Manthiram K, Ortega-Villa AM, Lapidus S, Bowes M, Romeo T , et al.
The Journal of pediatrics •
To identify clinical features associated with response to tonsillectomy among children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome and to determine optimal management of children with continued episodes after tonsillectomy. Patients with PFAPA seen at Vanderbilt University Children's Hospital and the National Institutes of Health (NIH) who underwent tonsillectomy were enrolled and queried regarding symptoms before and after surgery. Ninety-seven subjects with PFAPA (43 Vanderbilt, 54 NIH) were followed for a median of 49 months following tonsillectomy. Nearly half of participants reported complete resolution of PFAPA episodes (65% at Vanderbilt and 35% at NIH), while 25% had less severe or frequent episodes, 23% had a period of remission with recurrence, and 4% had no change in episodes. By logistic regression, factors associated with a full response to tonsillectomy were episode resolution with glucocorticoid treatment, presence of exudative pharyngitis, absence of rash, and absence of arthralgia/myalgia during pre-tonsillectomy PFAPA flares. Among those requiring treatment for persistent flares post-tonsillectomy, 15/19 (79%) reported improvement with cimetidine or famotidine prophylaxis. Tonsillectomy remains effective in improving PFAPA flares in most patients. However, unique episode features prior to tonsillectomy appear to be clinical predictors of response to tonsillectomy. Histamine receptor 2 antagonists like cimetidine were effective prophylactic agents for refractory cases post-tonsillectomy. Patients with incomplete response to tonsillectomy may represent a subset of PFAPA with unique factors affecting their pathogenesis.
Espahbodi M, Edwards KM, Goudy SL, Penn EB, Manthiram K
BMC pediatrics •
Recurrent tonsillitis is a common indication for tonsillectomy in children and has phenotypic overlap with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. We sought to characterize symptoms associated with PFAPA among children undergoing tonsillectomy. Parents/guardians of children undergoing tonsillectomy at Vanderbilt Children's Hospital over a six-week period were queried regarding symptoms of recurrent fever. Follow-up questionnaires were administered 3 and 12 months after tonsillectomy. 82% (120/147) of patients who underwent tonsillectomy during the study period participated. Provider-documented indications for tonsillectomy were obstructive sleep apnea in 88% and recurrent tonsillitis in 33%. 11% (13/120) reported[Formula: see text]6 episodes of stereotypical fever in a one-year period. During febrile episodes among these 13 subjects, 11 had tonsillitis, 5 had cervical adenitis, 3 had aphthous stomatitis, and three reported regular and predictable episode timing. In addition, participants with ≥3 episodes/year of recurrent febrile tonsillitis (N = 33) had a significantly higher prevalence of recurrent aphthous ulcers than those without recurrent tonsillitis (24% vs. 9%, p = 0.04). All participants, including those with recurrent fever, reported fewer febrile tonsillitis episodes one year after tonsillectomy. In our survey of children undergoing tonsillectomy, a subpopulation had frequent, stereotypical fever episodes with recurrent tonsillitis, aphthous stomatitis, or regular timing like patients with PFAPA. Although we cannot diagnose such patients with PFAPA in this limited retrospective study, pediatricians and otolaryngologists evaluating patients for tonsillectomy should be aware of the clinical signs of PFAPA that may warrant additional evaluation and therapeutic approaches.
Manthiram K, Preite S, Dedeoglu F, Demir S, Ozen S , et al.
Proceedings of the National Academy of Sciences of the United States of America •
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of (rs17753641) is strongly associated with PFAPA (OR 2.13, = 6 × 10). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near , , and were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. alleles may be factors that influence phenotypes along this spectrum as we found new class I and II associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.
Amarilyo G, Rothman D, Manthiram K, Edwards KM, Li SC , et al.
Pediatric rheumatology online journal •
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. There is considerable heterogeneity in management strategies and a lack of evidence-based treatment guidelines. Consensus treatment plans (CTPs) are standardized treatment regimens that are derived based upon best available evidence and current treatment practices that are a way to enable comparative effectiveness studies to identify optimal therapy and are less costly to execute than randomized, double blind placebo controlled trials. The purpose of this project was to develop CTPs and response criteria for PFAPA. The CARRA PFAPA Working Group is composed of pediatric rheumatologists, infectious disease specialists, allergists/immunologists and otolaryngologists. An extensive literature review was conducted followed by a survey to assess physician practice patterns. This was followed by virtual and in-person meetings between 2014 and 2018. Nominal group technique (NGT) was employed to develop CTPs, as well as inclusion criteria for entry into future treatment studies, and response criteria. Consensus required 80% agreement. The PFAPA working group developed CTPs resulting in 4 different treatment arms: 1. Antipyretic, 2. Abortive (corticosteroids), 3. Prophylaxis (colchicine or cimetidine) and 4. Surgical (tonsillectomy). Consensus was obtained among CARRA members for those defining patient characteristics who qualify for participation in the CTP PFAPA study. The goal is for the CTPs developed by our group to lead to future comparative effectiveness studies that will generate evidence-driven therapeutic guidelines for this periodic inflammatory disease.
Manthiram K, Correa H, Boyd K, Roland J, Edwards K
Clinical rheumatology •
The objective of this study is to compare the histology and immune cell composition of tonsils from patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome to those from patients with obstructive sleep apnea (OSA). Patients with PFAPA and age-matched controls with OSA who had undergone tonsillectomy at Vanderbilt Children's Hospital were recruited. After informed consent, archival paraffin-embedded, formalin-fixed tonsil tissues were obtained. Sizes of major histologic regions were measured. Cores of germinal centers, crypts, and squamous epithelium were assembled on a tissue microarray for immunohistochemical staining and digital image analysis. Features of tonsils from PFAPA and OSA patients were compared with Wilcoxon signed-rank test. Samples from 16 cases with PFAPA and 16 controls with OSA were evaluated. Tonsils from PFAPA cases had significantly smaller germinal centers (0.18 vs. 0.47 mm, p = 0.001) and wider squamous epithelia (176 vs. 138 μm, p = 0.008) than those of OSA patients. The percentages of B and T lymphocytes and myeloid cells were comparable in germinal centers, crypts, and squamous epithelia from PFAPA and OSA patients. Longer time from the last febrile episode in PFAPA cases was associated with larger germinal center area (Spearman's rho = 0.61, p = 0.02). We found differences in the sizes of germinal centers and squamous epithelia in tonsils of patients with PFAPA and OSA, but the cellular compositions within these areas were comparable. Our results suggest that tonsils from patients with PFAPA change histologically over time with enlarging germinal centers following a febrile episode. Additional studies are needed to understand the pathogenesis of PFAPA.
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is considered the most common periodic fever syndrome of childhood. Although it was first described three decades ago, the pathogenesis has been poorly understood. Recent studies on the heritability and immunology of the disorder have begun to shed light into the mechanisms of this autoinflammatory disorder. This review will focus on the pathogenesis of PFAPA, especially as it pertains to the genetic susceptibility, tonsillar immunology, and the role of the microbiome. Recent literature provides insights into the heritability, potential genetic modifiers, and the immunologic and microbiological profile of the tonsils in this syndrome. Evidence is mounting that PFAPA is inherited as a complex genetic disease. Furthermore, tonsillectomy is curative in the majority of patients, including those who do not meet the complete clinical criteria for PFAPA. The tonsils in PFAPA patients may exhibit unique immunologic and microbiological features. The goal of this review is to outline these new developments.
Manthiram K, Li SC, Hausmann JS, Amarilyo G, Barron K , et al.
Rheumatology international •
To assess the practice patterns of pediatric rheumatology and infectious diseases subspecialists in the diagnosis and treatment of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. An online survey assessing diagnostic and treatment approaches was sent to 424 members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and 980 members of the Pediatric Infectious Disease Society (PIDS). 277 physicians (123 from CARRA and 154 from PIDS representing 21% of the total membership) completed the survey. To diagnose PFAPA, most respondents agreed that patients must have the following features of the diagnostic criteria: stereotypical fever episodes (95%), asymptomatic intervals between episodes (93%), and normal growth and development (81%). However, 71% of the respondents did not require age of onset <5 years, 33% did not require regular intervals between episodes, and 79% did not require the concomitant signs of aphthous stomatitis, adenitis, or pharyngitis during episodes as long as episodes were regular. Over half (58%) considered episode resolution with steroids to be diagnostic of PFAPA. Corticosteroids, antipyretics, tonsillectomy, and cimetidine were the most commonly prescribed treatments, while steroids and tonsillectomy were most effective. Subspecialists in pediatric rheumatology and infectious diseases showed limited adherence to the complete published criteria for diagnosing PFAPA suggesting heterogeneity in the characteristics of patients diagnosed with the disorder. These findings emphasize the need to develop consensus diagnostic and treatment guidelines in well-characterized patient populations.
Fotis L, Shaikh N, Baszis K, French A, Tarr P , et al.
Pediatric rheumatology online journal •
P1 Serologic evidence of gut-driven systemic inflammation in juvenile idiopathic arthritis Lampros Fotis, Nur Shaikh, Kevin Baszis, Anthony French, Phillip Tarr P2 Oral health and anti-citrullinated peptide antibodies (ACPA) in juvenile idiopathic arthritis Sriharsha Grevich, Peggy Lee, Sarah Ringold, Brian Leroux, Hannah Leahey, Megan Yuasa, Jessica Foster, Jeremy Sokolove, Lauren Lahey, William Robinson, Joshua Newsom, Anne Stevens P3 Novel autoantigens for endothelial cell antibodies in pediatric rheumatic diseases identified by proteomics Rie Karasawa, Mayumi Tamaki, Megumi Tanaka, Toshiko Sato, Kazuo Yudoh, James N. Jarvis P4 Transcriptional profiling reveals monocyte signature associated with JIA patient poor response to methotrexate Halima Moncrieffe, Mark F. Bennett, Monica Tsoras, Lorie Luyrink, Huan Xu, Sampath Prahalad, Paula Morris, Jason Dare, Peter A. Nigrovic, Margalit Rosenkranz, Mara Becker, Kathleen M. O’Neil, Thomas Griffin, Daniel J. Lovell, Alexei A. Grom, Mario Medvedovic, Susan D. Thompson P5 A multi-dimensional genomic map for polyarticular juvenile idiopathic arthritis Lisha Zhu, Kaiyu Jiang, Laiping Wong, Michael J Buck, Yanmin Chen, Halima Moncrieffe, Laura Brungs, Tao Liu, Ting Wang, James N Jarvis P6 Tocilizumab for treatment of children with refractory JIA Khaled Alsaeid, Jasim Alfailakawi, Hamid Alenezi, Hazim Alsaeed P7 Clinical characteristics of the initial patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry Tim Beukelman, Marc Natter, Norm Ilowite, Kelly Mieszkalski, Grendel Burrell, Brian Best, Helen Bristow, Shannon Carr, Anne Dennos, Rachel Kaufmann, Yukiko Kimura, Laura Schanberg P8 Comparative performance of small and large clinical centers in a comprehensive pediatric rheumatology disease registry Peter R Blier P9 Clinical characteristics of children with membranous lupus nephritis: The Childhood Arthritis and Rheumatology Research Alliance Legacy Registry Alexis Boneparth, Scott E. Wenderfer, L. Nandini Moorthy, Suhas M. Radhakrishna, Anna Carmela P. Sagcal-Gironella, Emily von Scheven P10 Rituximab use in pediatric lupus anticoagulant hypoprothrombinemia syndrome - a two center experience Kader Cetin Gedik, Salma Siddique, Cassyanne L. Aguiar, Doruk Erkan P11 Predictors of complementary and alternative medicine use and response in children with musculoskeletal conditions Ezra Cohen, Yvonne Lee, Michelle Dossett, Darshan Mehta, Roger Davis P12 Comparison of pediatric rheumatology and nephrology survey results for the treatment of refractory proliferative lupus nephritis and renal flare in juvenile SLE Mileka Gilbert, Beatrice Goilav, Esra Meidan, Joyce Hsu, Alexis Boneparth, Anabelle Chua, Stacy Ardoin, Scott E. Wenderfer, Emily Von Scheven, Natasha M. Ruth P13 Transitioning lupus patients from pediatric to adult rheumatology Joyce Hui-Yuen, Kader Cetin Gedik, Liza Bermudez, Ashlea Cook, Lisa Imundo, Amy Starr, Andrew Eichenfield, Anca Askanase P14 The systemic juvenile idiopathic arthritis cohort of the Childhood Arthritis & Rheumatology Research Alliance Registry Ginger Janow, Laura E. Schanberg, Soko Setoguchi, Victor Hasselblad, Elizabeth D. Mellins, Rayfel Schneider, Yukiko Kimura, The CARRA Legacy Registry Investigators P15 Results of the pilot study of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) consensus treatment plans for new-onset systemic juvenile idiopathic arthritis Yukiko Kimura, Sriharsha Grevich, Timothy Beukelman, Esi Morgan, T Brent Graham, Maria Ibarra, Yonit Sterba Ruas, Marisa Klein-Gitelman, Karen Onel, Sampath Prahalad, Marilynn Punaro, Sarah Ringold, Dana Toib, Heather Van Mater, Jennifer E. Weiss, Pamela F. Weiss, Kelly Mieszkalski, Laura E. Schanberg P16 A systemic review of pain relief modalities in juvenile idiopathic arthritis: First step in developing a novel decision support intervention Timothy S. H. Kwok, Jacinthe Bisaillon, Christine Smith, Lucie Brosseau, Jennifer Stinson, Adam M. Huber, Ciaran M. Duffy, Karine Toupin April P17 Barriers and facilitators to care retention for pediatric systemic lupus erythematous patients in South Africa: A qualitative study Laura B Lewandowski, Christiaan Scott P18 Evaluating the feasibility of conducting comparative effectiveness studies in juvenile Localized Scleroderma (jLS) Suzanne C. Li, Kathryn S. Torok, C. Egla Rabinovich, Sandy D. Hong, Mara L Becker, Fatma Dedeoglu, Maria F. Ibarra, Polly J Ferguson, Rob C. Fuhbrigge, Katie G. Stewart, Elena Pope, Ronald M. Laxer, Thomas G. Mason, Gloria C. Higgins, Xiaohu Li, Marilynn G. Punaro, George Tomlinson, Eleanor Pullenayegum, John Matelski, Laura Schanberg, Brian M. Feldman P19 Tonsillar histology in patients with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome Kalpana Manthiram, Hernan Correa, Kathryn Edwards P20 Clinical course of juvenile dermatomyositis presenting as skin predominant disease Edward J. Oberle, Michelle Bayer, Dominic O. Co, Hatice Ezgi Baris, Yvonne Chiu, Adam Huber, Susan Kim P21 A Survey of musculoskeletal ultrasound practices of pediatric rheumatologists in North America Edward J Oberle, Timothy Beukelman P22 Assessment, classification and treatment of calcinosis as a complication of juvenile dermatomyositis: A survey of pediatric rheumatologists by the Childhood Arthritis and Rheumatology Research Alliance Amir B. Orandi, Kevin W. Baszis, Vikas Dharnidharka, Mark F. Hoeltzel, for the CARRA JDM Committee P23 CARRA dermatomyositis CTP pilot study Ann Reed, Adam Huber, George Tomlinson, Eleanor Pullenayegum, John Matelski, Y. Ingrid Goh, Laura Schanberg, Brian M. Feldman P24 Unexpectedly high incidences and prolonged disease activity in children with chronic non-bacterial osteomyelitis (CNO) as compared to bacterial osteomyelitis Anja Schnabel, Ursula Range, Gabriele Hahn, Timo Siepmann, Reinhard Berner, Christian Michael Hedrich P25 Juvenile systemic sclerosis cohort within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry: Follow up characteristics Brandi Stevens, Kathryn S. Torok, Suzanne Li, Nicole Hershey, Megan Curran, Gloria Higgins, Katharine Moore, Egla Rabinovich, Anne M. Stevens, for the CARRA Registry Investigators P26 Development and usability testing of an iPad and desktop psycho-educational game for children with Juvenile Idiopathic Arthritis and their parents Jennifer Stinson, Mark Connelly, Adam Huber, Nadia Luca, Lynn Spiegel, Argerie Tsimicalis, Stephanie Luca, Naweed Tajuddin, Roberta Berard, Julia Barsalou, Sarah Campillo, Paul Dancey, Ciaran Duffy, Brian Feldman, Nicole Johnson, Patrick McGrath, Natalie Shiff, Shirley Tse, Lori Tucker, Charles Victor P27 : User-centred design and development of a smartphone app to support self-management for youth with arthritis pain Jennifer Stinson, Chitra Lalloo, Lauren Harris, Joseph Cafazzo, Lynn Spiegel, Brian Feldman, Nadia Luca, Ronald Laxer P28 Accessing pediatric rheumatology care: Despite barriers, few parents prefer telemedicine Danielle R. Bullock, Richard K. Vehe, Lei Zhang, Colleen K. Correll P29 Exploration of factors contributing to time to achieve clinically inactive disease (CID) in juvenile idiopathic arthritis (JIA): A preliminary report Suhas Ganguli, Max Shenberger, Ritesh Korumilli, Beth Gottlieb P30 Pediatric rheumatology referral patterns: Presenting complaints of new patients at a large, urban academic center Martha Rodriguez, Deirdre de Ranieri, Karen Onel, Linda Wagner-Weiner, Melissa Tesher P31 Quality improvement (QI) initiatives in childhood systemic lupus erythematosus (cSLE) Elizabeth Roth Wojcicki, Kristyn L. Maletta, Dominic O. Co, Marsha Malloy, Sarah Thomson, Judyann C. Olson P32 Proliferative lupus nephritis in juvenile SLE: Support from the pediatric nephrology community for the definitions of responsiveness and flare in the 2012 consensus treatment plans Scott E. Wenderfer, Mileka Gilbert, Joyce Hsu, Sangeeta Sule, Tamar B. Rubinstein, Beatrice Goilav, Daryl M. Okamura, Annabelle Chua, Laurence A. Greenbaum, Jerome C. Lane, Emily von Scheven, Stacy P. Ardoin, Natasha M. Ruth P33 The steroid taper app: Making of a mobile app Jennifer M. P. Woo, Marsha M. Malloy, James A. Jegers, Dustin J. Hahn, Mary K. Hintermeyer, Stacey M. Martinetti, Gretchen R. Heckel, Elizabeth L. Roth-Wojcicki, Dominic O. Co
To assess the long-term outcomes of patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. Patients enrolled in a PFAPA registry were contacted and surveyed. Patients in the registry (n = 59) were surveyed with a follow-up time ranging from 12 to 21 years. Fifty patients had complete symptom resolution, with mean symptom duration of 6.3 years (95% CI, 5.4-7.3), and no sequelae developed. Nine patients continued to have persistent symptoms for a mean duration of 18.1 years (95% CI, 17.4-18.8). There were no differences in initial presentation between subjects with resolved PFAPA and subjects with persistent PFAPA. In subjects with persistent PFAPA, the mean duration of fever >38.3°C decreased from 3.6 days at onset to 1.8 days at follow-up (P = .01), and the mean symptom-free interval between episodes increased from 29 to 159 days (P < .005). Thirty-seven of 44 patients treated with corticosteroids reported prompt symptom resolution. Twelve patients underwent tonsillectomy or adenotonsillectomy; 9 of these patients experienced markedly reduced symptoms, and 6 patients had resolution of symptoms. Two subjects received other diagnoses. In long-term follow-up, most patients with PFAPA experienced spontaneous symptom resolution without sequelae. Patients with persistent symptoms had episodes of shorter duration and reduced frequency.
Proceedings of the National Academy of Sciences of the United States of America •
The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4(+)/CD25(+) T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4(+)/HLA-DR(+) T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker.
