SnapShot: Jak-STAT Signaling II.

The JAK-STAT pathway is an evolutionarily conserved signal transduction paradigm, providing mechanisms for rapid receptor-to-nucleus communication and transcription control. Discoveries in this field provided insights into primary immunodeficiencies, inherited autoimmune and autoinflammatory diseases, and hematologic and oncologic disorders, giving rise to a new class of drugs, JAK inhibitors (or Jakinibs).

Enhancer RNAs are an important regulatory layer of the epigenome.

Noncoding RNAs (ncRNAs) direct a remarkable number of diverse functions in development and disease through their regulation of transcription, RNA processing and translation. Leading the charge in the RNA revolution is a class of ncRNAs that are synthesized at active enhancers, called enhancer RNAs (eRNAs). Here, we review recent insights into the biogenesis of eRNAs and the mechanisms underlying their multifaceted functions and consider how these findings could inform future investigations into enhancer transcription and eRNA function.

Hydroxychloroquine in Patients with Rheumatic Disease Complicated by COVID-19: Clarifying Target Exposures and the Need for Clinical Trials.

Objective: To characterize hydroxychloroquine (HCQ) exposure in patients with rheumatic disease receiving longterm HCQ compared to target concentrations with reported antiviral activity against the coronavirus disease 2019 caused by SARS-CoV-2 (COVID-19).

Methods: We evaluated total HCQ concentrations in serum and plasma from published literature values, frozen serum samples from a pediatric systemic lupus erythematosus trial, and simulated concentrations using a published pharmacokinetic model during pregnancy. For each source, we compared observed or predicted HCQ concentrations to target concentrations with reported antiviral activity against SARS-CoV-2.

Utility of the Brief Illness Perception Questionnaire to Monitor Patient Beliefs in Systemic Vasculitis.

Objective: To assess the validity and clinical utility of the Brief Illness Perception Questionnaire (BIPQ) to measure illness perceptions in multiple forms of vasculitis.

Methods: Patients with giant cell arteritis (GCA), Takayasu arteritis (TA), antineutrophil cytoplasmic antibody-associated vasculitis (AAV), and relapsing polychondritis (RP) were recruited into a prospective, observational cohort. Patients independently completed the BIPQ, Multidimensional Fatigue Inventory (MFI), Medical Outcomes Study 36-item Short Form survey (SF-36), and a patient global assessment (PtGA) at successive study visits.

Genetic and pharmacologic modulation of cementogenesis via pyrophosphate regulators.

Pyrophosphate (PP) serves as a potent and physiologically important regulator of mineralization, with systemic and local concentrations determined by several key regulators, including: tissue-nonspecific alkaline phosphatase (ALPL gene; TNAP protein), the progressive ankylosis protein (ANKH; ANK), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1; ENPP1). Results to date have indicated important roles for PP in cementum formation, and we addressed several gaps in knowledge by employing genetically edited mouse models where PP metabolism was disrupted and pharmacologically modulating PP in a PP-deficient mouse model. We demonstrate that acellular cementum growth is inversely proportional to PP levels, with reduced cementum in Alpl KO (increased PP levels) mice and excess cementum in Ank KO mice (decreased PP levels).

Dental and craniofacial defects in the Crtap mouse model of osteogenesis imperfecta type VII.

Background: Inactivating mutations in the gene for cartilage-associated protein (CRTAP) cause osteogenesis imperfecta type VII in humans, with a phenotype that can include craniofacial defects. Dental and craniofacial manifestations have not been a focus of case reports to date. We analyzed the craniofacial and dental phenotype of Crtap mice by skull measurements, micro-computed tomography (micro-CT), histology, and immunohistochemistry.

Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus.

Type III IFN lambdas (IFN-λ) have recently been described as important mediators of immune responses at barrier surfaces. However, their role in autoimmune diseases such as systemic lupus erythematosus (SLE), a condition characterized by aberrant type I IFN signaling, has not been determined. Here, we identify a nonredundant role for IFN-λ in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus.

Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: a case report.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases. Pathophysiology remains elusive and therapeutic options are limited. Cases refractory to corticosteroid therapy pose a clinical challenge and approximately 30% of patients with DiHS/DRESS develop complications, including infections and inflammatory and autoimmune diseases.

Neutrophil dysregulation is pathogenic in idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIM) are characterized by muscle inflammation and weakness, myositis-specific autoantibodies (MSAs), and extramuscular organ damage. The role of neutrophil dysregulation and neutrophil extracellular traps (NETs) in IIM is unclear. We assessed whether pathogenic neutrophil subsets (low-density granulocytes [LDGs]) and NETs were elevated in IIM, associated with clinical presentation and MSAs, and their effect on skeletal myoblasts and myotubes.

Deadliest catch: neutrophil extracellular traps in autoimmunity.

Purpose Of Review: To summarize recent evidence on the pathogenic effects of neutrophils and neutrophil extracellular traps (NETs) in autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis.

Recent Findings: NETs can orchestrate innate and adaptive immune dysregulation through diverse mechanisms. NETs induce potent inflammatory responses and represent sources of many autoantigens, creating a feed-forward loop that may perpetuate disease and lead to organ damage.

Clinical Evaluation of Melorheostosis in the Context of a Natural History Clinical Study.

Melorheostosis is a rare dysostosis involving cortical bone overgrowth that affects the appendicular skeleton. Patients present with pain, deformities, contractures, range of motion limitation(s), and limb swelling. It has been described in children as well as adults.

Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC.

HOIP is the catalytic subunit of the linear ubiquitination chain assembly complex (LUBAC) that is essential for NF-κB signaling and thus proper innate and adaptive immunity. To date only one patient with HOIP deficiency has been reported with clinical characteristics that include autoinflammation, immunodeficiency, amylopectinosis, and systemic lymphangiectasia. We sought to identify a genetic cause of a disease for an 8 year-old girl who presented with early-onset immune deficiency and autoinflammation.

Effect of Treatment on Imaging, Clinical, and Serologic Assessments of Disease Activity in Large-vessel Vasculitis.

Objective: Disease activity in large-vessel vasculitis (LVV) is traditionally assessed by clinical and serological variables rather than vascular imaging. This study determined the effect of treatment on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) vascular activity in relation to clinical- and serologic-based assessments.

Methods: Patients with giant cell arteritis (GCA) or Takayasu arteritis (TA) were prospectively evaluated at 6-month intervals in an observational cohort.

Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption.

This is the first study to our knowledge to report a novel mutation in the interferon regulatory factor 8 gene (IRF8 ) associated with multiple idiopathic tooth root resorption, a form of periodontal disease. The IRF8 variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. Functional assays demonstrated that the IRF8 mutant promoted osteoclastogenesis and failed to inhibit NFATc1-dependent transcriptional activation when compared with IRF8 control.

Natural killer cell expression of Ki67 is associated with elevated serum IL-15, disease activity and nephritis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder whose pathology involves multiple immune cell types, including B and T lymphocytes as well as myeloid cells. While it is clear that autoantibody-producing B cells, as well as CD4 T cell help, are key contributors to disease, little is known regarding the role of innate lymphoid cells such as natural killer (NK) cells in the pathogenesis of SLE. We have characterized the phenotype of NK cells by multi-color flow cytometry in a large cohort of SLE patients.

Persistent upregulation of the β-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle.

In healthy adult skeletal muscle fibers microtubules form a three-dimensional grid-like network. In the mdx mouse, a model of Duchenne muscular dystrophy (DMD), microtubules are mostly disordered, without periodicity. These microtubule defects have been linked to the mdx mouse pathology.

Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7-dependent lupus.

The peptidylarginine deiminases PAD2 and PAD4 are implicated in the pathogenesis of several autoimmune diseases. PAD4 may be pathogenic in systemic lupus erythematosus (SLE) through its role in neutrophil extracellular trap (NET) formation that promotes autoantigen externalization, immune dysregulation, and organ damage. The role of this enzyme in mouse models of autoimmunity remains unclear, as pan-PAD chemical inhibitors improve clinical phenotype, whereas PAD4-KO models have given conflicting results.

Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thromboembolic events and pregnancy loss. We sought to characterize the DNA methylation profile of primary APS in comparison to healthy controls and individuals with SLE. In primary APS neutrophils compared to controls, 17 hypomethylated and 25 hypermethylated CpG sites were identified.

Minimal Clinically Important Improvement of Routine Assessment of Patient Index Data 3 in Rheumatoid Arthritis.

Objective: To estimate minimal clinically important improvement (MCII) of RAPID-3 (Routine Assessment of Patient Index Data 3) in rheumatoid arthritis (RA).

Methods: RAPID-3 was computed before and after treatment escalation in a prospective study of adults with active RA. Patient judgment of improvement was used as the standard for a receiver-operating characteristic curve, from which MCII was estimated.