Primary Autoimmune Diseases Research Articles

Skin as a Reflection of Gut Health: An Overview of Dermatological Manifestations in Primary Neoplastic and Autoimmune Gastrointestinal Disorders

Skin as a Reflection of Gut Health: An Overview of Dermatological Manifestations in Primary Neoplastic and Autoimmune Gastrointestinal Disorders

Unusual demyelinating disease in a patient with HIV infection.

Demyelinating central nervous system (CNS) disorders are a diverse group of conditions characterised by damage to the myelin sheath. These include not only primary autoimmune disorders such as multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), but secondary demyelinating conditions caused by infection and neoplasm, where immunosuppressive therapy may worsen the condition or delay definitive treatment. We describe a young man with an unusual presentation of CNS demyelinating disease associated with HIV infection and positive syphilis serology. MRI brain and spine showed a demyelinating tumefactive lesion accompanied by longitudinal extensive transverse myelitis, and we initially suspected NMOSD. However anti-aquaporin 4 antibodies were negative, going against a diagnosis of NMOSD and he then tested positive for HIV which led us to consider TB myelitis, neurosyphilis and HIV vacuolar myelopathy. He was commenced on highly active retroviral therapy and treated with steroids and immunosuppression. He did not respond to treatment as expected so a brain biopsy was required to narrow the differential. Brain biopsy initially raised the possibility of progressive multifocal leukoencephalopathy which is associated with infection with the John Cunningham (JC) virus. Ultimately JC Virus PCR on the biopsy was negative, the final report suggesting nonspecific active chronic inflammation. We detail his clinical course and the diagnostic challenges along the way.

Long-term in vitro maintenance of plasma cells in a hydrogel-enclosed human bone marrow microphysiological 3D model system

Plasma cells (PCs) in bone marrow (BM) play an important role in both protective and pathogenic humoral immune responses, e.g. in various malignant and non-malignant diseases such as multiple myeloma, primary and secondary immunodeficiencies and autoimmune diseases. Dedicated microenvironmental niches in the BM provide PCs with biomechanical and soluble factors that support their long-term survival. There is a high need for appropriate and robust model systems to better understand PCs biology, to develop new therapeutic strategies for PCs-related diseases and perform targeted preclinical studies with high predictive value. Most preclinical data have been derived from in vivo studies in mice, as in vitro studies of human PCs are limited due to restricted survival and functionality in conventional 2D cultures that do not reflect the unique niche architecture of the BM. We have developed a microphysiological, dynamic 3D BM culture system (BM-MPS) based on human primary tissue (femoral biopsies), mechanically supported by a hydrogel scaffold casing. While a bioinert agarose casing did not support PCs survival, a photo-crosslinked collagen-hyaluronic acid (Col-HA) hydrogel preserved the native BM niche architecture and allowed PCs survival in vitro for up to 2 weeks. Further, the Col-HA hydrogel was permissive to lymphocyte migration into the microphysiological system´s circulation. Long-term PCs survival was related to the stable presence in the culture of soluble factors, as APRIL, BAFF, and IL-6. Increasing immunoglobulins concentrations in the medium confirm their functionality over culture time. To the best of our knowledge, this study is the first report of successful long-term maintenance of primary-derived non-malignant PCs in vitro. Our innovative model system is suitable for in-depth in vitro studies of human PCs regulation and exploration of targeted therapeutic approaches such as CAR-T cell therapy or biologics.

Clinical outcomes, demographics and associative analysis of lung cancer patients with Lambert-Eaton myasthenic syndrome: Insights from the National Inpatient Sample (NIS) database.

e20134 Background: Lambert-Eaton myasthenic syndrome (LEMS) is a rare neuromuscular junction disorder that may present as a paraneoplastic syndrome or a primary autoimmune disorder. Approximately 60% of LEMS patients have an underlying tumor, with the paraneoplastic form predominantly associated with small cell lung cancer (SCLC). Understanding the clinical outcomes and risks associated in lung cancer patients with LEMS is crucial in effective management of such patients. Methods: This retrospective study utilized inpatient hospitalization data from the National Inpatient Sample (NIS) between January 1, 2016, and December 31, 2019. Data of patients with a primary or secondary discharge diagnosis of lung cancer (ICD10-CM codes C34, C78.0, C46.5, D02.2) were obtained. Then, out of this population, we identified Lambert-Eaton myasthenic syndrome with ICD-10 codes (G70.80, G70.81, G73.1). The objective was to run a descriptive analysis of clinical outcomes, risks, demographics and associations of LEMS in patients with lung cancer. Results: A total of 204 cases of lung cancer hospitalizations with LEMS were analyzed. The mean age was 68.23 years, with a slight female (51.72%) preponderance as compared to male (48.28%). Race distribution revealed increased prevalence in White Caucasians (83%), followed by Black (7%), Hispanic (4.5%), Asian or Pacific Islander (3%), Native American (0.5%), and Other (2%). The majority were covered by Medicare (66.33%), followed by private insurance (26.13%). The mortality rate was 8.9%, with a mean length of stay of 10.35 days and mean hospital charges of $118,676. Clinical outcomes and risks were analyzed, with sepsis occurring in 17.6% of cases, pneumonia in 22.5%, and acute respiratory failure in 26.9%. Intubation/mechanical ventilation was necessary in 18.1% of cases. The incidence of urinary tract infection (UTI) was 16.7%, acute kidney injury (AKI) was 17.2%, and venous thromboembolism (VTE) was 6.4%. Additionally, interventions such as intravenous immunoglobulin (IVIG) therapy and blood transfusions were also noted. Conclusions: This study provides insights into the demographic characteristics and clinical outcomes of lung cancer patients with Lambert-Eaton myasthenic syndrome (LEMS). The findings highlight the need for comprehensive management strategies targeting associated complications like acute respiratory failure, intubation and need for mechanical ventilation, pneumonia, UTI, AKI, and VTE to improve patient outcomes, quality of care and effective patient education with regards to their diagnosis of LEMS in lung cancer.

Anti-vitiligo effect of Thespesia populnea L. bark against Tyrosinase enzyme using In-silico model

Background: Siddha medicine is one among the popular traditional systems of medicine in treating various diseases. Vitiligo is a primary autoimmune de-pigmentary disorder. Generally, melanin pigment production is diminished in vitiligo. By improving tyrosinase activity, melanogenesis can be achieved in vitiligo. Hence the phytocomponents which bind with the target Tyrosinase enzyme, act as a potential treatment for vitiligo. Objective: The objective of this study is to find the lead molecules that bind with these core bio active amino acid residues namely His 190, His54, His63, His194, His38 and His216.These bioactive residues mediates the enzymatic action of tyrosinase enzyme and tends to enhance the action of tyrosinase enzyme which improves melanogenesis. Methods: Auto dock program was used for the molecular docking studies against Tyrosinase enzyme. Results: From reported data of the herb, the phytochemicals Myricetin reveals highiest of 4 interactions with the core active amino acid residues of the target Tyrosinase enzyme.Second highiest level is reached by the compounds such as Catechin, Apigenin and Cinnamic acid with the 3 interactions with the active site . Gallic acid and Quercetin reveal 2 interactions over the target enzyme. From the results of docking study of the herb, the leads such as Catechin, Myricetin, Apigenin and Cinnamic acid possess 3-4 interactions with core target amino acids of Tyrosinase enzyme and helps in treatment and management of vitiligo. Conclusion: These phytochemicals exhibit anti-vitiligo activity by harmonising the action of tyrosinase enzyme in vitiligo treatment. Further clinical trials need to be performed for identifying the efficacy and effectiveness of Thespesia populnea in the treatment and management of vitiligo.

Primary hyperparathyroidism and autoimmune disorder: coealiac disease

Primary hyperparathyroidism and autoimmune disorder: coealiac disease

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations.

The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

Assessment of bidirectional relationships between autoimmune diseases and primary ovarian insufficiency: insights from a bidirectional two-sample Mendelian randomization analysis.

The simultaneous occurrence of primary ovarian insufficiency (POI) and autoimmune diseases has been noted and debated in some epidemiological research. This bidirectional two-sample Mendelian randomization (MR) study aimed to investigate the causal relationships between autoimmune diseases and POI. We obtained summary-level data for ten autoimmune diseases and POI from published large-scale genome-wide association studies and the FinnGen consortium of European ancestry. A series of filtering steps was performed to discern independent genetic variants. Causal estimates were mainly calculated by the inverse variance weighting method and verified through multiple sensitivity analyses. Of the ten autoimmune diseases, genetically predicted Addison's disease (odds ratio [OR] = 1.26, 95% confidence interval [CI]: 1.09-1.47, P = 0.003) and systemic lupus erythematosus (OR = 1.12, 95% CI 1.02-1.24, P = 0.021) were associated with an increased risk of POI, and sensitivity analyses confirmed the robustness of the results. In addition, there were weak associations between liability to POI and elevated risks of type 1 diabetes (OR = 1.05, 95% CI 1.00-1.10, P = 0.046) and autoimmune thyroid disease (OR = 1.03, 95% CI 1.01-1.05, P = 0.015). This study revealed that Addison's disease and systemic lupus erythematosus are potential risk factors for POI, underscoring the necessity to consider the impact of autoimmune factors in the diagnosis and treatment of POI.

Sporadic inclusion body myositis-derived myotube culture revealed muscle cell-autonomous expression profiles.

Sporadic inclusion body myositis (sIBM) is a muscle disease in older people and is characterized by inflammatory cell invasion into intact muscle fibers and rimmed vacuoles. The pathomechanism of sIBM is not fully elucidated yet, and controversy exists as to whether sIBM is a primary autoimmune disease or a degenerative muscle disease with secondary inflammation. Previously, we established a method of collecting CD56-positive myoblasts from human skeletal muscle biopsy samples. We hypothesized that the myoblasts derived from these patients are useful to see the cell-autonomous pathomechanism of sIBM. With these resources, myoblasts were differentiated into myotubes, and the expression profiles of cell-autonomous pathology of sIBM were analyzed. Myoblasts from three sIBM cases and six controls were differentiated into myotubes. In the RNA-sequencing analysis of these "myotube" samples, 104 differentially expressed genes (DEGs) were found to be significantly upregulated by more than twofold in sIBM, and 13 DEGs were downregulated by less than twofold. For muscle biopsy samples, a comparative analysis was conducted to determine the extent to which "biopsy" and "myotube" samples differed. Fifty-three DEGs were extracted of which 32 (60%) had opposite directions of expression change (e.g., increased in biopsy vs decreased in myotube). Apolipoprotein E (apoE) and transmembrane protein 8C (TMEM8C or MYMK) were commonly upregulated in muscle biopsies and myotubes from sIBM. ApoE and myogenin protein levels were upregulated in sIBM. Given that enrichment analysis also captured changes in muscle contraction and development, the triggering of muscle atrophy signaling and abnormal muscle differentiation via MYMK or myogenin may be involved in the pathogenesis of sIBM. The presence of DEGs in sIBM suggests that the myotubes formed from sIBM-derived myoblasts revealed the existence of muscle cell-autonomous degeneration in sIBM. The catalog of DEGs will be an important resource for future studies on the pathogenesis of sIBM focusing on primary muscle degeneration.

Prevalence and Spectrum of Autoimmune Diseases Among Patients with Telomere Biology Disorder

Introduction Telomeres are the protective ends of linear chromosomes that prevent DNA degradation with each replication. Premature attrition or dysfunction of telomeres due to an inherited defect in a telomere maintenance gene results in a spectrum of phenotypes collectively known as telomere biology disorders (TBD). To date, 18 genes have been implicated in TBD. Disease phenotypes are variable including bone marrow failure, immunodeficiency, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), idiopathic pulmonary fibrosis (IPF), liver cirrhosis, nail dystrophy, and premature graying of hair. Short telomeres have been observed in patients with autoimmune disorders (AID) and have been shown to increase the risk of AID. Furthermore, TBD have been associated with T cell dysfunction and exhaustion, mechanisms which may predispose to autoimmune phenotypes. Given the potential relationship between short telomeres and immune dysregulation, we hypothesize that the prevalence of AID may be increased in patients with a diagnosis of TBD. The aim of this study is to describe the prevalence and spectrum of AID in a cohort of patients with TBD. Methods Health record data were reviewed for 34 adult patients with confirmed TBD treated at the University of Wisconsin-Madison. A TBD diagnosis was established for patients who had a compatible clinical history plus either critically short lymphocyte telomere lengths (<1 st percentile for age as measured by FlowFISH) or one or more pathogenic/likely pathogenic variant(s) in a gene known to cause TBD. Demographics, rheumatologic history, serologies, and family history were collected. AID were included if diagnoses were made by a rheumatologist or other appropriate specialist with clinical features, physical exam findings, and/or serologies meeting diagnostic criteria per subspecialty guidelines. Results Eight of 34 patients (23.5%) with TBD had a concomitant diagnosis of a primary autoimmune condition. Specific AID included inflammatory bowel disease, Graves' disease, Hashimoto's thyroiditis, rheumatoid arthritis, scleroderma, and Sjogren's syndrome (Table 1). Two patients had autoimmune cytopenias, including steroid-responsive immune thrombocytopenic purpura and pure red cell aplasia (PRCA). Patient 8 was diagnosed with PRCA mixed with spur cell anemia prior to transplant, and bone marrow biopsy showed pure erythroid hypoplasia without evidence of malignancy. He responded to treatment with steroids and immunosuppression. Of the eight patients with a primary autoimmune condition, two had pathogenic/like pathogenic variants, two had rare variants of uncertain significance, and four had no detectable variants in a telomere associated gene. Twenty-three patients (67.6%) had a first- or second-degree relative with an autoimmune disorder. Conclusions An AID, as defined by strict diagnostic criteria per subspecialty guidelines, was present in 23.5% of patients with TBD defined by conservative diagnostic criteria. The spectrum of AID was diverse, including two patients with autoimmune hematologic disorders, and the majority had a family history of various AID. Thus, TBD may be associated with an increased prevalence of AID, though confirmation in a larger cohort of genetically defined TBD patients is needed. In the absence of a causative genetic lesion, diagnosis of a TBD based on critically short telomeres in those with multisystem autoimmune disorders with features that overlap TBD phenotypes can be challenging. Screening for AID as part of routine TBD comprehensive assessments as well as offering germline genetic testing for individuals with primary autoimmune disease with a compatible TBD phenotypes and studies to determine the mechanistic relationship between telomere length and autoimmunity are warranted.

Therapy-Related Myeloid Neoplasms: Predisposition and Clonal Evolution.

Therapy-related Myeloid Neoplasm (t-MN) represents one of the worst long-term consequences of cytotoxic therapy for primary tumors and autoimmune disease. Poor survival and refractoriness to current treatment strategies characterize affected patients from a clinical point of view. In our aging societies, where newer therapies and ameliorated cancer management protocols are improving the life expectancy of cancer patients, therapy-related Myeloid Neoplasms are an emerging problem. Although several research groups have contributed to characterizing the main risk factors in t-MN development, the multiplicity of primary tumors, in association with the different therapeutic strategies available and the new drugs in development, make interpreting the current data still complex. The main risk factors involved in t-MN pathogenesis can be subgrouped into patient-specific, inherited, and acquired predispositions. Although t-MN can occur at any age, the risk tends to increase with advancing age, and older patients, characterized by a higher number of comorbidities, are more likely to develop the disease. Thanks to the availability of deep sequencing techniques, germline variants have been reported in 15-20% of t-MN patients, highlighting their role in cancer predisposition. It is becoming increasingly evident that t-MN with driver gene mutations may arise in the background of Clonal Hematopoiesis of Indeterminate Potential (CHIP) under the positive selective pressure of chemo and/or radiation therapies. Although CHIP is generally considered benign, it has been associated with an increased risk of t-MN. In this context, the phenomenon of clonal evolution may be described as a dynamic process of expansion of preexisting clones, with or without acquisition of additional genetic alterations, that, by favoring the proliferation of more aggressive and/or resistant clones, may play a crucial role in the progression from preleukemic states to t-MN.

A Retrospective Study of Clinical Profile of Patients with Autoimmune Inner Ear Disease.

Bilateral sensorineural hearing loss can be a very distressing symptom and can affect the efficiency of a person and one's quality of life. Conditions causing bilateral hearing loss are very few and autoimmune aetiology is one of them. Autoimmune ear disease is characterised by bilateral, mostly fluctuating audiovestibular symptoms and symptoms which respond to steroids. Diagnosis of AIED presents a unique challenge to clinicians due to the lack of standardized diagnostic criteria or reliable pathognomonic tests. The purpose of the study is to evaluate the patients who fit into criteria of autoimmune inner ear disease and understand the clinical features and response to medications for the same. A retrospective chart review of patients presenting with rapidly progressive bilateral hearing loss was done. The clinical presentation including detailed history and examination findings along with the blood investigation reports and audiograms were recorded in a tabular form. The study included 6 patients - 3 male and 3 female patients. Age of the patients at onset of hearing loss varied between 24-35 years. 3 of 6 patients presented with primary autoimmune ear disease and other 3 had hearing loss secondary to systemic autoimmune disease. All patients were treated with systemic steroids, but however showed a varied response. Patients with primary AIED were administered inner ear steroid therapy as well. AIED is thus a diagnosis of exclusion done with high index of suspicion. Patients with bilateral progressive sensorineural hearing loss should be evaluated for autoimmune etiology. Oral steroids with intratympanic steroids are currently the mainstay of treatment for AIED. Guarded prognosis of hearing improvement is noted in these patients. Hence, emphasis should be placed on early hearing rehabilitation for better quality of life.

Pathophysiological features of chronic IgE-mediated rhinosinusitis of bacterial etiology

Chronic rhinosinusitis (CRS) is a disease caused by inflammation of the paranasal sinuses and its mucous membrane lasting for more than 4 weeks continuously. The aim of our study was to examine the main pathophysiological features of chronic IgE-mediated rhinosinusitis of bacterial etiology according to publications in the Russian Federation and in the world. A search was made through English- and Russian-language literature sources using the following databases: PubMed, MedLine, Web of Science, Russian Science Citation Index, Springer, Scopus, Scientific Research, Google Scholar, Crossref, eLibrary. The epidemiological features of CRS in the Russian Federation, bacterial pathogens and pathophysiological characteristics of CRS were analyzed. A 2-fold increase in the prevalence of CRS was registered over the past 20 years. Prevalence of the disease increases at longer age ranges. Chronic rhinosinusitis ranks first among all chronic diseases in the field of otorhinolaryngology. Allergic rhinitis, asthma, bronchiectasia, immunodeficiencies, cystic fibrosis, primary ciliary dyskinesia and autoimmune diseases are associated with CRS. The most common bacterial pathogens are S. aureus, Staphylococcus epidermidis and Propionibacterium acnes, Prevotella, Streptococcus and Veillonella, and some Gram-negative bacteria, e.g., Pseudomonas aeruginosa (P. aeruginosa), Proteus mirabilis and Klebsiella pneumoniae. Staphylococcus aureus (S. aureus) is involved in pathogenesis of nasal polyps. The colonizing bacteria may contribute to pathogenesis of CRS through the formation of biofilms. Alterations in the sino-nasal microbiome may also contribute to the development of CRS. An association of the CRS and CFTR gene mutations plays a significant role in the pathogenesis of chronic rhinosinusitis. An “immune barrier hypothesis” has been proposed as potential mechanism of CRS. Reduced expression of SPINK5, impaired STAT3 signaling, and T2R38 bitter taste receptor polymorphism have been identified in the pathogenesis of CRS. The T2R38 gene stimulates epithelial cells to produce nitrous oxide with a bactericidal effect, promotes mucociliary elimination of pathogens and prevention of upper respiratory tract infections, the polymorphism of this gene predisposes patients to gram-negative infectious diseases, and therefore is a risk factor for the development of CRS. In addition, antibody deficiency is the most common primary immunodeficiency associated with CRS.Hence, the pathogenesis of chronic IgE-mediated rhinosinusitis of bacterial etiology is associated with defects in innate immunity and mucociliary clearance, influence of the sinonasal microbiome, allergies, and genetic factors. A comprehensive assessment of these factors is necessary for the development of new preventive and therapeutic options for the correction of CRS.

Postinfantile Giant Cell Hepatitis in Native and Allograft Livers: A Multi-Institutional Clinicopathologic Study of 70 Cases

Postinfantile giant cell hepatitis (PIGCH) is a rare hepatitis pattern in adults with variable etiologies and clinical outcomes. We conducted a multi-institutional retrospective study to define the clinicopathologic characteristics of patients with PIGCH. A total of 70 PIGCH cases were identified and reviewed for pathological features, including fibrosis, cholestasis, inflammation, steatosis, necrosis, and apoptosis, as well as the distribution of giant cells and the maximum number of giant cells per high-power field. Demographic and clinical data, including age, sex, laboratory results, etiologies, and follow-up results, were recorded. Among the 70 cases, 40% (28/70) were associated with autoimmune liver diseases, followed by 9 (13%) with unknown etiology, 8 (11%) with viral infection, 5 (7%) with medications, 5 with combined etiologies, and 4 (6%) with malignancies (mostly chronic lymphocytic leukemia). Notably, another 16% were de novo PIGCH in liver allografts, most of which occurred after a rejection event. During follow-up, 26 (37%) patients died of the disease and 44 (63%) were alive. Deceased patients were characterized by older age (mean age, 54.9 vs 45.5 years; P = .02), higher alkaline phosphatase level (mean value, 253.3U/L vs 166.3 U/L; P = .03), higher fibrosis stage (stage 3-4 vs stage 0-2, 57.7% vs 29.6%; P = .03), being more likely to have de novo PIGCH after transplantation (23.1% vs 11.4%; P = .04), and being less likely to have primary autoimmune liver disease etiology (26.9% vs 47.7%; P = .04). These results indicate that PIGCH is a rare pattern of liver injury associated with different etiologies and variable clinical outcomes. Autoimmune liver disease with PIGCH is associated with better survival, whereas de novo PIGCH in allografts is associated with poorer survival. Older age, higher alkaline phosphatase level, and advanced fibrosis are adverse prognostic factors.

Primary biliary cholangitis: primary autoimmune disease or primary secretory defect

ABSTRACT Introduction Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by the immune-mediated destruction of small and medium intrahepatic bile ducts, involving predominantly females. PBC has long been described as an autoimmune liver disease, also because it is very often associated with many autoimmune conditions. More recently, another pathogenic mechanism exploring the damage of cholangiocytes has been hypothesized, i.e. a defect in the biliary umbrella which is physiologically responsible for the exchange of the ions Cl− and HCO3 − and maintains the integrity of glycocalyx. To provide a state-of-the-art analysis of this topic, a systematic review of literature in PubMed, Scopus, and Science Direct was conducted (inclusive dates: 1986–2023). Area covered Although the etiology remains unknown, pathogenesis consists of a complex immune-mediated process resulting from a genetic susceptibility. PBC can be triggered by an immune-mediated response to an autoantigen, which leads to a progressive destruction of bile ducts and eventually to a progressive fibrosis with cirrhosis. The defect in the ‘bicarbonate umbrella’ acts as a protection against the toxic hydrophobic bile acids, leading to a toxic composition of bile. Expert opinion This review offers a summary of the current knowledge about the pathogenesis of PBC, indicating that this is probably based on the mutual relationship between the immune insult and the unbalanced secretory mechanisms.

Development of monoclonal antibodies and antigens as liquid biopsy reagents for IgA nephropathy

Abstract IgA nephropathy (IgAN) is the most common primary autoimmune glomerular disorder across the world. A renal biopsy examination is absolutely required for final diagnosis. In particular, IgAN has been categorized as an autoimmune disease that features IgA-ICs formed by galactose-deficient (Gd)-IgA1 (autoantigen) and corresponding IgG anti-Gd-IgA1 (autoantibody). Therefore, it is clinically warranted to develop a liquid kidney biopsy for non-invasive or only minimally invasive approaches for early diagnosis of IgAN and to ease monitoring the evolution of the disease. We have recently developed three monoclonal antibodies namely EASON1, EASON2, and EASON3, and each of them shows high discriminative rate in differentiating IgAN patients and healthy control subjects by doing ELISA-based analyses to determine serum Gd-IgA1 levels (Provisional patent - T2392-US, USAentitled “Production of IgG monoclonal antibody series anti-galactose deficient IgA1 and IgA1 bearing O-linked glycans; Provisional patent - 63/119,215, USAentitled “Development of a series of IgM monoclonal antibodies as non-invasive diagnostic reagents for IgA nephropathy; a regular patent application under review). Moreover, we have successfully developed 62 human hybridoma cell lines that produce Gd-IgA1, each of which will be useful in designing tests for the detection of serum IgG autoantibodies against Gd-IgA1 levels (Provisional patent - T2392-US, USA). In conclusion, both the 3 mouse monoclonal antibodies and 62 human Gd-IgA1-producing hybridoma cell lines may be further developed as promising diagnostic reagents for a liquid kidney biopsy for IgAN, allowing for early, rapid, and non-invasive tests for the renal disease. Supported by grants from Ministry of Science and Technology, Taiwan (MOST 108-2321-B-016-002, 109-2314-B-016 -034 -MY3)

Adolescents and Young Adults With Anti-N-methyl-D-aspartate Receptor Encephalitis With Excited Catatonia: Literature Review and 2Illustrative Cases.

Catatonia is a complex neuropsychiatric syndrome that can be associated with several underlying etiologies including primary psychiatric and autoimmune disorders. Anti-N-methyl-D-aspartate receptor encephalitis is an autoimmune disorder typically characterized by seizures, movement abnormalities, and behavioral changes. Anti-N-methyl-D-aspartate can present with complex neuropsychiatric symptoms including catatonia which can be challenging for clinicians to identify as excited catatonia can mimic delirium and psychiatric disorders such as psychosis and mania. To identify and present cases of anti-N-methyl-D-aspartate receptor encephalitis where excited catatonia is the presenting symptom. We present 2 case studies of agitation and disinhibition in an adolescent and young adult that were ultimately found to be secondary to autoimmune receptor encephalitis, in both cases, confirmed by cerebrospinal fluid analysis to be due to anti-N-methyl-D-aspartate receptor antibodies. Excited catatonia was suspected and initially treated with immunological therapy and high doses of lorazepam. As the severity of catatonia progressed with limited improvement with lorazepam, both cases were ultimately effectively treated with electroconvulsive therapy. Excited catatonia should be considered with presentations of bizarre behavior, agitation, disinhibition, and other psychotic symptoms in patients with no prior psychiatric history. Although the primary treatment for catatonia associated with anti-N-methyl-D-aspartate receptor encephalitis is immunomodulatory therapy paired with benzodiazepines, electroconvulsive therapy has been shown to be an effective and safe adjuvant treatment that is especially useful for management of excited catatonia.

Checkpoint Inhibitor-Associated Scleroderma and Scleroderma Mimics.

Immune checkpoint inhibitors (ICI) are the standard of care for various malignancies and have been associated with a wide spectrum of complications that are phenotypically akin to primary autoimmune diseases. While the literature on these toxicities is growing, there is a paucity of data regarding ICI-associated scleroderma which can carry significant morbidity and limit the ability to continue effective ICI therapy. Our review aimed to analyze the current literature on ICI-associated systemic scleroderma (ICI-SSc) and key scleroderma mimics. Cases of ICI-SSc had notable differences from primary SSc, such as fewer vascular features and less seropositivity (such as scleroderma-specific antibodies and antinuclear antibodies). We found that patients with a diagnosis of SSc prior to the start of ICI can also experience flares of pre-existing disease after ICI treatment used for their cancer. Regarding scleroderma mimics, several cases of ICI-eosinophilic fasciitis have also been described with variable clinical presentations and courses. We found no cases of scleroderma mimics: ICI-scleromyxedema or ICI-scleroedema. There is a critical need for multi-institutional efforts to collaborate on developing a patient database and conducting robust, prospective research on ICI-scleroderma. This will ultimately facilitate more effective clinical evaluations and management for ICI-scleroderma.

Characterization of IVIG infusion adverse reactions reported at a tertiary care immunology infusion center

IVIG is utilized in the treatment of various medical conditions including primary immunodeficiencies and autoimmune disorders. Anaphylaxis is rare and can be seen in IgA-deficient patients, although reactions rates and associated risks are poorly understood. We aim to characterize IVIG reaction severity and associated clinical factors in this cohort.

Association Between Rheumatic Autoantibodies and Immune-Related Adverse Events.

Side effects of immune checkpoint inhibitors (ICIs), called immune-related adverse events (irAEs), closely resemble primary autoimmune or rheumatic diseases. We aimed to understand the clinical utility of rheumatic autoantibodies (rhAbs) for diagnosing irAEs. Patients without pre-existing autoimmune disease (pAID) who had cancer treated with ICI(s) treatment from 1/1/2011 to 12/21/2020 and a rhAb checked were retrospectively identified. Logistic regression assessed associations between autoantibodies and irAEs, cancer outcome, and survival. Specificity, sensitivity, and positive/negative predictive values (PPV, NPV) were estimated for key rhAbs and ICI-arthritis. Kaplan-Meier analyzed objective response rate (ORR) and overall survival (OS). A total of 2662 patients were treated with≥1 ICIs. One hundred and thirty-five without pAID had ≥ 1 rhAb tested. Of which 70/135(52%) were female; median age at cancer diagnosis was 62 years with most common cancers: melanoma (23%) or non-small cell lung cancer (21%), 96/135 (75%) were anti-PD1/PDL1 treated. Eighty had a rhAb ordered before ICI, 96 after ICI, and 12 before and after. Eighty-two (61%) experienced an irAE, 33 (24%) with rheumatic-irAE. Pre-ICI RF showed significant association with rheumatic-irAEs (OR = 25, 95% CI, 1.52-410.86, P = .024). Pre- and post-ICI RF yielded high specificity for ICI-arthritis (93% and 78%), as did pre- and post-ICI CCP (100% and 91%). Pre-ICI RF carried 93% NPV and pre-ICI CCP had 89% PPV for ICI-arthritis. No variables were significantly correlated with ORR. Any-type irAE, rheumatic-irAE and ICI-arthritis were all associated with better OS (P = .000, P = .028, P = .019). Pre-ICI RF was associated with higher odds of rheumatic-irAEs. IrAEs had better OS; therefore, clinical contextualization for rhAbs is critical to prevent unnecessary withholding of lifesaving ICI for fear of irAEs.