Diana Golden, Antonina Kolmakova, Sunitha Sura, Anthony T. Vella, Ani Manichaikul, Xin-Qun Wang, Suzette J. Bielinski, Kent D. Taylor, Yii-Der Ida Chen, Stephen S. Rich, Annabelle Rodriguez
Jennifer K Roe, Niclas Thomas, Eliza Gil, Katharine Best, Evdokia Tsaliki, Stephen Morris‑Jones, Sian Stafford, Nandi Simpson, Karolina D Witt, Benjamin Chain, Robert F Miller, Adrian Martineau, Mahdad Noursadeghi
BACKGROUND. Alopecia areata (AA) is an autoimmune disease characterized by hair loss mediated by CD8+ T cells. There are no reliably effective therapies for AA. Based on recent developments in the understanding of the pathomechanism of AA, JAK inhibitors appear to be a therapeutic option; however, their efficacy for the treatment of AA has not been systematically examined.
METHODS. This was a 2-center, open-label, single-arm trial using the pan-JAK inhibitor, tofacitinib citrate, for AA with >50% scalp hair loss, alopecia totalis (AT), and alopecia universalis (AU). Tofacitinib (5 mg) was given twice daily for 3 months. Endpoints included regrowth of scalp hair, as assessed by the severity of alopecia tool (SALT), duration of hair growth after completion of therapy, and disease transcriptome.
RESULTS. Of 66 subjects treated, 32% experienced 50% or greater improvement in SALT score. AA and ophiasis subtypes were more responsive than AT and AU subtypes. Shorter duration of disease and histological peribulbar inflammation on pretreatment scalp biopsies were associated with improvement in SALT score. Drug cessation resulted in disease relapse in 8.5 weeks. Adverse events were limited to grade I and II infections. An AA responsiveness to JAK/STAT inhibitors score was developed to segregate responders and nonresponders, and the previously developed AA disease activity index score tracked response to treatment.
CONCLUSIONS. At the dose and duration studied, tofacitinib is a safe and effective treatment for severe AA, though it does not result in a durable response. Transcriptome changes reveal unexpected molecular complexity within the disease.
TRIAL REGISTRATION. ClinicalTrials.gov NCT02197455 and NCT02312882.
FUNDING. This work was supported by the US Department of Veterans Affairs Office of Research and Development, National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health grant R01 AR47223 and U01 AR67173, the National Psoriasis Foundation, the Swedish Society of Medicine, the Fernström Foundation, the Locks of Love Foundation, the National Alopecia Areata Foundation, and the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.
Milène Kennedy Crispin, Justin M. Ko, Brittany G. Craiglow, Shufeng Li, Gautam Shankar, Jennifer R. Urban, James C. Chen, Jane E. Cerise, Ali Jabbari, Mårten C.G. Winge, M. Peter Marinkovich, Angela M. Christiano, Anthony E. Oro, Brett A. King
Julian Mackay-Wiggan, Ali Jabbari, Nhan Nguyen, Jane E. Cerise, Charlotte Clark, Grace Ulerio, Megan Furniss, Roger Vaughan, Angela M. Christiano, Raphael Clynes
Patrick H. Lizotte, Elena V. Ivanova, Mark M. Awad, Robert E. Jones, Lauren Keogh, Hongye Liu, Ruben Dries, Christina Almonte, Grit S. Herter-Sprie, Abigail Santos, Nora B. Feeney, Cloud P. Paweletz, Meghana M. Kulkarni, Adam J. Bass, Anil K. Rustgi, Guo-Cheng Yuan, Donald W. Kufe, Pasi A. Jänne, Peter S. Hammerman, Lynette M. Sholl, F. Stephen Hodi, William G. Richards, Raphael Bueno, Jessie M. English, Mark A. Bittinger, Kwok-Kin Wong
Ashutosh Lal, Esteban Gomez, Cassandra Calloway
Suresh Gopi Kalathil, Amit Anand Lugade, Austin Miller, Renuka Iyer, Yasmin Thanavala
Zoheb B. Kazi, Sean N. Prater, Joyce A. Kobori, David Viskochil, Carrie Bailey, Renuka Gera, David W. Stockton, Paul McIntosh, Amy S. Rosenberg, Priya S. Kishnani
BACKGROUND. Children treated with cerebrospinal fluid (CSF) shunts to manage hydrocephalus frequently develop shunt failure and/or infections, conditions that present with overlapping symptoms. The potential life-threatening nature of shunt infections requires rapid diagnosis; however, traditional microbiology is time consuming, expensive, and potentially unreliable. We set out to identify a biomarker that would identify shunt infection.
METHODS. CSF was assayed for the soluble membrane attack complex (sMAC) by ELISA in patients with suspected shunt failure or infection. CSF was obtained at the time of initial surgical intervention. Statistical analysis was performed to assess the diagnostic potential of sMAC in pyogenic-infected versus noninfected patients.
RESULTS. Children with pyogenic shunt infection had significantly increased sMAC levels compared with noninfected patients (3,211 ± 1,111 ng/ml vs. 26 ± 3.8 ng/ml,
CONCLUSION. Elevated CSF sMAC levels are both sensitive and specific for diagnosing pyogenic shunt infection and may serve as a useful prognostic biomarker during recovery from infection.
FUNDING. This work was supported in part by the Impact Fund of Children’s of Alabama.
Theresa N. Ramos, Anastasia A. Arynchyna, Tessa E. Blackburn, Scott R. Barnum, James M. Johnston
Michael P. Whyte, Katherine L. Madson, Dawn Phillips, Amy L. Reeves, William H. McAlister, Amy Yakimoski, Karen E. Mack, Kim Hamilton, Kori Kagan, Kenji P. Fujita, David D. Thompson, Scott Moseley, Tatjana Odrljin, Cheryl Rockman-Greenberg
Marlise R. Luskin, Phyllis A. Gimotty, Catherine Smith, Alison W. Loren, Maria E. Figueroa, Jenna Harrison, Zhuoxin Sun, Martin S. Tallman, Elisabeth M. Paietta, Mark R. Litzow, Ari M. Melnick, Ross L. Levine, Hugo F. Fernandez, Selina M. Luger, Martin Carroll, Stephen R. Master, Gerald B.W. Wertheim
Victor Gura, Matthew B. Rivara, Scott Bieber, Raj Munshi, Nancy Colobong Smith, Lori Linke, John Kundzins, Masoud Beizai, Carlos Ezon, Larry Kessler, Jonathan Himmelfarb
BACKGROUND. Paneth cell dysfunction has been implicated in a subset of Crohn’s disease (CD) patients. We previously stratified clinical outcomes of CD patients by using Paneth cell phenotypes, which we defined by the intracellular distribution of antimicrobial proteins. Animal studies suggest that Paneth cells shape the intestinal microbiome. However, it is unclear whether Paneth cell phenotypes alter the microbiome complexity in CD subjects. Therefore, we analyzed the correlation of Paneth cell phenotypes with mucosal microbiome composition and ileal RNA expression in pediatric CD and noninflammatory bowel disease (non-IBD) patients.
METHODS. Pediatric CD (
RESULTS. The prevalence of abnormal Paneth cells was higher in pediatric versus adult CD cohorts. For pediatric CD patients, those with abnormal Paneth cells showed significant changes in their ileal mucosal microbiome, highlighted by reduced protective microbes and enriched proinflammatory microbes. Ileal transcriptome profiles showed reduced transcripts for genes that control oxidative phosphorylation in CD patients with abnormal Paneth cells. These transcriptional changes in turn were correlated with specific microbiome alterations. In non-IBD patients, a subset contained abnormal Paneth cells. However, this subset was not associated with alterations in the microbiome or host transcriptome.
CONCLUSION. Paneth cell abnormalities in human subjects are associated with mucosal dysbiosis in the context of CD, and these changes are associated with alterations in oxidative phosphorylation, potentially in a feedback loop.
FUNDING. The research was funded by Helmsley Charitable Trust (to T.S. Stappenbeck, R.J. Xavier, and D.P.B. McGovern), Crohn’s and Colitis Foundation of America (to N.H. Salzman, T.S. Stappenbeck, R.J. Xavier, and C. Huttenhower), and Doris Duke Charitable Foundation grant 2014103 (to T.C. Liu).
Ta-Chiang Liu, Bhaskar Gurram, Megan T. Baldridge, Richard Head, Vy Lam, Chengwei Luo, Yumei Cao, Pippa Simpson, Michael Hayward, Mary L. Holtz, Pavlos Bousounis, Joshua Noe, Diana Lerner, Jose Cabrera, Vincent Biank, Michael Stephens, Curtis Huttenhower, Dermot P.B. McGovern, Ramnik J. Xavier, Thaddeus S. Stappenbeck, Nita H. Salzman
Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
Maria Lucia L. Madariaga, Philip J. Spencer, Kumaran Shanmugarajah, Kerry A. Crisalli, David C. Chang, James F. Markmann, Nahel Elias, A. Benedict Cosimi, David H. Sachs, Tatsuo Kawai
BACKGROUND. Kidney function decreases with age. A potential mechanistic explanation for kidney and allograft half-life has evolved through the realization that linear reduction in glomerular podocyte density could drive progressive glomerulosclerosis to impact both native kidney and allograft half-lives.
METHODS. Predictions from podometrics (quantitation of podocyte parameters) were tested using independent pathologic, functional, and outcome data for native kidneys and allografts derived from published reports and large registries.
RESULTS. With age, native kidneys exponentially develop glomerulosclerosis, reduced renal function, and end-stage kidney disease, projecting a finite average kidney life span. The slope of allograft failure rate versus age parallels that of reduction in podocyte density versus age. Quantitative modeling projects allograft half-life at any donor age, and rate of podocyte detachment parallels the observed allograft loss rate.
CONCLUSION. Native kidneys are designed to have a limited average life span of about 100–140 years. Allografts undergo an accelerated aging-like process that accounts for their unexpectedly short half-life (about 15 years), the observation that older donor age is associated with shorter allograft half-life, and the fact that long-term allograft survival has not substantially improved. Podometrics provides potential readouts for these processes, thereby offering new approaches for monitoring and intervention.
FUNDING: National Institutes of Health.
Abhijit S. Naik, Farsad Afshinnia, Diane Cibrik, Jeffrey B. Hodgin, Fan Wu, Min Zhang, Masao Kikuchi, Larysa Wickman, Milagros Samaniego, Markus Bitzer, Jocelyn E. Wiggins, Akinlolu Ojo, Yi Li, Roger C. Wiggins
BACKGROUND. Failed myocardial reperfusion is common and prognostically important after acute ST-elevation myocardial infarction (STEMI). The purpose of this study was to investigate coronary flow reserve (CFR), a measure of vasodilator capacity, and the index of microvascular resistance (IMR; mmHg × s) in the culprit artery of STEMI survivors.
METHODS. IMR (
RESULTS. Myocardial hemorrhage and microvascular obstruction occurred in 89 (42%) and 114 (54%) patients with evaluable T2*-MRI maps. IMR and CFR were associated with microvascular pathology (none vs. microvascular obstruction only vs. microvascular obstruction and myocardial hemorrhage) (median [interquartile range], IMR: 17 [12.0–33.0] vs. 17 [13.0–39.0] vs. 37 [21.0–63.0],
CONCLUSIONS. IMR is more closely associated with microvascular pathology, left ventricular remodeling, and health outcomes than the angiogram or CFR.
TRIAL REGISTRATION. NCT02072850.
FUNDING. A British Heart Foundation Project Grant (PG/11/2/28474), the National Health Service, the Chief Scientist Office, a Scottish Funding Council Senior Fellowship, a British Heart Foundation Intermediate Fellowship (FS/12/62/29889), and a nonfinancial research agreement with Siemens Healthcare.
David Carrick, Caroline Haig, Jaclyn Carberry, Vannesa Teng Yue May, Peter McCartney, Paul Welsh, Nadeem Ahmed, Margaret McEntegart, Mark C. Petrie, Hany Eteiba, Mitchell Lindsay, Stuart Hood, Stuart Watkins, Ahmed Mahrous, Samuli M.O. Rauhalammi, Ify Mordi, Ian Ford, Aleksandra Radjenovic, Naveed Sattar, Keith G. Oldroyd, Colin Berry
BACKGROUND. Some adult patients presenting with unexplained pyrexia, serositis, skin rashes, arthralgia, myalgia, and other symptoms commonly found in autoinflammatory disorders may not fit a specific diagnosis, either because their clinical phenotype is nondiagnostic or genetic tests are negative. We used the term undifferentiated systemic autoinflammatory disorder (uSAID) to describe such cases. Given that well-defined autoinflammatory diseases show responses to IL-1 blockade, we evaluated whether anakinra was useful for both diagnosing and treating uSAID patients.
METHODS. We performed a retrospective analysis of consecutive patients presenting with uSAID between 2012–2015 who were treated with the recombinant IL-1 receptor antagonist anakinra. uSAID was diagnosed after excluding malignancy, infection, and pathogenic mutations in known hereditary fever syndromes (HFS) genes and where clinical criteria for adult onset Still’s disease (AOSD) were not met.
RESULTS. A total of 11 patients presented with uSAID (5 males and 6 females), with a mean time to diagnosis of 3.5 years (1–8 years). Patients were unresponsive or only partially controlled on disease-modifying antirheumatic drug (DMARD)/steroid treatment. Anakinra controlled symptoms within 4–6 weeks of starting treatment in 9 of 11 cases. Two patients discontinued therapy — one due to incomplete response and another due to severe injection-site reactions.
CONCLUSION. This retrospective case series demonstrates that the spectrum of poorly defined autoinflammatory disorders that show responsiveness to anakinra is considerable. Anakinra seems a viable treatment option for these patients, who are unresponsive to standard steroid/DMARD treatments. Moreover, given the mechanisms of action, response to anakinra implicates underlying IL-1 dysregulation in the disease pathogenesis of responding uSAIDs patients.
Stephanie R. Harrison, Dennis McGonagle, Sharmin Nizam, Stephen Jarrett, Jeroen van der Hilst, Michael F. McDermott, Sinisa Savic
Ryan J. Adam, Katherine B. Hisert, Jonathan D. Dodd, Brenda Grogan, Janice L. Launspach, Janel K. Barnes, Charles G. Gallagher, Jered P. Sieren, Thomas J. Gross, Anthony J. Fischer, Joseph E. Cavanaugh, Eric A. Hoffman, Pradeep K. Singh, Michael J. Welsh, Edward F. McKone, David A. Stoltz
BACKGROUND. Kidney transplant biopsies offer an opportunity to understand the pathogenesis of organ fibrosis. We studied the relationships between the time of biopsy after transplant (TxBx), histologic fibrosis, diseases, and transcript expression.
METHODS. Expression microarrays from 681 kidney transplant indication biopsies taken either early (
RESULTS. Fibrosis was absent at transplantation but was present in some early biopsies by 4 months after transplant, apparently as a self-limited response to donation implantation injury not associated with progression to failure. The molecular phenotype of early biopsies represented the time sequence of the response to wounding: immediate expression of acute kidney injury transcripts, followed by fibrillar collagen transcripts after several weeks, then by the appearance of immunoglobulin and mast cell transcripts after several months as fibrosis appeared. Fibrosis in late biopsies correlated with injury, fibrillar collagen, immunoglobulin, and mast cell transcripts, but these were independent of time. Pathway analysis revealed epithelial response-to-wounding pathways such as Wnt/β-catenin.
CONCLUSION. Fibrosis in late biopsies had different associations because many kidneys had potentially progressive diseases and subsequently failed. Molecular correlations with fibrosis in late biopsies were independent of time, probably because ongoing injury obscured the response-to-wounding time sequence. The results indicate that fibrosis in kidney transplants is driven by nephron injury and that progression to failure reflects continuing injury, not autonomous fibrogenesis.
TRIAL REGISTRATION. INTERCOM study (www.clinicalTrials.gov; NCT01299168).
FUNDING. Canada Foundation for Innovation and Genome Canada.
Jeffery M. Venner, Konrad S. Famulski, Jeff Reeve, Jessica Chang, Philip F. Halloran
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