C5b-9, RGC-32 has an impact on energy expenditure as well as lipid and glucose metabolic homeostasis. All of this evidence, taken together, indicates an important role for complement activation in metabolic diseases.
10.1007/s12026-015-8783-5
Impact of blood-brain barrier disruption on newly diagnosed neuromyelitis optica spectrum disorder symptoms and prognosis.
Liang Shuolin,Qin Qiuhong,Tang Yulan,Liao Weijing,Yang Yi,He Jinrong,Li Liangsheng
Annals of palliative medicine
BACKGROUND:Blood-brain barrier (BBB) disruption and ensuing immune activation are central to the pathogenesis of central nervous system (CNS) inflammatory diseases. However, the influence of BBB permeability on the clinical signs and prognosis of newly diagnosed neuromyelitis optica spectrum disorder (NMOSD) has not been examined. We investigate the relationships between BBB permeability as showed by the albumin quotient (qalb) and clinical features of NMOSD. METHODS:Demographic and clinical data of 46 patients, including peripheral blood (PB) measures (serum albumin concentration and total leukocyte, neutrophil, total lymphocyte, CD4+ T cell, and CD8+ T cell counts, complement C3 and C4 concentrations, AQP4-IgG titer),autoimmune antibody titers (ANA/SSA/SSB/Ro-52), and cerebrospinal fluid (CSF) parameters (total leukocyte count, total protein and albumin concentrations, AQP4-IgG titer), were compared between qalb(BBB permeability) increased and normal groups. Complete measures were not obtained from 9 patients, but all other measures were included in the analysis. RESULTS:According to the calculated qalb, 15 patients with albumin quotient (qalb) > (4 + age/15) × 10-3 were assigned to the qalb increased (high BBB permeability) group (33%) and the remainder to the qalb normal group. Compared to the qalb normal group, the qalb increased group exhibited significantly lower serum albumin (P=0.001) and CD4+ T cell count (P=0.044), CD8+ T cell count (P=0.014), and total T lymphocyte count (P=0.016). The qalb increased group proved higher CSF albumin, total protein, leukocyte count, and IgG titer (all P=0.000). Optic neuritis and optic nerve abnormalities on magnetic resonance images were also more frequent in the qalb increased group (P=0.037 and 0.038, respectively). Patients in the qalb increased group showed significantly poorer treatment response as indicated by the lower post-treatment change in Expanded Disability Status Scale (EDSS) score compared to the qalb normal group. CONCLUSIONS:BBB permeability is strongly associated with the clinical features and treatment response of newly diagnosed NMOSD. The qalb is a potentially valuable indicator of disease severity and an index to guide personalized treatment.
10.21037/apm.2019.12.12
Chinese SLE Treatment and Research group (CSTAR) registry: I. Major clinical characteristics of Chinese patients with systemic lupus erythematosus.
Li M,Zhang W,Leng X,Li Z,Ye Z,Li C,Li X,Zhu P,Wang Z,Zheng Y,Li X,Zhang M,Zhang F,Zhao Y,Zeng X,
Lupus
The Chinese systemic lupus erythematosus (SLE) treatment and research group (CSTAR) provides major clinical characteristics of SLE in China and establishes a platform to provide resources for future basic and clinical studies. CSTAR originated as a multicentre, consecutive, and prospective design. The data were collected online from 104 rheumatology centers, which covered 30 provinces in China. The registered patients were required to meet four or more of the American College of Rheumatology (ACR) criteria for the classification of SLE. All CSTAR centers use the same protocol-directed methods to provide uniform evaluations, which included demographic data, clinical features, laboratory examinations, and disease activity evaluations. The patient samples, including DNA samples and sera, were also collected for further quality controls and additional studies. Preliminary analysis from 2104 baseline evaluations was available for this analysis. Of 1914 female and 190 male patients (F:M=10.1), the mean age at onset was 29.2 y with confirmed diagnosis one year later at the age of 30.3 y. Eighty four (4.2%) of 2002 patients had a family history of rheumatic diseases, including 34 (1.7%) cases with SLE. In addition, one hundred and seven (5.2%) abnormal pregnancies were recorded among 2026 experiences. The characteristics of the CSTAR cohort were compared to similarly sized cohorts from other studies. We found that 56.1% of patients presented with concurrent hematological disorders compared to only 18.2% of European patients. Moreover, 47.4% of patients presented with nephropathy compared to 27.9% of European patients. Conversely, neurological manifestations were only seen in 4.8% of Chinese SLE patients compared to 19.4% of European patients, 12.1% of U.S. patients, 22.8% of Malaysian patients and 26.4% of Latin Americans. Pulmonary arterial hypertension and interstitial lung diseases were complications identified in 3.8% and 4.2% of Chinese lupus patients, respectively. The CSTAR registry has provided epidemiological data and phenotypes of Chinese patients with SLE, and has demonstrated several differences between ethnicities. Clinical data and biologic samples would be valuable resources for future translational studies with national and international collaboration.
10.1177/0961203313499086
Chinese SLE Treatment and Research group (CSTAR) registry: V. gender impact on Chinese patients with systemic lupus erythematosus.
Zhang S,Su J,Li X,Zhang X,Liu S,Wu L,Ma L,Bi L,Zuo X,Sun L,Huang C,Zhao J,Li M,Zeng X,
Lupus
INTRODUCTION:Many studies have shown that differences were observed between male and female lupus patients. Although systemic lupus erythematosus (SLE) affects mostly females (female:male ratio 9:1), male SLE patients show higher mortality due to kidney and neurological disease. Currently there are limited epidemiological data concerning lupus in the Chinese population. As such, the Chinese SLE Treatment and Research group (CSTAR) developed the first online registry of Chinese lupus patients in 2009, and represents a multicenter observational study that attempts to describe and compile the major clinical characteristics of lupus in Chinese patients. OBJECTIVE:To investigate the effect of gender on the phenotypes of Chinese SLE patients. PATIENTS AND METHODS:Data for 2104 SLE patients were prospectively collected and included in the CSTAR registry. Patients fulfilled the 1997 American College of Rheumatology (ACR) SLE classification criteria. We conducted a cross-sectional case-control study to analyze patient clinical and laboratory data at onset and at enrollment. SLE disease activity scores (SLEDAI) were also measured at enrollment. RESULTS:This study included 1914 women and 190 men. Males and females showed no differences in mean ages at onset, delay of diagnosis and disease duration. Males presented more frequently with fever (p = 0.003), while musculoskeletal involvement (p = 0.001) and cytopenia (p = 0.017) was more common in females as the initial manifestation at onset of SLE. For manifestations at enrollment, males presented more frequently with fever (p = 0.005), renal disease (p = 0.019), vasculitis (p = 0.032) and neuropsychiatric lupus (p = 0.007). For cumulative manifestations at enrollment, males presented more frequently with discoid rash (p < 0.001) and neuropsychiatric lupus (p = 0.036), while less frequently with arthritis (p = 0.011). However, the laboratory data showed no significant differences between the two groups at enrollment. Males also had higher SLEDAI scores at enrollment (p = 0.002). CONCLUSIONS:Renal disease, vasculitis and neuropsychiatric lupus are more common in male SLE patients with higher SLEDAI scores compared to female SLE patients in China.
10.1177/0961203315585813
[Analysis of the clinical features at onset of primary Sjögren's syndrome].
He Jing,Ding Yan,Li Yu-hui,Feng Min,Dai Yi-jun,Zhang Xue-wu,Li Zhan-guo
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences
OBJECTIVE:To comprehend clinical features at onset of primary Sjogren's syndrome (pSS) in order to provide useful data for its clinical management. METHODS:In the study, 224 patients diagnosed with pSS in the Department of Rheumatology and Immunology of Peking University People's Hospital from Jun. 1st, 2007 to Aug. 1st, 2008 were investigated, including gender, age of onset, time and site of first hospitalization and definite diagnosis, etc. RESULTS:In this 224 pSS cohort (213 females and 11 males), the male/female ratio was 1:19.4, the mean age of onset was (53.5±11.7) years, and median duration was 9.4 years (ranging from 0.2 to 40.0 years).The manifestations showed that up to 33% of the patients (74/224) had leukopenia, 25% (56/224) polyarthralgia, 16.5% (37/224) raynaud phenomenon, 15.6% (35/224) hepatic injury, 12.1% (27/224) pulmonary interstitial fibrosis, 11.6% (26/224) purpuras on lower extremities, 8.0% (18/224) hemogram abnormal, 5.8% (13/224) thrombopenia, and 3.6% (8/224) renal tubule acidosis. When the risk factor of the systemic involvements, was analyzed, two factors were significantly associated with pulmonary interstitial fibrosis: age (OR=1.074, 95% CI=1.031-1.118), and duration (OR=1.075, 95% CI=1.023-1.128). Liver involvement was associated with duration (OR=1.050, 95% CI=1.002-1.100). In addition, 8.0% of the pSS patients(18/224)showed family history of autoimmune diseases and 11.2%(25/224)had family history of tumor. CONCLUSION:In this cohort of the pSS patients, female is predominant and the incidence of extro-glandular manifestations, such as leukopenia, lung and liver involvements is high, and pSS has inheritance intention.
Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide.
Hor Jyh Yung,Asgari Nasrin,Nakashima Ichiro,Broadley Simon A,Leite M Isabel,Kissani Najib,Jacob Anu,Marignier Romain,Weinshenker Brian G,Paul Friedemann,Pittock Sean J,Palace Jacqueline,Wingerchuk Dean M,Behne Jacinta M,Yeaman Michael R,Fujihara Kazuo
Frontiers in neurology
Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon inflammatory disease of the central nervous system, manifesting clinically as optic neuritis, myelitis, and certain brain and brainstem syndromes. Cases clinically diagnosed as NMOSD may include aquaporin 4 (AQP4)-antibody-seropositive autoimmune astrocytopathic disease, myelin oligodendrocyte glycoprotein (MOG)-antibody-seropositive inflammatory demyelinating disease, and double-seronegative disease. AQP4-antibody disease has a high female-to-male ratio (up to 9:1), and its mean age at onset of ~40 years is later than that seen in multiple sclerosis. For MOG-antibody disease, its gender ratio is closer to 1:1, and it is more common in children than in adults. Its clinical phenotypes differ but overlap with those of AQP4-antibody disease and include acute disseminated encephalomyelitis, brainstem and cerebral cortical encephalitis, as well as optic neuritis and myelitis. Double-seronegative disease requires further research and clarification. Population-based studies over the past two decades report the prevalence and incidence of NMOSD in different populations worldwide. One relevant finding is the varying prevalence observed in different racial groups. Consistently, the prevalence of NMOSD among Whites is ~1/100,000 population, with an annual incidence of <1/million population. Among East Asians, the prevalence is higher, at ~3.5/100,000 population, while the prevalence in Blacks may be up to 10/100,000 population. For MOG-antibody disease, hospital-based studies largely do not observe any significant racial preponderance so far. This disorder comprises a significant proportion of NMOSD cases that are AQP4-antibody-seronegative. A recent Dutch nationwide study reported the annual incidence of MOG-antibody disease as 1.6/million population (adult: 1.3/million, children: 3.1/million). Clinical and radiological differences between AQP4-antibody and MOG-antibody associated diseases have led to interest in the revisions of NMOSD definition and expanded stratification based on detection of a specific autoantibody biomarker. More population-based studies in different geographical regions and racial groups will be useful to further inform the prevalence and incidence of NMOSD and their antibody-specific subgroups. Accessibility to AQP4-antibody and MOG-antibody testing, which is limited in many centers, is a challenge to overcome. Environmental and genetic studies will be useful accompaniments to identify other potential pathogenetic factors and specific biomarkers in NMOSD.
10.3389/fneur.2020.00501
Painful tonic spasms and brainstem involvement in a patient with neuromyelitis optica spectrum disorder.
Roman-Filip Corina,Ungureanu Aurelian,Cernuşcă-Miţaru Mihaela
Neurologia i neurochirurgia polska
Neuromyelitis optica (NMO) is an inflammatory-demyelinating disease of the central nervous system classically characterized by optic neuritis and severe myelitis. New diagnostic criteria defined neuromyelitis optica spectrum disorder as limited forms of NMO or diverse neurologic presentations in the presence of specific antiaquaporin-4 antibodies. We report the case of a 57-year-old woman admitted in our department for recurrent attacks of optic neuritis, tetraparesis with severe painful tonic spasms of the left limbs and brainstem involvement. Painful tonic spasms have been described as movement disorders associated with multiple sclerosis, but a growing number of reports describe them in cases of NMO.
10.1016/j.pjnns.2015.10.010
The complement and immunoglobulin levels in NMO patients.
Chen Ying,Li Rui,Wu Ai Ming,Shu Ya Qing,Lu Zheng Qi,Hu Xue Qiang
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
Since the discovery of aquaporin-4 (AQP4) antibody a decade ago, neuromyelitis optica (NMO) has been distinguished from multiple sclerosis (MS). MS mainly features T lymphocyte-oriented autoimmune responses while NMO is more precisely influenced by humoral immunity, among which the complement activation has always been reckoned as an important mechanism. The AQP4 antibody, namely NMO-IgG, adds to new evidence of how complement affects the severity of NMO. We compared the levels of complement (C3, C4, CH50) and immunoglobulins (IgG, IgM, IgA) between NMO patients and controls. Groups with AQP4 antibody positive and negative NMO patients were also compared with controls, respectively, aiming to elaborate on the relationship between complement activation and immunoglobulins. We also compared these indexes together with expanded disability status scale (EDSS) between two different groups in NMO patients and endeavored to figure out their correlations with each other. Complement and immunoglobulins were compared between NMO patients in acute phase and non-acute phase of the disease to find out the level fluctuation of CH50 and other indexes during different stages of NMO. We analyzed NMO patients (n = 88) and controls (n = 44) for IgG, IgM, IgA, other indexes like CH50, C3, C4 have also been explored between the two groups. Furthermore, we investigated whether these antibodies could mediate complement-dependent cytotoxicity. Thus, the NMO patients were split into two groups with or without AQP4 antibody to find out the status of NMO-IgG in the development and severity of the disease. EDSS was used as criteria for the evaluating the seriousness of NMO. Comparison between NMO patients in acute stage and non-acute stage of the disease was also made for a better understanding of the disease. Compared with controls, NMO patients had much higher IgG (13.984 ± 5.981 mg/ml, 11.430 ± 3.254 mg/ml, P < 0.01) but lower CH50 (respectively, 43.55 ± 12.172 U/L, 50.66 ± 12.523 U/L, P < 0.01). While IgG increased in Anti-AQP4 antibody-positive NMO patients, CH50 dropped in this group when compared with AQP4-negative patients. When compared with controls, both of the NMO groups had enhanced IgG and decreased CH50 though only AQP4-positive NMO patients showed significance (IgG 15.004 ± 6.613 mg/ml, 11.430 ± 3.254 mg/ml, P < 0.01) (CH50, respectively, 41.12 ± 12.581U/L, 50.66 ± 12.523 U/L, P < 0.01). C4 was also decreased though without evident significance (0.215 ± 0.118 mg/ml, 0.260 ± 0.133 mg/ml, P = 0.069). Those NMO patients in acute phase (with the course of newly attack of less than 1 month) had increased immunoglobulin (IgG 14.991 ± 6.639 mg/ml, 12.460 ± 4.490 mg/ml) but decreased complement (CH50 42.755 ± 12.403 U/L, 44.743 ± 11.890 U/L) than those who passed the acute phase. There was correlation between IgG and CH50 (R = -0.402, P < 0.01) in NMO patients. Relationship was also found between IgG and EDSS (R = 0.609, P < 0.001), CH50 and EDSS (R = -0.333, P < 0.01). These results indicate that NMO patients had enhanced immunoglobulin in acute phase but decreased complement. The complement was correlated with immunoglobulin. Among the two NMO groups, the complement system was only activated in NMO-IgG positive patients, which might indicate a potential different pathogenetic mechanism in NMO-IgG negative patients. Also, patients' disability of the former group was more serious than their counterparts. Those patients in acute phase obviously had increased immunoglobulin but decreased complement. Thus, we have come to the conclusion that in AQP4-positive NMO patients, immunoglobulin activates complement system, which influences the functions of NMO patients.
10.1007/s10072-013-1481-y