Rheumatoid arthritis Genetic studies in rheumatoid arthritis continued with collaborative projects over the past year. We contributed genotypes of NARAC replication cases and controls to a study that identified fourteen non-HLA loci in common between rheumatoid arthritis and celiac disease. Previous genome-wide association studies for disease susceptibility loci for each disease found 6 loci in common for the two diseases and suggested that additional loci likely exist. We therefore performed a meta-analysis of two existing large genome-wide association datasets (RA and celiac disease) with over 38,000 combined samples. After genotyping the top associated single nucleotide polymorphisms (SNPs) in additional replication samples (2,169 celiac disease cases and 2,255 controls, and 2,845 RA cases and 4,944 controls), eight additional SNPs demonstrated P less than 5 times 10 to the negative eighth, including four SNPs previously identified in one disease that were extended to the other disease and four SNPs that have not been previously confirmed in either disease. The fourteen shared celiac disease-RA risk loci, TNFRSF14, IL2/IL21, TNFAIP3, CTLA4, REL, TAGAP, SH2B3, 8q24.2, TRAF1, STAT4, DDX6, CD247, UBE2L3, and UBASH3A, point to T-cell receptor signaling as a key shared pathway of disease pathogenesis for RA and celiac disease. We also contributed genotype data for the NARAC collection that were used to develop and demonstrate the effectiveness of a simple new method to include related individuals in case control association studies. This is particularly important to leverage the maximum information from collections of samples such as the NARAC collection, which were collected targeting sib-pair or other family relationship samples. PFAPA During the last year we have completed a comprehensive study of patients with PFAPA during and between febrile episodes. Although we have observed that PFAPA patients frequently have relatives who experienced one or more features of PFAPA in childhood, there is not a Mendelian pattern of inheritance, and the pathogenesis is unknown. Using a systems biology approach we analyzed blood samples from PFAPA patients after genetic testing to exclude other known hereditary periodic fevers (HPFs), from healthy children, and from pediatric HPF patients. Gene expression profiling clearly distinguished symptomatic and asymptomatic periods in PFAPA patients and symptomatic periods in children with HPFs. During symptomatic PFAPA episodes, complement (C1QB, C2, SERPING1), interleukin (IL)-1-related (IL1B, IL1RN, CASP1, IL18RAP), and interferon-induced (AIM2, IP10/CXCL10) genes were significantly overexpressed, while T cell-associated transcripts (CD3, CD8B) were downregulated. At the protein level, symptomatic PFAPA episodes manifested significantly increased serum levels of granulocyte colony-stimulating factor, proinflammatory cytokines (IL-18, IL-6), and chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9). A relative lymphopenia was also noted during PFAPA attacks. Activated CD4 positive/CD25 positive T lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, but positively with those of IL-1 receptor antagonist. Based on the evidence for IL-1beta activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist at the beginning of a flare and all five demonstrated a prompt clinical and IP-10/CXCL10 response. These data suggest a host-derived activation of complement, IL-1beta, and IL-18 during symptomatic PFAPA episodes, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for the treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential new biomarker. Earlier this year this work was published in the PNAS.

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Manthiram, Kalpana; Correa, Hernan; Boyd, Kelli et al. (2018) Unique histologic features of tonsils from patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Clin Rheumatol 37:1309-1317
Gourh, Pravitt; Remmers, Elaine F; Boyden, Steven E et al. (2018) Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans. Arthritis Rheumatol 70:1654-1660
Richards, Robert I; Robertson, Sarah A; Kastner, Daniel L (2018) Neurodegenerative diseases have genetic hallmarks of autoinflammatory disease. Hum Mol Genet 27:R108-R118
Arthur, Victoria L; Shuldiner, Emily; Remmers, Elaine F et al. (2018) IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol 70:1319-1330
Manthiram, Kalpana; Li, Suzanne C; Hausmann, Jonathan S et al. (2017) Physicians' perspectives on the diagnosis and management of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Rheumatol Int 37:883-889
Manthiram, Kalpana; Lapidus, Sivia; Edwards, Kathryn (2017) Unraveling the pathogenesis of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis through genetic, immunologic, and microbiologic discoveries: an update. Curr Opin Rheumatol 29:493-499
Ombrello, Michael J; Arthur, Victoria L; Remmers, Elaine F et al. (2017) Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications. Ann Rheum Dis 76:906-913
Morgan, Nadia D; Shah, Ami A; Mayes, Maureen D et al. (2017) Clinical and serological features of systemic sclerosis in a multicenter African American cohort: Analysis of the genome research in African American scleroderma patients clinical database. Medicine (Baltimore) 96:e8980
Ombrello, Michael J; Remmers, Elaine F; Tachmazidou, Ioanna et al. (2015) HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. Proc Natl Acad Sci U S A 112:15970-5
Ombrello, Michael J; Sikora, Keith A; Kastner, Daniel L (2014) Genetics, genomics, and their relevance to pathology and therapy. Best Pract Res Clin Rheumatol 28:175-89

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