Rheumatic Diseases Clinics of North America

There has been increasing understanding of the role of inflammation in seizures and epilepsy, as well as targeted immunomodulatory treatments. In children, immune-mediated seizures often present acutely in the setting of autoimmune encephalitis and are very responsive to immunotherapy with low rates of subsequent epilepsy. Conversely, seizures in autoimmune-associated epilepsies, such as Rasmussen syndrome, can remain refractory to multimodal therapy, including immunomodulation. In this review, the authors discuss the presentations of immune-mediated seizures in children, underlying mechanisms, and emerging therapies...

Inflammatory bowel disease (IBD) represents a spectrum of disease, which is characterized by chronic gastrointestinal inflammation. Monogenic mutations driving IBD pathogenesis are more highly represented in early-onset compared to adult-onset disease. The pathogenic genes which dysregulate host immune responses in monogenic IBD affect both the innate (ie, intestinal barrier, phagocytes) and adaptive immune systems (ie, T cells, B cells). Advanced genomic and targeted functional testing can improve clinical decision making and present increased opportunities for precision medicine approaches in this important patient population...

As a disorder of immune dysregulation, autoimmune lymphoproliferative syndrome (ALPS) stems from pathogenic variants in the first apoptosis signal-mediated apoptosis (Fas) and Fas-ligand pathway that result in elevations of CD3+ TCRαβ+ CD4- CD8- T cells along with chronic lymphoproliferation, a heightened risk for malignancy, and importantly for the rheumatologist, increased risk of autoimmunity. While immune cytopenias are the most encountered autoimmune phenomena, there is increasing appreciation for ocular, musculoskeletal, pulmonary and renal inflammatory manifestations similar to more common rheumatology diseases...

Regulatory T cells (Tregs) are critical for enforcing peripheral tolerance. Monogenic "Tregopathies" affecting Treg development, stability, and/or function commonly present with polyautoimmunity, atopic disease, and infection. While autoimmune manifestations may present in early childhood, as more disorders are characterized, conditions with later onset have been identified. Treg numbers in the blood may be decreased in Tregopathies, but this is not always the case, and genetic testing should be pursued when there is high clinical suspicion...

The NF-κB pathway is a cardinal signaling pathway that has been implicated in the development of a diverse range of clinical diseases. Numerous cellular processes converge on this pathway, which results in cell proliferation and survival. Defects in this pathway and in its upstream regulators have been described as causing immunodeficiency. However, there is a growing body of literature connecting autoimmune and autoinflammatory conditions to NF-κB pathway dysfunction. This review serves as a current appraisal of the literature of these disorders...

COPA syndrome is a recently described autosomal dominant inborn error of immunity characterized by high titer autoantibodies and interstitial lung disease, with many individuals also having arthritis and nephritis. Onset is usually in early childhood, with unique disease features including alveolar hemorrhage, which can be insidious, pulmonary cyst formation, and progressive pulmonary fibrosis in nonspecific interstitial pneumonia or lymphocytic interstitial pneumonia patterns. This review explores the clinical presentation, genetics, molecular mechanisms, organ manifestations, and treatment approaches for COPA syndrome, and presents a diagnostic framework of suggested indications for patient testing...

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic vasculitis syndrome caused by biallelic mutations in the adenosine deaminase 2 gene. The diagnosis of DADA2 is confirmed by decreased enzymatic activity of ADA2 and genetic testing. Symptoms range from cutaneous vasculitis and polyarteritis nodosa-like lesions to stroke. The vasculopathy of DADA2 can affect many organ systems, including the gastrointestinal and renal systems. Hematologic manifestations occur early with hypogammaglobulinemia, lymphopenia, pure red cell aplasia, or pancytopenia...

Suppressor of cytokine signaling 1 (SOCS1) is a negative regulator of cytokine signaling that inhibits the activation of Janus kinases. A human disease caused by SOCS1 haploinsufficiency was first identified in 2020. To date, 18 cases of SOCS1 haploinsufficiency have been described. These patients experience enhanced activation of leukocytes and multiorgan system immunodysregulation, with immune-mediated cytopenia as the most common feature. In this review, the authors provide an overview on the biology of SOCS1 and summarize their knowledge of SOCS1 haploinsufficiency including genetics and clinical manifestations...

This review will discuss when clinicians should consider evaluating for Type I interferonopathies, review clinical phenotypes and molecular defects of Type I interferonopathies, and discuss current treatments.

Inborn errors of immunity are now understood to encompass manifold features including but not limited to immunodeficiency, autoimmunity, autoinflammation, atopy, bone marrow defects, and/or increased malignancy risk. As such, it is essential to maintain a high index of suspicion, as these disorders are not limited to specific demographics such as children or those with recurrent infections. Clinical presentations and standard immunophenotyping are informative for suggesting potential underlying etiologies, but integration of data from multimodal approaches including genomics is often required to achieve diagnosis...

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Predictions for a general path forward in vasculitis care and research are provided based on advances made in the past 20 years. Prospects for advances in translational research with potential to improve care are highlighted, including identification of hemato-inflammatory diseases, autoantigens, disease mechanisms in animal models, and biomarkers. A list of active randomized trials is provided, and areas of potential paradigm shifts in care are highlighted. The importance of patient involvement and international collaboration is noted, and a plea is made for innovative trial designs that would improve access of patients to trials and to clinical experts at referral centers...

The coronavirus disease 2019 (COVID-19) pandemic has led to the emergence of multiple challenges in the care of patients with systemic rheumatic diseases. Patients with vasculitis represent a group of particular concern due to existing risk factors which include a higher burden of comorbidities and specific immunosuppressive therapies used for treatment. Vaccination and the use of other risk mitigation strategies are crucial for the care of these patients. This review provides an overview of existing evidence to contribute to the understanding and specific requirements of the treatment and management of patients with vasculitis during the time of COVID-19...

Family planning in women with vasculitis requires an interdisciplinary approach. This article summarizes recommendations and guidance for each phase of family planning in persons with vasculitis including preconception counseling, birth control, pregnancy, and breastfeeding. Pregnancy complications are presented by category of vasculitis with accompanying diagnostic and therapeutic recommendations. Birth control and assisted reproductive technology options are reviewed with special considerations for women who are high risk or have a history of blood clots...

Kawasaki disease and multisystem inflammatory syndrome in children are hyperinflammatory conditions that share similar emerging pathophysiology hypotheses, clinical features, treatment strategies, and outcomes. Although both conditions have key differences, growing evidence suggests that both conditions might be closely related on a larger spectrum of postinfectious autoimmune responses.

Multisystem inflammatory syndrome in children (MIS-C) is a delayed postinflammatory disorder associated with the previous infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Initially, MIS-C was described as highly similar to Kawasaki disease (KD), a pediatric febrile systemic vasculitis that can lead to the development of coronary artery aneurysms (CAAs). While KD and MIS-C are both inflammatory disorders, the 2 entities differ in their epidemiological, clinical, immunological, and pathological features...

Auricular, nasal, and laryngeal manifestations occur frequently in rheumatic diseases. Inflammatory ear, nose, and throat (ENT) processes often result in organ damage and have profound effects on quality of life. Herein, we review the otologic, nasal, and laryngeal involvement of rheumatic diseases, focusing on their clinical presentation and diagnosis. ENT manifestations generally respond to treatment of the systemic disease, which is outside the scope of this review; however, adjunctive topical and surgical treatment approaches, as well as treatment of idiopathic inflammatory ENT manifestations will be reviewed...

The approach to diagnosis of primary systemic vasculitis can be challenging, often requiring consideration of important secondary causes of vasculitis and non-inflammatory mimics. An atypical pattern of vascular involvement and/or atypical features of primary vasculitis (eg, cytopenia, lymphadenopathy) should prompt a more thorough investigation into other diseases. Herein, we review selected mimics organized by the size of blood vessels typically affected.

Central nervous system vasculitis (CNSV) is a group of disorders leading to inflammatory vasculopathy within the brain, spinal cord, and leptomeninges. CNSV is divided into primary angiitis of the central nervous system (PACNS) and secondary CNSV based on the underlying etiology. PACNS is a rare inflammatory disorder with poorly understood pathophysiology and heterogeneous and highly variable clinical features. The diagnosis depends on a combination of clinical and laboratory variables, multimodal imaging, and histopathological examination as well as exclusion of mimics...