Faculty Bibliography

Autoinflammatory diseases are disorders of the innate immune system, which can be either monogenic due to a specific genetic mutation or complex multigenic due to the involvement of multiple genes. The aim of this review is to explore and summarize the recent advances in pathogenesis, diagnosis, and management of genetically complex autoinflammatory diseases, such as Schnitzler's syndrome; adult-onset Still's disease; synovitis, acne, pustulosis, hyperostosis, osteitis syndrome/chronic recurrent multifocal osteomyelitis/chronic non-bacterial osteomyelitis; Adamantiades-Behçet's disease; Yao syndrome; and periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome. The PubMed database was screened for relevant articles using free text words and specific search strings. The search was limited to English-language articles, reporting the results of studies in humans, published through March 2021. Evidence from literature suggest that these rare multigenic autoinflammatory diseases can present with different clinical features and the diagnosis of these diseases can be challenging due to a combination of nonspecific manifestations that can be seen in a variety of other conditions. Diagnostic delays and disease complications may occur due to low disease awareness and the lack of pathognomonic markers. The pathogeneses of these diseases are complex and in some cases precise pathogenesis is not clearly understood. Conventional treatments are commonly used for the management of these conditions, but biologics have shown promising results. Biologics targeting proinflammatory cytokines including IL-1, IL-6, TNF-α, IL-17A and IL-18 have been shown to ameliorate signs and symptoms of different multigenic autoinflammatory diseases.

OBJECTIVES/OBJECTIVE:Adult Onset Still's Disease (AOSD) is a rare autoinflammatory disorder. There is relatively little known about the impact of social determinants of health on its outcomes. Our goal is to describe the racial/ethnic variations, morbidity and mortality of AOSD hospitalized patients in the US. MATERIALS AND METHODS/METHODS:Adult US hospitalized patients between 2009-13 from a nationwide inpatient sample (NIS) database with AOSD were identified using ICD-9 code 714.2. NIS is the largest all-payer US inpatient database with approximately 8 million hospitalizations yearly. Patients with other autoimmune diseases were excluded. We used descriptive statistics to summarize patient and hospital characteristics. We performed survey-weighted logistic regression models adjusting for confounders to study our primary outcome: in-hospital mortality. RESULTS:Between 2009-13, 5,820 AOSD patients were hospitalized with a mean age of 53.6 (SE-0.61) years. 3817 (65.6%) were female, 56% white and 3% Asian. Macrophage Activating Syndrome (1.7%), Disseminated Intravascular Coagulation (DIC-1.1%) and Thrombotic Thrombocytopenic Purpura (0.4%), respectively, complicated the hospital course. There were 154 inpatient deaths in study period (mortality 2.6%). Mean age of patients who died in hospital was higher (62.4 years ± 3.1) and 13.9% were Asians. Patients of Asian origin had significantly higher odds of in-hospital death compared to whites (aOR = 6.39, 95% CI 1.77-23.1, p = 0.005). Mortality was significantly higher for patients whose hospital course was complicated by DIC (aOR = 29.69, 95% CI 5.5-160.41, p = 0.006). CONCLUSIONS:In this national sample of patients hospitalized for AOSD, we found significant variations in In-hospital mortality.

OBJECTIVES/OBJECTIVE:To describe the efficacy, safety, and exposure-response relationship of canakinumab in a subgroup of patients with systemic juvenile idiopathic arthritis (SJIA) aged ≥16 years, representative of adult-onset Still's disease (AOSD) patients, and to compare this subgroup with those of children and young adolescents with SJIA by pooling clinical data collected during the development programme of canakinumab. METHODS:Safety and efficacy data on canakinumab-treated patients were pooled from 4 SJIA studies (NCT00426218, NCT00886769, NCT00889863, and NCT00891046). In the majority of patients, canakinumab was administered at 4 mg/kg every 4 weeks. Efficacy parameters (adapted American College of Rheumatology [aACR] paediatric and juvenile idiopathic arthritis [JIA] ACR responses), quality of life, C-reactive protein levels, safety, and exposure-response relationship were assessed over 12 weeks in 3 age groups (children 2-<12, young adolescents 12-<16 and older adolescents and young adults ≥16 years). RESULTS:Efficacy outcomes were analysed in 216 children, 56 young adolescents and 29 older adolescents and young adults. Efficacy parameters across 3 age groups were largely comparable. At Day 15, at least 50% of patients from each age group exhibited aACR ≥70 and ACR responses. The safety profile of canakinumab was similar across age groups. One death was reported. CONCLUSIONS:Pooled analyses from SJIA studies indicate that older adolescents and young adults SJIA patients show similar efficacy, safety, and exposure-response relationship on a weight-based dosing regimen as observed in children and adolescent SJIA patients. These analyses suggest that canakinumab may be an effective therapy in young adults with Still's disease.

IgG4-related disease (IgG4-RD) encompasses a spectrum of complex fibro-inflammatory disorders which are often under diagnosed due to unfamiliarity by clinicians. A challenging multitude of clinical manifestations makes the diagnosis cumbersome. The primary clinical feature in IgG4-RD entails a tumor-like presentation coupled with tissue-destructive lesions. Histopathological findings include lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. These findings, in combination with elevated serum immunoglobulin G4 levels, are diagnostic in the setting of single- or multi-organ involvement. A closer understanding of the role of T cells and B cells in the increased production of IgG4 has led to a notion that IgG4 can act as a pathogen, anti-inflammatory agent, or rheumatoid factor. Glucocorticoids are the primary treatment modality; however, relapse is common with prolonged therapy. Alternatively, immunomodulatory agents are being increasingly used as therapy. The aim of this article is to raise awareness of IgG4-RD and review the diagnostic algorithm, as IgG4-RD often mimics a wide array of clinical conditions. In addition, we summarize the pathogenesis and current treatment guidelines of IgG4-RD for clinicians. Awareness and accurate diagnosis are crucial in preventing progression to chronic diseases, thereby diminishing disease-related morbidity and mortality.

Tumor necrosis factor-associated periodic syndrome is an autoinflammatory disorder classified under hereditary periodic fever syndromes. Mutations in the tumor necrosis factor receptor contribute to tumor necrosis factor-associated periodic syndrome. Decreased shedding of receptors and increased mitochondrial reactive oxygen species production leading to elevated proinflammatory cytokines are documented. Inflammation in various organs is hallmark of tumor necrosis factor-associated periodic syndrome and manifests as spiking fever, abdominal pain, conjunctivitis and polyserositis in adults. The ongoing challenge is to diagnose the disease early in its course to prevent amyloidosis. The treatment options have evolved from use of nonsteroidal anti-inflammatory drugs and corticosteroids to targeted therapy like tumor necrosis factor receptor inhibitors and interleukin-1 blockers. The aim of this review is to give an overview of the pathogenesis, clinical features and the various treatment modalities available for tumor necrosis factor-associated periodic syndrome and aid physicians in recognizing the signs of the disease earlier.