Faculty Bibliography

Background/Purpose: To characterize regulatory surface receptors on blood plasmacytoid dendritic cells (PDCs) of lupus patients and controls to determine if receptor expression and function associates with disease activity or clinical characteristics in SLE.
Method(s): Quantitative multicolor flow cytometry was used to measure immunoglobulin like transcript 7 (ILT7), bone marrow derived antigen 2 (BDCA2), ILT3, Fc epsilon receptor I (FcRI), leukocyte-associated immunoglobulin-receptor 1 (LAIR1), natural killer cell P44-related protein (NKp44), bone marrow stromal cell antigen 2 (BST2), dendritic cell (DC) immunoreceptor (DCIR), and Fc gamma receptor IIa (FcgammaRII) on PDCs of peripheral blood mononuclear cells (PBMC) from 65 SLE patients and 15 controls. For functional studies, PBMC from 9 SLE and 9 controls were treated with ILT7 and BDCA2 crosslinking antibodies followed by TLR9 agonists.
Result(s): Significant associations were found between multiple receptors, IFN levels, SLEDAI scores, and autoreactive antibody titers. ILT7 expression correlated inversely with SLEDAI, and ANA titers. High IFN SLE patients had increased levels of the ILT7 ligand BST2 and at the same time reduced ILT7 expression. BDCA2 levels were 5-fold higher than ILT7 levels, and were also inversely correlated with SLEDAI. Crosslinking ILT7 only weakly inhibited IFN secretion. Crosslinking BDCA2 significantly reduced IFN production in SLE patient cells, but this was much greater in patients with low SLEDAI scores than those with high SLEDAI scores.
Conclusion(s): We identify associations between PDC regulatory receptors and clinical disease in lupus patients, and dominant inhibitory function of BDCA2 over ILT7 in pDC type I IFN secretion with dependency upon disease activity

Background/Purpose: The impact of the COVID-19 pandemic on the number of pediatric patients evaluated in North America for recurrent fevers and autoinflammatory diseases is unknown; however, there have been reports of increased numbers of children presenting with these concerns. The purpose of this project was to determine the number of new patients evaluated for recurrent fevers in temporal relation to the COVID-19 pandemic in North America.
Method(s): The Childhood Arthritis and Rheumatology Research Alliance (CARRA) Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis Syndrome (PFAPA)/Autoinflammatory Disease Working Group used previously determined recurrent fever ICD-10 codes, including periodic fever and autoinflammatory syndromes, to quantify monthly numbers of new pediatric patients evaluated for recurrent fever diagnoses by outpatient subspecialists from March 1, 2019 to February 29, 2020 (pre-pandemic) and from March 1, 2020 to February 28, 2021 (during the pandemic). The proportion of new visits evaluated for recurrent fever diagnoses relative to all new visit diagnoses during these two years were compared using a two-sample test of proportions. This study was determined to be IRB exempt by the Cincinnati Children's Hospital IRB.
Result(s): Twenty-four sites reported 1684 new patient visits coded with recurrent fever diagnoses pre-pandemic compared with 2181 during the first year of the pandemic. There was an increase in the total number of recurrent fever evaluations after the onset of the pandemic compared to the year prior in 20 of 24 sites (range-48% to +360%). Of the 20 sites who provided the total number of new visits for all diagnoses, there were 19305 new visits pre-pandemic of which 1318 (6.83%) had a recurrent fever code compared to 17040 new visits during the pandemic with 1690 (9.92%) who received a recurrent fever diagnosis code. The difference between the proportion of new recurrent fever evaluations and total number of new visits pre-pandemic versus during the pandemic was statistically significant (p< 0.0001).
Conclusion(s): Across 24 CARRA-associated North American centers, there was an increase in pediatric patients evaluated for new recurrent fever diagnoses during the first year of the COVID-19 pandemic compared to the year prior, despite a decrease in the total number of new patients. An increase in recurrent fever evaluations merits further investigation given that many daycare centers and schools were closed during a time of increased infection control precautions and attention to fevers. A speculated potential etiology is that unknown, noninfectious triggers precipitate recurrent fever syndromes. The CARRA PFAPA/Autoinflammatory Disease Working Group's project is the first collaborative, multidisciplinary effort to assess the number of children evaluated for recurrent fevers in relation to the COVID-19 pandemic in North America

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity. BACKGROUND: We find that a number of IFN pathway lupus risk alleles significantly impact mortality following COVID-19 infection. These data support the idea that type I IFN pathway risk alleles for autoimmune disease may persist in high frequency in modern human populations due to a benefit in our defense against viral infections. TRANSLATIONAL SIGNIFICANCE: We develop multivariate prediction models which combine genetics and known biomarkers of severity to result in greatly improved prediction of mortality in acute COVID-19. The specific associated alleles provide some clues about key points in our defense against COVID-19.

Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity.

Background/Purpose: Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common alleles contribute to the genetic high IFN trait. In this study, we examine whether these common gain-of-function alleles in the type I IFN pathway are associated with protection from mortality in acute COVID-19.
Method(s): We studied IFN pathway SLE risk genes in patients with acute COVID-19 admitted to NYU Langone hospitals (751 European-American and 398 African-American ancestry). The samples were genotyped using low depth sequencing and imputation, and we analyzed data from the following SNPs: IRF5 (rs2004640, rs3807306, rs10488631, rs2280714), IRF7/PHRF (rs1131665, rs4963128), IRF8 (rs17445836, rs12444486), and PRKG1 (rs7897633). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome.
Result(s): We observed specific IRF5 haplotypes that are protective against SLE risk were associated with increased risk of mortality in acute COVID-19 patients in European-American ancestry (OR=3.74, p=0.015). Alleles of PRKG1 were also associated with mortality from COVID-19 in the European-American ancestry cohort (OR=1.80, p=0.0057), and this risk factor was particularly strong in younger patients (OR=29.2, p=0.01 in ages 45-54). IRF8 genotype at rs1244486 was associated with protection from mortality in COVID-19 in African-American subjects aged 65 and older (OR=0.34, p=0.04).
Conclusion(s): We find that a number of type I IFN pathway genes associated with risk of SLE also modulate risk of death during acute COVID-19. Similar to their associations with SLE, these alleles are variably associated with COVID-19 mortality across ancestral backgrounds, suggesting ancestral differences in the genetic regulation of the IFN pathway. These data confirm the critical role of the IFN pathway in our defense against viral infections, and support the idea that some common SLE risk alleles exert protective effects in anti-viral immunity

The search for effective COVID-19 management strategies continues to evolve. Current understanding of SARS-CoV-2 mechanisms suggests a central role for exaggerated activation of the innate immune system as an important contributor to COVID-19 adverse outcomes. The actions of colchicine, one of the oldest anti-inflammatory therapeutics, target multiple mechanisms associated with COVID-19 excessive inflammation. While many COVID-19 trials have sought to manipulate SARS-CoV-2 or dampen the inflammatory response once patients are hospitalised, few examine therapeutics to prevent the need for hospitalisation. Colchicine is easily administered, generally well tolerated and inexpensive, and holds particular promise to reduce the risk of hospitalisation and mortality due to COVID-19 in the outpatient setting. Successful outpatient treatment of COVID-19 could greatly reduce morbidity, mortality and the demand for rare or expensive care resources (front-line healthcare workers, hospital beds, ventilators, biological therapies), to the benefit of both resource-replete and resource-poor regions.

Cryopyrin-associated periodic syndromes (CAPS) are a group of autoinflammatory diseases associated with NLRP3 gain of function mutations. CAPS associated mutations are found predominantly in exon 3. The objective of this study is to describe a new variant on NRLP3 gene and its phenotype. Case report description of a new NRLP3 pathogenic variant and literature case-based search through INFEVERS database. A 21-year old male who presented multiple tonic-clonic seizures on his 3rd day of life. At age 2, he had recurrent central facial palsy, high fever (40 °C), painful and persistent oral ulcers, abdominal pain, nausea and vomiting, and delayed neuropsychomotor development, with polyarthritis in wrists and knees. Over the years, several symptoms were observed: livedo reticularis, Raynaud's phenomenon, positive pathergy test, heat allodynia, extremely painful genital ulcers, and sporadic conjunctivitis. Laboratory studies revealed persistently elevated inflammatory markers and serum amyloid protein A (30 μg/l). The genetic panel for autoinflammatory diseases revealed heterozygous mutation in the NLRP3, (c.2068G > C, p.E690Q) with 0% of frequency in the general population. The patient denies rash and did not have frontal bossing or patellar overgrowth. We found a positive familial history on mother and brother, who carried the same mutation. The patient was started on canakinumab which controlled his symptoms. Currently, 241 missense variants in the NLRP3 have been described. We presented a new mutation in exon 3 of the NRLP3 gene in a patient that fulfills clinical criteria for CAPS who had complete clinical response to Canakinumab, supporting the idea that this mutation is pathogenic.

Macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) are increasingly recognized as being on a continuum of cytokine storm syndromes, with different initiating pathways culminating in cytotoxic dysfunction and uncontrolled activation and proliferation of T lymphocytes and macrophages. The activated immune cells produce large amounts of proinflammatory cytokines, including interleukin 1β (IL)-1β. Management depends on the recognized diagnosis. In the setting of a cytokine storm syndrome and infection, collaborative involvement of specialists, including infectious disease and rheumatology is ideal. Anakinra, a recombinant IL-1 receptor antagonist, has been used subcutaneously and intravenously in pediatric patients and is considered a first-line treatment for MAS and secondary HLH (sHLH) among many pediatric rheumatologists. Previous reports of anakinra used in adults for treatment of MAS or sHLH are limited to subcutaneous administration. In this issue, Moneagudo et al. present a series of adult patients with sHLH treated with intravenous anakinra, including patients in whom subcutaneous anakinra was insufficient. As the authors suggest, there is a potential therapeutic use for anakinra in sHLH or the cytokine storm syndrome triggered by COVID19. Trial design will be key, with the patient subpopulation, timing of intervention, and doses tested important.

Background/Purpose: International registries have significantly enhanced the understanding of the genetics, phenotype, prognosis, and treatment of Systemic Autoinflammatory Diseases (SAIDs) that could be further augmented by including a genetically heterogeneous Northern American cohort. The objective is to explore the need for and value of developing a Childhood Arthritis and Rheumatology Research Alliance (CARRA) Autoinflammatory Disease Network to enhance quality of care and accelerate research in SAIDs.
Method(s): A team within CARRA composed of pediatric rheumatologists, infectious disease physicians, immunologists, otolaryngologists, geneticists, parents/patients, and members of the Autoinflammatory Alliance met in person and via teleconferences to discuss the benefits of SAIDs networks from 2016 to the present. A literature search on the topic using keywords such as "EuroFever", "pharmacosurveillance", and "autoinflammatory registry" was reviewed to identify stakeholders and methods for establishing clinics. Physicians who were involved in establishing SAIDs programs shared their experiences. To explore the feasibility of and need for this network, 17 physicians from different sites approximated total patient numbers seen in their programs, as determined by ICD-10 codes when available.
Result(s): The workgroup participants agreed by consensus that a CARRA Autoinflammatory Disease Network would be instrumental to improve clinical care, enhance research, facilitate international collaboration, and improve patient and family involvement in research planning. The literature search highlighted the benefits of this approach in rare diseases in preventing diagnostic delay, understanding the epigenetics of SAIDs, and providing an opportunity for pharmacosurveillance in a cohort of patients exposed to biologics in a real world setting. Data was collected from 17 sites in the US, Canada, Israel, and Ukraine, to assess the number of potential patients this network could reach. Collectively these sites (~10% of CARRA sites) care for 2493 SAID patients, including 1029 coded with periodic fever syndromes, 81 with CAPS, 786 with other defined SAIDs (including PFAPA), 160 with undefined SAIDs, and 437 with CNO/CRMO. We found significant variability in how ICD-10 codes were utilized among this small survey of US centers. ICD-10 codes were not necessarily in concordance with the physicians' diagnosis, and across the majority of sites (82%), most visits were coded as periodic fever syndrome (M04.1).
Conclusion(s): CARRA physicians manage thousands of patients in North America with SAIDs, which emphasizes the need for a CARRA Autoinflammatory Disease Network to facilitate earlier diagnoses, education, and access to expert and multidisciplinary quality care. This network will also create an infrastructure for clinical and translational research. Future work will focus on more precisely characterizing the patients seen across CARRA Registry sites. Given the genetically diverse populations in North America, an autoinflammatory network built around the CARRA Registry would facilitate collaborations with international colleagues to benefit patients worldwide.(Figure Presented)