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Multiple Sclerosis (Houndmills,... Oct 2023Most patients with neuromyelitis optica spectrum disorders (NMOSD) test positive for aquaporin-4 antibody (AQP4-IgG) or myelin oligodendrocyte glycoprotein antibodies... (Review)
Review
Most patients with neuromyelitis optica spectrum disorders (NMOSD) test positive for aquaporin-4 antibody (AQP4-IgG) or myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Those who are negative are termed double-negative (DN) NMOSD and may constitute a diagnostic and therapeutic challenge. DN NMOSD is a syndrome rather than a single disease, ranging from a (postinfectious) monophasic illness to a more chronic syndrome that can be indistinguishable from AQP4-IgG+ NMOSD or develop into other mimics such as multiple sclerosis. Thus, underlying disease mechanisms are likely to be heterogeneous. This topical review aims to (1) reappraise antibody-negative NMOSD definition as it has changed over time with the development of the AQP4 and MOG-IgG assays; (2) outline clinical characteristics and the pathophysiological nature of this rare entity by contrasting its differences and similarities with antibody-positive NMOSD; (3) summarize laboratory characteristics and magnetic resonance imaging findings of DN NMOSD; and (4) discuss the current treatment for DN NMOSD.
Topics: Humans; Neuromyelitis Optica; Aquaporin 4; Myelin-Oligodendrocyte Glycoprotein; Immunoglobulin G; Multiple Sclerosis; Autoantibodies
PubMed: 37740717
DOI: 10.1177/13524585231199819 -
Neurologic Clinics Feb 2024Aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) and myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are... (Review)
Review
Aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) and myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are antibody-associated diseases targeting astrocytes and oligodendrocytes, respectively. Their recognition as distinct entities has led to each having its own diagnostic criteria that require a combination of clinical, serologic, and MRI features. The therapeutic approach to acute attacks in AQP4+NMOSD and MOGAD is similar. There is now class 1 evidence to support attack-prevention medications for AQP4+NMOSD. MOGAD lacks proven treatments although clinical trials are now underway. In this review, we will outline similarities and differences between AQP4+NMOSD and MOGAD in terms of diagnosis and treatment.
Topics: Humans; Myelin-Oligodendrocyte Glycoprotein; Immunoglobulin G; Autoantibodies; Neuromyelitis Optica; Aquaporin 4; Central Nervous System Diseases; Central Nervous System
PubMed: 37980124
DOI: 10.1016/j.ncl.2023.06.009 -
JAMA Dermatology Sep 2023Dupilumab is a theoretically novel therapy for bullous pemphigoid (BP). However, its effectiveness and safety have yet to be confirmed in a large-scale study.
IMPORTANCE
Dupilumab is a theoretically novel therapy for bullous pemphigoid (BP). However, its effectiveness and safety have yet to be confirmed in a large-scale study.
OBJECTIVE
To assess the efficacy and safety of dupilumab in patients with BP and evaluate factors that potentially affect short-term and long-term outcomes.
DESIGN, SETTING, AND PARTICIPANTS
A retrospective cohort study was conducted from January 1, 2021, to July 31, 2022. The median (IQR) follow-up period was 24.6 (11.5-38.4) weeks. This multicenter study was performed in 6 dermatology departments of the National Autoimmune Bullous Diseases Cooperative Group of China. Adult patients with BP that received 300 mg of dupilumab every 2 weeks following an initial dose of 600 mg were included. Patients were eligible if they had a clinical presentation of BP combined with immunological or pathological evidence. Patients with drug-induced BP, with less than 4 weeks of follow-up, and who received dupilumab or any other biologics within 6 months were excluded.
MAIN OUTCOMES AND MEASURES
The primary outcome was the proportion of patients who achieved disease control within 4 weeks. Disease control was defined as the absence of new lesions and pruritus, combined with the healing of existing lesions. Complete remission rates, relapse rates, changes in Bullous Pemphigoid Disease Area Index (BPDAI) scores, itching numerical rating scale (NRS) scores, laboratory results within 64 weeks, and adverse events (AEs) were also assessed.
RESULTS
Among 146 patients (median [IQR] age, 73 [64-85] years; 86 [58.9%] male patients) included in the study, 127 (87.0%) patients achieved disease control within 4 weeks, with a median (IQR) time of 14 (7-14) days. A total of 52 (35.6%) patients achieved complete remission, and 13 (8.9%) patients relapsed during the observation period. The complete remission rate and cumulative relapse rate at week 64 were 62.5% (5 of 8) and 30.9%, respectively. There was rapid and sustained improvement in clinical indicators and laboratory examination results after dupilumab treatment, including BPDAI scores, itching NRS scores, serum anti-BP180 and anti-BP230 antibodies, total IgE levels, and eosinophil count. Of these 146 patients, 107 (73.3%) did not report any AEs. The most common AEs were infections and eosinophilia. Serum anti-BP180 antibody levels of greater than 50 relative units (RU)/mL (OR, 3.63; 95% CI, 0.97-12.61; P = .045) were associated with 4-week disease control, and male patients were more likely to relapse (HR, 10.97; 95% CI, 1.42-84.92; P = .02).
CONCLUSIONS AND RELEVANCE
In this retrospective cohort study, dupilumab treatment was associated with improved clinical symptoms in patients with BP. The safety profile was favorable, although concurrent infection and eosinophilia might pose potential concerns. This study suggests that patients with anti-BP180 antibody levels of at least 50 RU/mL and female sex may respond better.
Topics: Adult; Humans; Male; Female; Aged; Pemphigoid, Bullous; Retrospective Studies; Pruritus; Autoimmune Diseases; Autoantibodies; Autoantigens; Recurrence
PubMed: 37531116
DOI: 10.1001/jamadermatol.2023.2428 -
Journal of Neurology Aug 2023New diagnostic criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) have recently been proposed, distinguishing this syndrome from other... (Review)
Review
New diagnostic criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) have recently been proposed, distinguishing this syndrome from other inflammatory diseases of the central nervous system. Seropositivity status for MOG-IgG autoantibodies is important for diagnosing MOGAD, but only in the context of robust clinical characterization and cautious interpretation of neuroimaging. Over the last several years, access to cell-based assay (CBA) techniques has improved diagnostic accuracy, yet the positive predictive value of serum MOG-IgG values varies with the prevalence of MOGAD in any given patient population. For this reason, possible alternative diagnoses need to be considered, and low MOG-IgG titers need to be carefully weighted. In this review, cardinal clinical features of MOGAD are discussed. Key challenges to the current understanding of MOGAD are also highlighted, including uncertainty regarding the specificity and pathogenicity of MOG autoantibodies, the need to identify immunopathologic targets for future therapies, the quest to validate biomarkers that facilitate diagnosis and detect disease activity, and the importance of deciphering which patients with MOGAD require long-term immunotherapy.
Topics: Humans; Myelin-Oligodendrocyte Glycoprotein; Autoantibodies; Central Nervous System; Immunotherapy; Immunoglobulin G; Aquaporin 4; Neuromyelitis Optica
PubMed: 37154894
DOI: 10.1007/s00415-023-11737-8 -
Molecular Cell Jul 2023Kinetochore is an essential protein complex required for accurate chromosome segregation. The constitutive centromere-associated network (CCAN), a subcomplex of the...
Kinetochore is an essential protein complex required for accurate chromosome segregation. The constitutive centromere-associated network (CCAN), a subcomplex of the kinetochore, associates with centromeric chromatin and provides a platform for the kinetochore assembly. The CCAN protein CENP-C is thought to be a central hub for the centromere/kinetochore organization. However, the role of CENP-C in CCAN assembly needs to be elucidated. Here, we demonstrate that both the CCAN-binding domain and the C-terminal region that includes the Cupin domain of CENP-C are necessary and sufficient for chicken CENP-C function. Structural and biochemical analyses reveal self-oligomerization of the Cupin domains of chicken and human CENP-C. We find that the CENP-C Cupin domain oligomerization is vital for CENP-C function, centromeric localization of CCAN, and centromeric chromatin organization. These results suggest that CENP-C facilitates the centromere/kinetochore assembly through its oligomerization.
Topics: Humans; Kinetochores; Centromere; Chromosomal Proteins, Non-Histone; Chromatin; Centromere Protein A
PubMed: 37295434
DOI: 10.1016/j.molcel.2023.05.023 -
Journal of Neurology Oct 2023Optic neuritis (ON) is the most common cause of subacute optic neuropathy in young adults. Although most cases of optic neuritis (ON) are classified as typical, meaning...
Optic neuritis (ON) is the most common cause of subacute optic neuropathy in young adults. Although most cases of optic neuritis (ON) are classified as typical, meaning idiopathic or associated with multiple sclerosis, there is a growing understanding of atypical forms of optic neuritis such as antibody mediated aquaporin-4 (AQP4)-IgG neuromyelitis optica spectrum disorder (NMOSD) and the recently described entity, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). Differentiating typical ON from atypical ON is important because they have different prognoses and treatments. Findings of atypical ON, including severe vision loss with poor recovery with steroids or steroid dependence, prominent optic disc edema, bilateral vision loss, and childhood or late adult onset, should prompt serologic testing for AQP4-IgG and MOG-IgG. Although the traditional division of typical and atypical ON can be helpful, it should be noted that there can be severe presentations of otherwise typical ON and mild presentations of atypical ON that blur these traditional lines. Rare causes of autoimmune optic neuropathies, such as glial fibrillary acidic protein (GFAP) and collapsin response-mediator protein 5 (CRMP5) autoimmunity also should be considered in patients with bilateral painless optic neuropathy associated with optic disc edema, especially if there are other accompanying suggestive neurologic symptoms/signs. Typical ON usually recovers well without treatment, though recovery may be expedited by steroids. Atypical ON is usually treated with intravenous steroids, and some forms, such as NMOSD, often require plasma exchange for acute attacks and long-term immunosuppressive therapy to prevent relapses. Since treatment is tailored to the cause of the ON, elucidating the etiology of the ON is of the utmost importance.
Topics: Humans; Papilledema; Myelin-Oligodendrocyte Glycoprotein; Autoantibodies; Optic Neuritis; Neuromyelitis Optica; Optic Nerve Diseases; Aquaporin 4; Vision Disorders; Immunoglobulin G
PubMed: 37542657
DOI: 10.1007/s00415-023-11920-x -
Journal of Hepatology Dec 2023IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder. The pathogenesis of... (Review)
Review
IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder. The pathogenesis of IgG4-RD and IRC is currently viewed as multifactorial, as there is evidence of a genetic predisposition while environmental factors, such as blue-collar work, are major risk factors. Various autoantigens have been described in IgG4-RD, including annexin A11 and laminin 511-E8, proteins which may exert a partially protective function in cholangiocytes by enhancing secretion and barrier function, respectively. For the other recently described autoantigens, galectin-3 and prohibitin 1, a distinct role in cholangiocytes appears less apparent. In relation to these autoantigens, oligoclonal expansions of IgG4 plasmablasts are present in patients with IRC and disappear upon successful treatment. More recently, specific T-cell subtypes including regulatory T cells, follicular T helper 2 cells, peripheral T helper cells and cytotoxic CD8 and CD4 SLAMF7 T cells have been implicated in the pathogenesis of IgG4-RD. The clinical presentation of IRC often mimics other biliary diseases such as primary sclerosing cholangitis or cholangiocarcinoma, which may lead to inappropriate medical and potentially invalidating surgical interventions. As specific biomarkers are lacking, diagnosis is made according to the HISORt criteria comprising histopathology, imaging, serology, other organ manifestations and response to therapy. Treatment of IRC aims to prevent or alleviate organ damage and to improve symptoms and consists of (i) remission induction, (ii) remission maintenance and (iii) long-term management. Glucocorticosteroids are highly effective for remission induction, after which immunomodulators can be introduced for maintenance of remission as glucocorticosteroid-sparing alternatives. Increased insight into the pathogenesis of IRC will lead to improved diagnosis and novel therapeutic strategies in the future.
Topics: Humans; Immunoglobulin G; Immunoglobulin G4-Related Disease; Cholangitis; Autoantigens; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangitis, Sclerosing; Autoimmune Diseases
PubMed: 37598939
DOI: 10.1016/j.jhep.2023.08.005 -
Journal of Neuroimaging : Official... 2023Differentiating multiple sclerosis (MS) from other relapsing inflammatory autoimmune diseases of the central nervous system such as neuromyelitis optica spectrum... (Review)
Review
Differentiating multiple sclerosis (MS) from other relapsing inflammatory autoimmune diseases of the central nervous system such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is crucial in clinical practice. The differential diagnosis may be challenging but making the correct ultimate diagnosis is critical, since prognosis and treatments differ, and inappropriate therapy may promote disability. In the last two decades, significant advances have been made in MS, NMOSD, and MOGAD including new diagnostic criteria with better characterization of typical clinical symptoms and suggestive imaging (magnetic resonance imaging [MRI]) lesions. MRI is invaluable in making the ultimate diagnosis. An increasing amount of new evidence with respect to the specificity of observed lesions as well as the associated dynamic changes in the acute and follow-up phase in each condition has been reported in distinct studies recently published. Additionally, differences in brain (including the optic nerve) and spinal cord lesion patterns between MS, aquaporin4-antibody-positive NMOSD, and MOGAD have been described. We therefore present a narrative review on the most relevant findings in brain, spinal cord, and optic nerve lesions on conventional MRI for distinguishing adult patients with MS from NMOSD and MOGAD in clinical practice. In this context, cortical and central vein sign lesions, brain and spinal cord lesions characteristic of MS, NMOSD, and MOGAD, optic nerve involvement, role of MRI at follow-up, and new proposed diagnostic criteria to differentiate MS from NMOSD and MOGAD were discussed.
Topics: Adult; Humans; Neuromyelitis Optica; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Magnetic Resonance Imaging; Central Nervous System; Aquaporin 4
PubMed: 37322542
DOI: 10.1111/jon.13137 -
Brain : a Journal of Neurology Sep 2023The spectrum of MOG-IgG-associated disease (MOGAD) includes optic neuritis (ON), myelitis (MY), acute disseminated encephalomyelitis (ADEM), brainstem encephalitis,...
The spectrum of MOG-IgG-associated disease (MOGAD) includes optic neuritis (ON), myelitis (MY), acute disseminated encephalomyelitis (ADEM), brainstem encephalitis, cerebral cortical encephalitis (CE) and AQP4-IgG-negative neuromyelitis optica spectrum disorder (NMOSD). In MOGAD, MOG-IgG are usually detected in sera (MOG-IgGSERUM), but there have been some seronegative MOGAD cases with MOG-IgG in CSF (MOG-IgGCSF), and its diagnostic implications remains unclear. In this cross-sectional study, we identified patients with paired serum and CSF sent from all over Japan for testing MOG-IgG. Two investigators blinded to MOG-IgG status classified them into suspected MOGAD (ADEM, CE, NMOSD, ON, MY and Others) or not based on the current recommendations. The MOG-IgGSERUM and MOG-IgGCSF titres were assessed with serial 2-fold dilutions to determine end point titres [≥1:128 in serum and ≥1:1 (no dilution) in CSF were considered positive]. We analysed the relationship between MOG-IgGSERUM, MOG-IgGCSF and the phenotypes with multivariable regression. A total of 671 patients were tested [405 with suspected MOGAD, 99 with multiple sclerosis, 48 with AQP4-IgG-positive NMOSD and 119 with other neurological diseases (OND)] before treatment. In suspected MOGAD, 133 patients (33%) tested MOG-IgG-positive in serum and/or CSF; 94 (23%) double-positive (ADEM 36, CE 15, MY 8, NMOSD 9, ON 15 and Others 11); 17 (4.2%) serum-restricted-positive (ADEM 2, CE 0, MY 3, NMOSD 3, ON 5 and Others 4); and 22 (5.4%) CSF-restricted-positive (ADEM 3, CE 4, MY 6, NMOSD 2, ON 0 and Others 7). None of AQP4-IgG-positive NMOSD, multiple sclerosis or OND cases tested positive for MOG-IgGSERUM, but two with multiple sclerosis cases were MOG-IgGCSF-positive; the specificities of MOG-IgGSERUM and MOG-IgGCSF in suspected MOGAD were 100% [95% confidence interval (CI) 99-100%] and 99% (95% CI 97-100%), respectively. Unlike AQP4-IgG-positive NMOSD, the correlation between MOG-IgGSERUM and MOG-IgGCSF titres in MOGAD was weak. Multivariable regression analyses revealed MOG-IgGSERUM was associated with ON and ADEM, whereas MOG-IgGCSF was associated with ADEM and CE. The number needed to test for MOG-IgGCSF to diagnose one additional MOGAD case was 13.3 (14.3 for ADEM, 2 for CE, 19.5 for NMOSD, infinite for ON, 18.5 for MY and 6.1 for Others). In terms of MOG-IgGSERUM/CSF status, most cases were double-positive while including either serum-restricted (13%) or CSF-restricted (17%) cases. These statuses were independently associated with clinical phenotypes, especially in those with ON in serum and CE in CSF, suggesting pathophysiologic implications and the utility of preferential diagnostic testing. Further studies are warranted to deduce the clinical and pathological significance of compartmentalized MOG-IgG.
Topics: Humans; Aquaporin 4; Autoantibodies; Cross-Sectional Studies; Encephalitis; Immunoglobulin G; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Myelitis; Neuromyelitis Optica; Optic Neuritis
PubMed: 37061817
DOI: 10.1093/brain/awad122 -
JAMA Neurology Sep 2023Differential diagnosis of patients with seronegative demyelinating central nervous system (CNS) disease is challenging. In this regard, evidence suggests that...
IMPORTANCE
Differential diagnosis of patients with seronegative demyelinating central nervous system (CNS) disease is challenging. In this regard, evidence suggests that immunoglobulin (Ig) A plays a role in the pathogenesis of different autoimmune diseases. Yet little is known about the presence and clinical relevance of IgA antibodies against myelin oligodendrocyte glycoprotein (MOG) in CNS demyelination.
OBJECTIVE
To investigate the frequency of MOG-IgA and associated clinical features in patients with demyelinating CNS disease and healthy controls.
DESIGN, SETTING, AND PARTICIPANTS
This longitudinal study comprised 1 discovery and 1 confirmation cohort derived from 5 centers. Participants included patients with suspected or confirmed demyelinating diseases and healthy controls. MOG-IgA, MOG-IgG, and MOG-IgM were measured in serum samples and cerebrospinal fluid (CSF) of patients, who were assessed from September 2012 to April 2022.
MAIN OUTCOMES AND MEASURES
Frequency and clinical features of patients who were seropositive for MOG-IgA and double-seronegative for aquaporin 4 (AQP4) IgG and MOG-IgG.
RESULTS
After the exclusion of 5 participants with coexisting AQP4-IgG and MOG-IgA, MOG-IgG, and/or MOG-IgM, 1339 patients and 110 healthy controls were included; the median follow-up time was 39 months (range, 0-227 months). Of included patients with isolated MOG-IgA, 11 of 18 were female (61%), and the median age was 31.5 years (range, 3-76 years). Among patients double-seronegative for AQP4-IgG and MOG-IgG (1126/1339; 84%), isolated MOG-IgA was identified in 3 of 50 patients (6%) with neuromyelitis optica spectrum disorder, 5 of 228 patients (2%) with other CNS demyelinating diseases, and 10 of 848 patients (1%) with multiple sclerosis but in none of the healthy controls (0/110). The most common disease manifestation in patients seropositive for isolated MOG-IgA was myelitis (11/17 [65%]), followed by more frequent brainstem syndrome (7/16 [44%] vs 14/75 [19%], respectively; P = .048), and infrequent manifestation of optic neuritis (4/15 [27%] vs 46/73 [63%], respectively; P = .02) vs patients with MOG-IgG. Among patients fulfilling 2017 McDonald criteria for multiple sclerosis, MOG-IgA was associated with less frequent CSF-specific oligoclonal bands (4/9 [44%] vs 325/351 [93%], respectively; P < .001) vs patients with multiple sclerosis who were MOG-IgG/IgA seronegative. Further, most patients with isolated MOG-IgA presented clinical attacks after recent infection or vaccination (7/11 [64%]).
CONCLUSION AND RELEVANCE
In this study, MOG-specific IgA was identified in a subgroup of patients who were double-seronegative for AQP4-/MOG-IgG, suggesting that MOG-IgA may be a novel diagnostic biomarker for patients with CNS demyelination.
Topics: Humans; Female; Male; Myelin-Oligodendrocyte Glycoprotein; Longitudinal Studies; Neuromyelitis Optica; Aquaporin 4; Brain Stem; Multiple Sclerosis; Autoantibodies; Immunoglobulin G; Immunoglobulin A; Immunoglobulin M
PubMed: 37548987
DOI: 10.1001/jamaneurol.2023.2523