Absence Of Autoantibodies Research Articles

Biologics or Janus Kinase Inhibitors in Rheumatoid Arthritis Patients Who are Insufficient Responders to Conventional Anti-Rheumatic Drugs.

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can induce progressive disability if not properly treated early. Over the last 20 years, the improvement of knowledge on the pathogenesis of the disease has made available several drugs targeting key elements of the pathogenetic process, which now represent the preferred treatment option after the failure of first-line therapy with conventional drugs such as methotrexate (MTX). To this category of targeted drugs belong anti-cytokine or cell-targeted biological agents and more recently also Janus kinase inhibitors (JAKis). In the absence to date of specific biomarkers to guide the therapeutic choice in the context of true precision medicine, the choice of the first targeted drug after MTX failure is guided by treatment cost (especially after the marketing of biosimilar products) and by the clinical characteristics of the patient (age, sex, comorbidities and compliance) and the disease (presence or absence of autoantibodies and systemic or extra-articular manifestations), which may influence the efficacy and safety profile of the available products. This viewpoint focuses on the decision-making process underlying the personalized approach to RA therapy and will analyse the evidence in the literature supporting the choice of individual products and in particular the differential choice between biological drugs and JAKis.

Amyopathic dermatomyositis may be on the spectrum of autoinflammatory disease: A clinical review.

Systemic autoinflammatory diseases (SAIDs) are distinct from autoimmune diseases. The former primarily results from abnormal innate immune response and genetic testing is crucial for disease diagnosis. Similar cutaneous involvement is a main feature for both SAID and dermatomyositis (DM), so they can be confused with each other. A literature search of PubMed and MEDLINE was conducted for relevant articles. The similarities and differences between these two types of diseases were analyzed. We found phenotypic similarities between these two types of disorders. Accumulating data supports a major role of the innate immune system and a similar cytokine profile. Molecular testing using an autoinflammatory disease gene panel may help identify SAID patients from the DM population and may offer therapeutic benefit using interleukin-1 (IL-1) inhibitors. A subset of DM, notably amyopathic dermatomyositis in the absence of autoantibodies may be on the spectrum of autoinflammatory disease.

Synovial Tissue Insights into Heterogeneity of Rheumatoid Arthritis.

Rheumatoid arthritis is one of the most common rheumatic and autoimmune diseases. While it can affect many different organ systems, RA primarily involves inflammation in the synovium, the tissue that lines joints. Patients with RA exhibit significant clinical heterogeneity in terms of presence or absence of autoantibodies, degree of permanent deformities, and most importantly, treatment response. These clinical characteristics point to heterogeneity in the cellular and molecular pathogenesis of RA, an area that several recent studies have begun to address. Single-cell RNA-sequencing initiatives and deeper focused studies have revealed several RA-associated cell populations in synovial tissues, including peripheral helper T cells, autoimmunity-associated B cells (ABCs), and NOTCH3+ sublining fibroblasts. Recent large transcriptional studies and translational clinical trials present frameworks to capture cellular and molecular heterogeneity in RA synovium. Technological developments, such as spatial transcriptomics and machine learning, promise to further elucidate the different types of RA synovitis and the biological mechanisms that characterize them, key elements of precision medicine to optimize patient care and outcomes in RA. This review recaps the findings of those recent studies and puts our current knowledge and future challenges into scientific and clinical perspective.

Clinical Impact of Pre-Existing Autoantibodies in Patients With SCLC Treated With Immune Checkpoint Inhibitor: A Multicenter Prospective Observational Study

IntroductionAlthough pretreatment autoantibodies have been associated with immune-related adverse events (irAEs) and immune checkpoint inhibitor treatment efficacy in some types of cancer, their importance has not been evaluated in patients with SCLC. MethodsA multicenter prospective observational study was conducted on a total of 52 patients with extensive-disease SCLC who received immune checkpoint inhibitors in combination with chemotherapy as the first-line treatment at either of the six participating centers in Japan. Pretreatment serum samples were collected and analyzed for autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid). Moreover, 12 antineuronal antibodies (AMPH, CV2, PNMA2, Ri, Yo, Hu, Recoverin, SOX1, Titin, Zic4, GAD65, and Tr) were analyzed using immunoblot assays. The primary end point was the incidence of irAEs with or without autoantibodies. The secondary end points were progression-free survival (PFS) and overall survival (OS) on the basis of the presence or absence of autoantibodies. ResultsPFS and OS were 4.4 and 25.3 months, respectively. Autoantibodies (rheumatoid factor, antinuclear antibodies, and antithyroid antibodies) were detected in 29 patients (56%). In total, irAEs were observed in 18 patients (35%); irAE incidence was 48% in the autoantibody-positive group and 17% in the autoantibody-negative group (p = 0.039). There was no difference in PFS or OS between patients with and without autoantibodies (4.4 mo versus 4.6 mo, p = 0.36; 15.3 mo versus 18.2 mo, p = 0.36). Antineuronal antibodies were detected in 16 patients (31%). However, the development of neurologic irAEs was not observed in both groups. ConclusionsVigilance is required against the development of irAEs in pretreatment antibody-positive patients.

Differential regulation of the interferon response in systemic lupus erythematosus distinguishes patients of Asian ancestry

ObjectivesType I interferon (IFN) plays a role in the pathogenesis of systemic lupus erythematosus (SLE), but insufficient attention has been directed to the differences in IFN responses between ancestral populations....

Monogenic autoinflammatory disease-associated cardiac damage.

Autoinflammatory diseases (AIDs) constitute several disorders that are characterized by the presence of recurrent episodes of unprovoked inflammation due to dysregulated innate immune system in the absence of autoantibodies or infections. Most of them have a strong genetic background, with mutations in single genes involved in inflammation referred to monogenic AIDs. In this article, we will review the cardiac manifestations in various monogenic AIDs. Various cardiac manifestations can be seen in various monogenic AIDs, including pericarditis, valvular diseases, coronary diseases, cardiomyopathies, and pulmonary hypertension, especially in Familial Mediterranean fever (FMF). Monogenic AIDs can manifest a variety of cardiac lesions, the most common of which is pericardial effusion, which may be local pericardial inflammation secondary to systemic inflammatory responses. While, the pathogenesis and incidence are still unclear. More research is still needed to explore the relationship between monogenic AIDs and cardiac damage for better understanding these diseases.

Autoimmune Encephalitis: A Case Report from the Neurology Department of the Doctor Joseph Guislain Neuropsychiatric Centre in Lubumbashi and Review of the Literature

The term encephalitis refers to the inflammation of the parenchyma of the central nervous system, located in the cranial cavity. We report the case of a 17-year-old female patient with a history of tuberculous gonarthritis, who was admitted for convulsive seizures complicated by status epilepticus. Medical imaging did not reveal any brain lesions and biology revealed an elevated PCT. Through this case, we underline the risk of diagnostic errancy and thus of delay in the treatment of autoimmune encephalitis which, in 70% of cases, is effective. It also seemed important to us to insist on the fact that the absence of autoantibodies does not invalidate the diagnosis of autoimmune encephalitis, especially in developing countries where the technical platform to search for them is lacking both in terms of equipment and human resources. Finally, it should be noted that new autoantibodies are found almost every year by teams in developed countries. Thus, in front of any acute or sub-acute neurological picture not explained, it is necessary to think about autoimmune encephalitis and to start an immunomodulatory treatment, which guarantees the cure or the substantial improvement in most cases.

Side Effects of Cancer Immunotherapies: Dermatologic and Rheumatologic Toxicities.

Dermatologic and rheumatologic toxicities are frequent adverse events during treatment with immune checkpoint inhibitors in oncology. Timely identification of these events and the referral to the oncologist or dermatologist are important in daily practice, such an organ damage involvements can be severe and sometimes life-threatening. The diagnosis and management of cutaneous toxicities, such as maculopapular rash and bullous dermatitis in particular, must be based on the body surface affected by skin lesions. Corticosteroids are basic treatment in moderate to severe cases. Rheumatologic toxicities are rarer and more heterogeneous, and they are often underestimated. They can occur in the absence of autoantibodies, and myositis can be life-threatening.

S3254 A CCase of Seronegative Autoimmune Hepatitis During Pregnancy

Introduction: Autoimmune hepatitis (AIH) is a rare disease that usually affects women at reproductive age and is associated with an increased risk of adverse maternal and fetal outcomes. Diagnosis of AIH during pregnancy, particularly in absence of autoantibodies, poses a challenge for clinicians. We present the case of a patient with new-onset seronegative AIH during pregnancy. Case Description/Methods: A 29-year-old Hispanic female, G2P101 at 19 weeks presents complaining of yellowing of her skin and eyes for 1 week, associated with nocturnal pruritus. Physical exam showed generalized jaundice and scleral icterus. Laboratory investigations showed significantly elevated AST (452 U/L), ALT (165 U/L), alkaline phosphatase (182 U/L), hyperbilirubinemia, elevated bile acids, and elevated INR. Hepatitis panel and autoimmune work up, were negative. Abdominal ultrasound was normal. MRCP showed nonspecific hepatic parenchyma heterogeneity on T2 signal suggestive of infiltrative process. A diagnosis of intrahepatic cholestasis of pregnancy (IHCP) with atypical presentation was made, and patient was started on ursodeoxycholic acid, which improved her symptoms. At day 15, she developed lower abdominal and vaginal bleeding, caused by placental abruption. The fetus was deemed non-viable and an emergent C-section was performed. Patient was eventually discharged with outpatient GI follow up. At follow up, recurrent rise in liver function tests were noted, and repeat autoimmune work up showed elevated IgG (3600). Liver biopsy was performed, which showed active chronic inflammation with lymphoplasmacytic infiltrates, moderate interface hepatitis with ballooning degeneration and emperipolesis, and moderate portal fibrosis with bridging fibrosis, suggestive of autoimmune hepatitis. Patient was subsequently started on steroid therapy, with appropriate response as symptoms progressively resolved and liver function tests normalized. Discussion: AIH is a rare condition that can manifest with antepartum and postpartum flares, having negative consequences to fetal and maternal outcomes, hence the importance of controlling AIH activity throughout pregnancy and in the postpartum period. Liver biopsy should be considered in cases of antibody negative AIH, however there is paucity of data regarding its safety in pregnancy. We present the rare case of an initially seronegative AIH flare during pregnancy, possibly attributed to the potential physiologic effects of pregnancy in the regulation of immune system mechanisms.

Genetic and clinical evaluation of congenital myasthenic syndromes with long-term follow-up: experience of a tertiary center in Turkey.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders affecting the safety factor which required for neuromuscular transmission. Here we reported our experience in children with CMS. We retrospectively collected the data of 18 patients with CMS who were examined in our outpatient clinic between January 2021 and January 2022. The diagnosis of CMS was based on the presence of clinical symptoms such as abnormal fatigability and weakness, absence of autoantibodies against acetylcholine receptor and muscle-specific kinase, electromyographic evidence of neuromuscular junction defect, molecular genetic confirmation, and response to treatment. The most common mutations were in the acetylcholine receptor (CHRNE) gene (8/18) and choline acetyltransferase (ChAT) (2/18) gene. Despite targeted gene sequencing and whole exome sequencing (WES) were underwent, we couldn't detect a genetic mutation in three out of patients. The most commonly determined initial finding was eyelid ptosis, followed by fatigable weakness, and respiratory insufficiency. Although the most commonly used drug was pyridostigmine, we have experienced that caution should be exercised as it may worsen some types of CMS. We reported in detail the phenotypic features of very rare gene mutations associated with CMS and our experience in the treatment of this disease. Although CMS are rare genetic disorder, the prognosis can be very promising with appropriate treatment in most CMS subtypes.

Intracellular Sensing of DNA in Autoinflammation and Autoimmunity.

Evidence has shown that DNA is a pathogen-associated molecular pattern, posing a unique challenge in the discrimination between endogenous and foreign DNA. This challenge is highlighted by certain autoinflammatory diseases that arise from monogenic mutations and result in periodic flares of inflammation, typically in the absence of autoantibodies or antigen-specific T lymphocytes. Several autoinflammatory diseases arise due to mutations in genes that normally prevent the accrual of endogenous DNA or are due to mutations that cause activation of intracellular DNA-sensing pathway components. Evidence from genetically modified murine models further support an ability of endogenous DNA and DNA sensing to drive disease pathogenesis, prompting the question of whether endogenous DNA can also induce inflammation in human autoimmune diseases. In this review, we discuss the current understanding of intracellular DNA sensing and downstream signaling pathways as they pertain to autoinflammatory disease, including the development of monogenic disorders such as Stimulator of interferon genes-associated vasculopathy with onset in infancy and Aicardi-Goutières syndrome. In addition, we discuss systemic rheumatic diseases, including certain forms of systemic lupus erythematosus, familial chilblain lupus, and other diseases with established links to intracellular DNA-sensing pathways, and highlight the lessons learned from these examples as they apply to the development of therapies targeting these pathways.

When All Is Not as It Seems: Recurrent Fever and New-onset Joint Pain in a 17-Month-old Girl.

When All Is Not as It Seems: Recurrent Fever and New-onset Joint Pain in a 17-Month-old Girl.

A Narrative Literature Review Comparing the Key Features of Musculoskeletal Involvement in Rheumatoid Arthritis and Systemic Lupus Erythematosus.

Although the clinical approach to the management of musculoskeletal manifestations in systemic lupus erythematosus (SLE) is often similar to that of rheumatoid arthritis (RA), there are distinct differences in immunopathogenesis, structural and imaging phenotypes and therapeutic evidence. Additionally, there are few published comparisons of these diseases. The objective of this narrative literature review is to compare the immunopathogenesis, structural features, magnetic resonance imaging (MRI) and musculoskeletal ultrasound (MSUS) studies and management of joint manifestations in RA and SLE. We highlight the key similarities and differences between the two diseases. Overall, the literature evaluated indicates that synovitis and radiographical progression are the key features in RA, while inflammation without swelling, tendinitis and tenosynovitis are more prominent features in SLE. In addition, the importance of defining patients with RA by the presence or absence of autoantibodies and categorizing patients with SLE by synovitis detected by musculoskeletal ultrasound and by structural phenotype (non-deforming, non-erosive arthritis, Jaccoud’s arthropathy and ‘Rhupus’) with respect to joint manifestations will also be discussed. An increased understanding of the joint manifestations in RA and SLE may inform evidence-based clinical decisions for both diseases.

Outcomes of Empirical Treatment With Intravenous Immunoglobulin G Combined With Low-Dose Aspirin in Women With Unexplained Recurrent Pregnancy Loss.

BackgroundTo assess the clinical efficacy of intravenous immunoglobulin G (IVIG) administration combined with low-dose aspirin in women with unexplained recurrent pregnancy loss (RPL).MethodsWe retrospectively analyzed the medical records of patients who had been diagnosed with unexplained RPL and treated with IVIG and low-dose aspirin between January 2000 and March 2020 at Asan Medical Center. We analyzed pregnancy outcomes and their association with the percentage of natural killer (NK) cells.ResultsThe study analyzed a total of 93 patients and 113 natural and assisted reproductive technology pregnancy cycles. The live birth rate per cycle was 73.5% (83/113), and the term delivery rate was 86.7% (72/83). The live birth rate was high regardless of the type of RPL, method of pregnancy, timing of IVIG treatment, and presence or absence of autoantibodies. In addition, the live birth rate was significantly higher in patients who received IVIG more than once, compared with patients who received IVIG only once (77.8% vs. 42.9%, P = 0.006). There was no significant association between the NK cell counts and live birth rate (65.5% in the group with NK cell < 12%, and 69.7% in that with NK cell ≥ 12%, P = 0.725). Among all patients, 87.6% had no complications, and there were no congenital malformation among newborn babies.ConclusionIVIG combined with low-dose aspirin treatment showed favorable pregnancy outcomes regardless of the patient’s NK cell counts (%).

Biologic disease-modifying antirheumatic drugs in the treatment of major monogenic autoinflammatory diseases: literature review and clinical observation

Autoinflammatory diseases (AIDs) are a heterogeneous group of rare genetically determined conditions, the main manifestations of which are episodes of fever in combination with other signs of systemic inflammation: skin rashes, musculoskeletal and neurological disorders, damage to the organs of vision, hearing, etc., as well as acute phase markers and the absence of autoantibodies. The use of biological therapy, especially inhibitors of interleukin 1 (iIL1), in most common monogenic AIDs (mAID) – FMF, TRAPS, HIDS/MKD, CAPS – has shown its high efficiency and led to significant progress in the treatment of these patients. Currently, iIL1 are the first-line drugs for mAIDs therapy, primarily CAPS. In the case of their ineffectiveness or intolerance in certain situations, other biologic disease-modifying antirheumatic drugs can also be used – inhibitors of tumor necrosis factor α and iIL6, but this issue needs further investigation. The article describes a patient with mAID, in whom the diagnosis was made more than 40 years after the onset; administration of targeted therapy even in the late stages of the disease led to a significant improvement in many symptoms and quality of life.

Identification of potential autoantigens in anti-CCP-positive and anti-CCP-negative rheumatoid arthritis using citrulline-specific protein arrays

The presence or absence of autoantibodies against citrullinated proteins (ACPAs) distinguishes two main groups of rheumatoid arthritis (RA) patients with different etiologies, prognoses, disease severities, and, presumably, disease pathogenesis. The heterogeneous responses of RA patients to various biologics, even among ACPA-positive patients, emphasize the need for further stratification of the patients. We used high-density protein array technology for fingerprinting of ACPA reactivity. Identification of the proteome recognized by ACPAs may be a step to stratify RA patients according to immune reactivity. Pooled plasma samples from 10 anti-CCP-negative and 15 anti-CCP-positive RA patients were assessed for ACPA content using a modified protein microarray containing 1631 different natively folded proteins citrullinated in situ by protein arginine deiminases (PADs) 2 and PAD4. IgG antibodies from anti-CCP-positive RA plasma showed high-intensity binding to 87 proteins citrullinated by PAD2 and 99 proteins citrullinated by PAD4 without binding significantly to the corresponding native proteins. Curiously, the binding of IgG antibodies in anti-CCP-negative plasma was also enhanced by PAD2- and PAD4-mediated citrullination of 29 and 26 proteins, respectively. For only four proteins, significantly more ACPA binding occurred after citrullination with PAD2 compared to citrullination with PAD4, while the opposite was true for one protein. We demonstrate that PAD2 and PAD4 are equally efficient in generating citrullinated autoantigens recognized by ACPAs. Patterns of proteins recognized by ACPAs may serve as a future diagnostic tool for further subtyping of RA patients.

The Epidemiology and Genetic Analysis of Children With Idiopathic Type 1 Diabetes in the State of Qatar.

ContextIdiopathic type 1 diabetes is characterized by the absence of autoantibodies and the underlying mechanisms are not clear.ObjectiveWe aimed to study the epidemiology, describe the clinical characteristics, and report results of genetic studies in pediatric patients with idiopathic type 1 diabetes.MethodsThis was a prospective study of type 1 diabetes patients attending Sidra Medicine from 2018 to 2020. Autoantibodies (GAD65, IAA, IA-2A, and ZnT8) were measured and genetic testing was undertaken in patients negative for autoantibodies to rule out monogenic diabetes. Demographic and clinical data of patients with idiopathic type 1 diabetes were compared with patients with autoimmune type 1 diabetes.ResultsOf 1157 patients with type 1 diabetes, 63 were antibody-negative. Upon genome sequencing, 4 had maturity onset diabetes of the young (MODY), 2 had Wolfram syndrome, 1 had H syndrome, and 3 had variants of uncertain significance in MODY genes; 53 patients had idiopathic type 1 diabetes. The most common age of diagnosis was 10 to 14 years. C-peptide level was low but detectable in 30 patients (56.6%) and normal in 23 patients (43.4%) The average body mass index was in the normal range and 33% of the patients had a history of diabetic ketoacidosis (DKA).ConclusionFour percent of the children had idiopathic type 1 diabetes. There were statistically significant differences in the C-peptide level and insulin requirement between the 2 groups. DKA was less common in the idiopathic group. Mutations in MODY genes suggest the importance of autoantibody testing and genetic screening for known causes of monogenic diabetes in idiopathic type 1 diabetes. The mechanism of idiopathic type 1 diabetes is unknown but could be due to defects in antibody production or due to autoantibodies that are not yet detectable or discovered.

Shared Pathogenetic Features Between Common Variable Immunodeficiency and Sjögren's Syndrome: Clues for a Personalized Medicine.

Common variable immunodeficiency disorders (CVID) are a group of rare diseases of the immune system and the most common symptomatic primary antibody deficiency in adults. The “variable” aspect of CVID refers to the approximately half of the patients who develop non-infective complications, mainly autoimmune features, in particular organ specific autoimmune diseases including thyroiditis, and cytopenias. Among these associated conditions, the incidence of lymphoma, including mucosal associated lymphoid tissue (MALT) type, is increased. Although these associated autoimmune disorders in CVID are generally attributed to Systemic Lupus Erythematosus (SLE), we propose that Sjogren’s syndrome (SS) is perhaps a better candidate for the associated disease. SS is an autoimmune disorder characterized by the lymphocytic infiltrates of lacrimal and salivary glands, leading to dryness of the eyes and mouth. Thus, it is a lymphocyte aggressive disorder, in contrast to SLE where pathology is generally attributed to auto-antibody and complement activation. Although systemic lupus erythematosus (SLE) shares these features with SS, a much higher frequency of MALT lymphoma distinguishes SS from SLE. Also, the higher frequency of germ line encoded paraproteins such as the monoclonal rheumatoid factor found in SS patients would be more consistent with the failure of B-cell VDJ switching found in CVID; and in contrast to the hypermutation that characterizes SLE autoantibodies. Thus, we suggest that SS may fit as a better “autoimmune” association with CVID. Examining the common underlying biologic mechanisms that promote lymphoid infiltration by dysregulated lymphocytes and lymphoma in CVID may provide new avenues for treatment in both the diseases. Since the diagnosis of SLE or rheumatoid arthritis is usually based on specific autoantibodies, the associated autoimmune features of CVID patients may not be recognized in the absence of autoantibodies.

The Acute Onset of Autoimmune Hepatitis During Pregnancy in the Absence of Hypergammaglobulinemia and Autoantibodies

The onset of autoimmune hepatitis (AIH) during pregnancy is rare and often poses a diagnostic challenge. A 29-year-old Japanese woman experienced epigastric pain and nausea during the third trimester of her third pregnancy. Three days after the symptom onset, an emergency Caesarean section was performed because of suspected acute fatty liver of pregnancy; however, the patient's liver dysfunction worsened afterward. Despite normal serum IgG concentration and absence of autoantibodies, biopsy-proven severe hepatitis with centrilobular zonal necrosis and good biochemical response to corticosteroids led to a diagnosis of AIH. Therefore, AIH should be included in the differential diagnosis of liver dysfunction during pregnancy.

DMARD-free remission as novel treatment target in rheumatoid arthritis: A systematic literature review of achievability and sustainability

ObjectivesAlthough current treatment guidelines for rheumatoid arthritis (RA) suggest tapering disease-modifying anti-rheumatic drugs (DMARDs), it is unclear whether DMARD-free remission (DFR) is an achievable and sustainable outcome. Therefore, we systematically...