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Current Opinion in Neurology Jun 2024We summarize the recent discoveries on genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes (PNS), emphasizing clinical and... (Review)
Review
PURPOSE OF REVIEW
We summarize the recent discoveries on genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes (PNS), emphasizing clinical and pathophysiological implications.
RECENT FINDINGS
The human leukocyte antigen (HLA) is the most studied genetic factor in autoimmune encephalitis and PNS. The HLA haplotype 8.1, which is widely known to be related to systemic autoimmunity, has been only weakly associated with a few types of autoimmune encephalitis and PNS. However, the strongest and most specific associations have been reported in a subgroup of autoimmune encephalitis that comprises antileucine-rich glioma-inactivated 1 (LGI1) limbic encephalitis, associated with DRB1∗07 : 01 , anticontactin-associated protein-like 2 (CASPR2) limbic encephalitis, associated with DRB1∗11 : 01 , and anti-IgLON5 disease, associated with DRB1∗10 : 01∼DQA1∗01∼DQB1∗05 . Non-HLA genes have been poorly investigated so far in autoimmune encephalitis, mainly in those lacking HLA associations such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, with only a few genome-wide association studies (GWAS) reporting equivocal results principally limited by small sample size.
SUMMARY
Genetic predisposition seems to be driven mostly by HLA in a group of autoimmune encephalitis characterized by being nonparaneoplastic and having predominantly IgG4 autoantibodies. The contribution of non-HLA genes, especially in those diseases lacking known or strong HLA associations, will require large cohorts enabling GWAS to be powerful enough to render meaningful results.
Topics: Humans; Autoantibodies; Encephalitis; Genetic Predisposition to Disease; Hashimoto Disease; HLA Antigens; Paraneoplastic Syndromes, Nervous System
PubMed: 38483154
DOI: 10.1097/WCO.0000000000001263 -
Advances in Pediatrics Aug 2023Myasthenia gravis (MG) is a rare condition that impairs function at the neuromuscular junction of skeletal muscles, seen less commonly in children. Causes include... (Review)
Review
Myasthenia gravis (MG) is a rare condition that impairs function at the neuromuscular junction of skeletal muscles, seen less commonly in children. Causes include autoimmune MG, congenital myasthenic syndromes, and transient neonatal myasthenia gravis. Symptoms of weakness, hypotonia, and fatigability can be reasonably explained by more common causes, thus children with MG disorders commonly experience delays in treatment with severe consequences. This leads to the progression of disease and serious complications including myasthenic crises and exacerbations. We describe 5 cases of MG, which illustrate clinical and genetic challenges in establishing diagnosis and subsequent consequences of delayed diagnosis.
Topics: Infant, Newborn; Infant; Child; Humans; Myasthenia Gravis; Myasthenic Syndromes, Congenital; Fatigue
PubMed: 37422299
DOI: 10.1016/j.yapd.2023.03.007 -
Inflammation Research : Official... Nov 2023Malignant neoplasms are a well-recognized global public health concern, with significant impacts on human health and quality of life. The interplay between tumors and... (Review)
Review
BACKGROUND
Malignant neoplasms are a well-recognized global public health concern, with significant impacts on human health and quality of life. The interplay between tumors and autoimmune rheumatic diseases is complex, and the resulting tumor-associated rheumatic diseases represent a rare and intricate group of conditions that occur in the context of malignant tumors. In addition, various rheumatic diseases can arise as a consequence of oncology treatment. These diseases present with intricate clinical manifestations and pathological features, often rendering them challenging to diagnose and impacting patients' quality of life. Despite this, they have yet to be fully recognized.
METHODS
This article presents a literature review of published original articles and review articles concerning paraneoplastic rheumatic syndromes and rheumatic diseases associated with cancer treatment. We conducted a comprehensive literature search in PubMed, Web of Science and Google Scholar databases, excluding duplicated and irrelevant studies. In cases of duplicated research, we selected articles with higher impact factors for the review.
RESULTS
This review focuses on the clinical features, diagnosis, and treatment of paraneoplastic rheumatic diseases, as well as the pathogenesis of these diseases. Additionally, we summarize the autoimmune rheumatic diseases associated with cancer treatment. Ultimately, the goal of this review is to enhance recognition and improve the management of autoimmune rheumatic diseases related to tumors.
Topics: Humans; Quality of Life; Neoplasms; Paraneoplastic Syndromes; Rheumatic Diseases; Autoimmune Diseases
PubMed: 37768354
DOI: 10.1007/s00011-023-01780-6 -
Handbook of Clinical Neurology 2024Paraneoplastic neurologic syndromes are rarely associated with hematologic malignancies. In their rarity, lymphomas are the diseases with more frequent paraneoplastic... (Review)
Review
Paraneoplastic neurologic syndromes are rarely associated with hematologic malignancies. In their rarity, lymphomas are the diseases with more frequent paraneoplastic neurologic syndrome. High-risk antibodies are absent in most lymphoma-associated paraneoplastic neurologic syndromes, with the exception of antibodies to Tr/DNER in paraneoplastic cerebellar degeneration, mGluR5 in limbic encephalitis, and mGluR1 in some cerebellar ataxias. Peripheral nervous system paraneoplastic neurologic syndromes are rare and heterogeneous, with a prevalence of demyelinating polyradiculoneuropathy in non-Hodgkin lymphoma. Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) is a rare, paraneoplastic syndrome due to an underlying plasma cell disorder. The diagnosis is based on defined criteria, and vascular endothelial growth factor (VEGF), not an antibody, is considered a reliable diagnostic marker that also mirrors therapy response. As with the paraneoplastic neurologic syndromes in solid tumors, therapies rely on cancer treatment associated with immunomodulatory treatment with better response in PNS with antibodies to surface antigens. The best outcome is generally present in Ophelia syndrome/limbic encephalitis with anti-mGluR5 antibodies, with frequent complete recovery. Besides patients with isolated osteosclerotic lesions (where radiotherapy is indicated), hematopoietic stem-cell transplantation is the therapy of choice in patients with POEMS syndrome. In the paraneoplastic neurologic syndromes secondary to immune checkpoint inhibitors, discontinuation of the drug together with immunomodulatory treatment is recommended.
Topics: Humans; Limbic Encephalitis; Vascular Endothelial Growth Factor A; Hematopoietic Stem Cell Transplantation; Lymphoma; Hematologic Neoplasms; Paraneoplastic Syndromes, Nervous System
PubMed: 38494294
DOI: 10.1016/B978-0-12-823912-4.00016-5 -
JCI Insight Jul 2023Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the...
Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the human system is required to improve treatment responses and identify off-target effects shaping long-term outcomes. For this reason, we studied a cohort of patients with MG treated with either eculizumab or azathioprine as well as treatment-naive patients using a combined proteomics and metabolomics approach. This strategy validated known effects of eculizumab on the terminal complement cascade. Beyond that, eculizumab modulated the serum proteometabolome as distinct pathways were altered in eculizumab-treated patients, including the oxidative stress response, mitogen-activated protein kinase signaling, and lipid metabolism with particular emphasis on arachidonic acid signaling. We detected reduced levels of arachidonate 5-lipoxygenase (ALOX5) and leukotriene A4 in eculizumab-treated patients. Mechanistically, ligation of the C5a receptor (C5aR) is needed for ALOX5 metabolism and generation of downstream leukotrienes. As eculizumab prevents cleavage of C5 into C5a, decreased engagement of C5aR may inhibit ALOX5-mediated synthesis of pro-inflammatory leukotrienes. These findings indicate distinct off-target effects induced by eculizumab, illuminating potential mechanisms of action that may be harnessed to improve treatment outcomes.
Topics: Humans; Complement C5; Complement System Proteins; Complement Activation; Myasthenia Gravis; Receptor, Anaphylatoxin C5a; Leukotrienes
PubMed: 37227781
DOI: 10.1172/jci.insight.169135 -
Handbook of Clinical Neurology 2024Treatment strategies in paraneoplastic neurological syndromes rely on the three pillars of tumor treatment, immunotherapy, and symptomatic treatment, the first one being... (Review)
Review
Treatment strategies in paraneoplastic neurological syndromes rely on the three pillars of tumor treatment, immunotherapy, and symptomatic treatment, the first one being by far the most important in the majority of patients and syndromes. Classically, antibodies against extracellular antigens are directly pathogenic, and patients with these syndromes are more responsive to immunomodulatory or immunosuppressive treatments than the ones with antibodies against intracellular targets. This chapter first discusses some general principles of tumor treatment and immunotherapy, followed by a closer look at specific treatment options for different clinical syndromes, focusing on symptomatic treatments.
Topics: Humans; Lambert-Eaton Myasthenic Syndrome; Paraneoplastic Syndromes; Neoplasms; Immunosuppressive Agents; Immunotherapy; Autoantibodies
PubMed: 38494299
DOI: 10.1016/B978-0-12-823912-4.00015-3 -
The Journal of Clinical Endocrinology... Jan 2024
Topics: Humans; Calcium; Bone and Bones; Osteomalacia; Calcium, Dietary; Paraneoplastic Syndromes
PubMed: 37466206
DOI: 10.1210/clinem/dgad430 -
Revue Medicale Suisse Apr 2024Myasthenia gravis (MG) is an autoimmune disease characterized by fluctuating weakness of skeletal muscles. Despite current treatments, a significant percentage of... (Review)
Review
Myasthenia gravis (MG) is an autoimmune disease characterized by fluctuating weakness of skeletal muscles. Despite current treatments, a significant percentage of patients remain symptomatic. This review explores new immunosuppressive therapies and ongoing clinical trials in MG, including depletion of B lymphocytes with agents such as rituximab and inebilizumab, as well as the use of eculizumab, efgartigimod, satralizumab, tocilizumab, and CAR-T (Chimeric Antigen Receptor-T) cell therapy. These advancements aim to improve disease control and patients' quality of life.
Topics: Myasthenia Gravis; Humans; Immunosuppressive Agents; Quality of Life; Immunomodulating Agents; B-Lymphocytes; Immunologic Factors
PubMed: 38665106
DOI: 10.53738/REVMED.2024.20.871.848 -
Annals of Neurology Dec 2023Small-cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses...
OBJECTIVE
Small-cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses against intracellular (Hu) or neuronal surface (GABA R) antigens. Our aim was to clarify whether the genomic and transcriptomic features of SCLC are different in patients with anti-GABA R or anti-Hu PNS compared with SCLC without PNS.
METHODS
A total of 76 SCLC tumor samples were collected: 34 anti-Hu, 14 anti-GABA R, and 28 SCLC without PNS. The study consisted of 4 steps: (1) pathological confirmation; (2) next generation sequencing using a panel of 98 genes, including those encoding the autoantibodies targets ELAVL1-4, GABBR1-2, and KCTD16; (3) genome-wide copy number variation (CNV); and (4) whole-transcriptome RNA sequencing.
RESULTS
CNV analysis revealed that patients with anti-GABA R PNS commonly have a gain in chromosome 5q, which contains KCTD16, whereas anti-Hu and control patients often harbor a loss. No significantly different number of mutations regarding any onconeural genes was observed. Conversely, the transcriptomic profile of SCLC was different, and the differentially expressed genes allowed effective clustering of the samples into 3 groups, reflecting the antibody-based classification, with an overexpression of KCTD16 specific to anti-GABA R PNS. Pathway analysis revealed that tumors of patients with anti-GABA R encephalitis were enriched in B-cell signatures, as opposed to those of patients with anti-Hu, in which T-cell- and interferon-γ-related signatures were overexpressed.
INTERPRETATION
SCLC genetic and transcriptomic features differentiate anti-GABA R, anti-Hu, and non-PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti-GABA R PNS. ANN NEUROL 2023;94:1102-1115.
Topics: Humans; Lung Neoplasms; DNA Copy Number Variations; Paraneoplastic Syndromes, Nervous System; ELAV Proteins; Autoantibodies
PubMed: 37638563
DOI: 10.1002/ana.26784 -
Journal of the American Academy of... Jul 2024Paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome (PNP/PAMS) is a highly fatal autoimmune blistering disease. The condition occurs in patients with... (Review)
Review
Paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome (PNP/PAMS) is a highly fatal autoimmune blistering disease. The condition occurs in patients with underlying benign or malignant neoplasms, most commonly lymphoproliferative disorders. Both humoral and cell-mediated immunities contribute to the pathogenesis, and autoantibodies against plakin family proteins are characteristic. Patients typically present with severe stomatitis and polymorphous skin lesions, which are often resistant to treatment. Bronchiolitis obliterans (BO) is a frequent complication which contributes to the high mortality rate of PNP/PAMS. Given the rarity of this disorder and heterogeneity of clinical presentation, clinicians should maintain a high index of suspicion for PNP/PAMS to avoid delayed diagnosis. In this first part of a two-part continuing medical education (CME) series, risk factors, pathogenesis, and clinical features of PNP/PAMS are discussed.
Topics: Humans; Pemphigus; Paraneoplastic Syndromes; Bronchiolitis Obliterans; Autoimmune Diseases; Multiple Organ Failure; Male; Autoantibodies; Female; Risk Factors
PubMed: 37597771
DOI: 10.1016/j.jaad.2023.08.020