In 1997, a group of researchers from around the globe discovered that the AIRE gene was the cause of APS Type 1. Since then, researchers have made great strides to better understand the processes behind APS Type 1, the AIRE gene, disease development over time, and the general impact on patients and families.

While researchers now understand a bit better how the disease works, and there have been a few developments in treatments, there is still a long way to go. The APS Type 1 Foundation is a committed research partner and has invested over $500,000 to support research to date.

Browse Published Research

We’ve curated a list of research articles, which fit generally into the following three categories:

For each article, we’ve provided a short summary and a few key quotations from the article. It may be necessary to enroll with a publication in order to view an article. For example, the New England Journal of Medicine gives access to three free articles a month if you apply for access online.

This is by no means an exhaustive list of the research that exists. We are fortunate that so many researchers have an interest in our rare disease. Research articles are not a substitute for direct medical advice. You should consult your own medical advisors with respect to your medical needs. The APS Type 1 Foundation does not endorse these articles and the views expressed in the articles are solely those of the authors. That said, we hope you find these articles informative and useful.

To learn more, consider signing up for a Google Scholar Email Alert for “APECED.”

APS Type 1 Research Articles

Authors

Kentaro Nagamine, Pärt Peterson, Hamish S. Scott, Jun Kudoh, Shinsei Minoshima, Maarit Heino, Kai J. E. Krohn, Maria D. Lalioti, Primus E. Mullis, Stylianos E. Antonarakis, Kazuhiko Kawasaki, Shuichi Asakawa, Fumiaki Ito & Nobuyoshi Shimizu

Publication

Nature Genetics

Date

December 1997

Description/Quotes

This article identifies the AIRE gene and its importance in understanding and treating autoimmune diseases.

“Autoimmune polyglandular syndrome type I (APS 1, also called APECED) is an autosomal-recessive disorder that maps to human chromosome 21q22.3 between markers D21S49 and D21S171 by linkage studies. We have isolated a novel gene from this region, AIRE (autoimmune regulator) […] The identification of the gene defective in APECED should facilitate the genetic diagnosis and potential treatment of the disease and further enhance our general understanding of the mechanisms underlying autoimmune diseases.”

Authors

Johanna Aaltonen, Petra Björses, Jaakko Perheentupa, Nina Horelli–Kuitunen, Aarno Palotie, Leena Peltonen, Yeon Su Lee, Fiona Francis, Steffen Henning, Cora Thiel, Hans Leharach & Marie–Laure Yaspo

Publication

Nature Genetics

Date

December 1997

Description/Quotes

This article Identifies the AIRE gene and its importance in understanding and treating autoimmune diseases.

“Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is the only described systemic autoimmune disease with established monogenic background, and the first autoimmune disorder localized outside the major histocompatibility complex (MHC) region. The primary biochemical defect in APECED is unknown. We have isolated a novel gene, AIRE, encoding for a putative nuclear protein featuring two PHD-type zinc-finger motifs, suggesting its involvement in transcriptional regulation. Five mutations in AIRE are reported in individuals with this disorder. This is the first report of a single-gene defect causing a systemic human autoimmune disease, providing a tool for exploring the molecular basis of autoimmunity.”

Authors

John D. Rioux & Abul K. Abbas

Publication

Nature

Date

June 2005

Description/Quotes

This article provides an easy to understand explanation of the differences between rare single gene autoimmune disorders, like APS Type 1, and more common multi-gene autoimmune disorders, such as Crohn’s disease. The AIRE mutation (genotype) leads directly to APS Type 1 (the disease state). In complex traits, like Type 1 diabetes, Graves’ disease, and rheumatoid arthritis, multiple genotypes and environmental factors (e.g., smoking, pregnancy, and diet) interact to produce the disease state. This illustrates why the very few, rare, single gene disorders like APS Type 1 can lead to breakthroughs in understanding common, complex autoimmune disorders.

“Here, we summarize our current understanding of the genetic basis of autoimmunity. […] A brief introduction to the mechanisms of self tolerance and its breakdown provide the foundation for the subsequent discussion of the genetics of autoimmune diseases.”

“In simple mendelian traits, the relationship between the causal genetic variant (genotype) and the disease state is deterministic. In complex traits, the clinically recognized disease state results from interactions between multiple genotypes and the environment.”

“The elegant simplicity of […] monogenic disorders has been key to using them to elucidate mechanisms of self tolerance and autoimmunity.”

Author

Michail S. Lionakis

Publication

Medical Mycology

Date

August 2014

Description/Quotes

The enhanced susceptibility of APS Type 1 patients to candida has provided clues to the basis of the autoimmune response to this widespread infection.  This article is the second of two seminal works by Dr. Lionakis predicting his future research into APS Type1 and chronic mucocutaneous candidiasis (CMC).

“Systemic infection caused by Candida species is the fourth leading cause of nosocomial bloodstream infection in modern hospitals and carries high morbidity and mortality despite antifungal therapy. A recent surge of immunological studies in the mouse models of systemic candidiasis and the parallel discovery and phenotypic characterization of inherited genetic disorders in antifungal immune factors that are associated with enhanced susceptibility or resistance to the infection have provided new insights into the cellular and molecular basis of protective innate immune responses against Candida.”

Authors

Michail S. Lionakis, Mihai G. Netea & Steven M. Holland

Publication

Cold Spring Harbor Perspectives in Medicine

Date

June 2014

Description/Quotes

This article is one of two seminal works by Dr. Michail Lionakis predicting his future research into APS Type1 and CMC. 

“A recent surge in newly described inborn errors of immune function-related genes that result in susceptibility to fungal disease has greatly enhanced our understanding of the cellular and molecular basis of antifungal immune responses.”

“Besides autoimmunity, APECED patients almost universally develop CMC, the sole consistent infectious disease phenotype.”

Because almost all APS Type 1 patients develop chronic mucocutaneous candidiasis (CMC), it is important to “[…] develop a detailed mechanistic understanding of how our immune system handles different fungi at different sites, which in turn should aide in devising better strategies for risk assessment, treatment and prognostication of patients with fungal disease.” 

“Finally, and most importantly, by synthesizing the knowledge provided by these experiments of nature, we should be able to develop a detailed mechanistic understanding of how our immune system handles different fungi at different sites, which in turn should aide in devising better strategies for risk assessment, treatment and prognostication of patients with fungal disease.”

“we should be able to develop a detailed mechanistic understanding of how our immune system handles different fungi at different sites, which in turn should aide in devising better strategies for risk assessment, treatment and prognostication of patients with fungal disease.” 

Authors

Lara E. Pereira, Pavel Bostik, & Aftab A. Ansari

Publication

Clinical & Developmental Immunology

Date

September 2005

Description/Quotes

The AIRE gene was first identified through the use of positional cloning which eventually led to the successful development of a mouse model for APECED.  The creation of Aire knockout mice has facilitated in-depth studies of this disease since Aire-deficient mice exhibit characteristics similar to APECED patients.

“Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy is a rare recessive autoimmune disorder caused by a defect in a single gene called AIRE (autoimmune regulator). Characteristics of this disease include a variable combination of autoimmune endocrine tissue destruction, mucocutaneous candidiasis and ectodermal dystrophies. The development of Aire-knockout mice has provided an invaluable model for the study of this disease. The aim of this review is to briefly highlight the strides made in APECED research using these transgenic murine models, with a focus on known roles of Aire in autoimmunity. The findings thus far are compelling and prompt additional areas of study which are discussed.”

Author

Adrian Liston

Publication

Drug Discovery Today: Disease Models

Date

2006

Description/Quotes

The development of the Aire knockout mouse as a tool to study APS 1 has given us a clearer understanding of how immunological tolerance works (autoimmunity).  This understanding can now be applied to better understanding other, common autoimmune disorders.

“Determination of the genetic basis of APS1 allowed the rational design of a murine mouse model, the Aire knockout mouse. As a tool to dissect the point of immunological tolerance failure in the human disease, the Aire knockout mouse has been indispensable. Use of the knockout has resulted in rapid elucidation of the key tolerogenic mechanisms of Aire, with direct translation to APS1. This has allowed the development of the current model by which Aire initiates thymic transcription of organ-specific antigens, allowing clonal deletion mechanisms to purge the T cell repertoire of autoreactive clones. It has also provided key insights on the mechanisms by which tolerance might be broken in common autoimmune diseases, beyond the rare condition of APS1.”

Authors

Jason Ossart, Anne Moreau, Elodie Autrusseau, Severine Menoret, Jerome C. Martin, Marine Besnard, Laure-Helene Ouisse, Laurent Tesson, Lea Flippe, Kai Kisand, Part Peterson, Francios-Xavier Hubert, Ignacio Anegon, Regis Josien, & Carole Guillonneau

Publication

The Journal of Immunology

Date

June 2018

Description/Quotes

A new animal model, AIRE deficient rats, has been developed, which will be useful and provide new insight into the role of AIRE.

“Several models of AIRE-deficient mice have been generated, and although they have been useful in understanding the role of AIRE in central tolerance, they do not reproduce accurately the APECED symptoms, and thus there is still a need for an animal model displaying APECED-like disease. […] To our knowledge, we generated the first AIRE-deficient rat model using zinc-finger nucleases and demonstrated that they display several of the key symptoms of APECED disease, including alopecia, skin depigmentation, and nail dystrophy, independently of the genetic background.”

Authors

Mark S. Anderson, Emily S. Venanzi, Ludger Klein, Zhibin Chen, Stuart P. Berzins, Shannon J. Turley, Harald von Boehmer, Roderick Bronson, Andree Dierich, Christophe Benoist & Diane Mathis

Publication

Science

Date

October 2002

Description/Quotes

This article presents an “elegant demonstration of the importance of AIRE-dependent thymic selection in self tolerance.”

“Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire-deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue– restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. […] These findings highlight the importance of thymically imposed ‘central’ tolerance in controlling autoimmunity.”

“Following clues from the human system, we anticipated that mice lacking the aire gene would prove key to addressing these issues. Autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy (APECED), also known as autoimmune polyendocrine syndrome–type 1 (APS-1), is a polyglandular disorder that classically manifests as spontaneous autoimmunity against the parathyroid and/or adrenal glands, and/or by a mucocutaneous candidiasis infection.”

Author

Leonard Sigal

Publication

JCR: Journal of Clinical Rheumatology

Date

February 2006

Description/Quotes

This article explores new insights into our understanding of AIRE with particular emphasis on the work of Mark Anderson’s group.

“One of the miracles of immunology is tolerance, the ability of the immune system to differentiate self from nonself and leave the former alone. Autoreactive thymocytes (the cells that would otherwise differentiate into mature autoaggressive T cells) are deleted from theemerging immunologic repertoire within the thymus; only a very small proportion of thymocytes survive the thymus—perhaps 2% to 5% emerge to become mature T cells in the periphery, the rest dying to assure tolerance. This apparent wastage somehow works to the benefit of the developing animal and if the process works, all goes well for the maturing immune system. In some autoimmune syndromes, autoreactive thymocytes are not eliminated  within the thymus by either clonal deletion or activation-induced cell death; these then emerge to wreak their havoc. However, how does this deletion happen? Recent research from a number of groups has (incredibly!) identified expression of nonthymic, nonlymphoid proteins within the thymus (casting of the ‘immunologic shadow of self’), and this is under the control of a single protein: AIRE (autoimmune regulator). By allowing autoreactive thymocytes to encounter a broad spectrum of proteins from extrathymic organs, aire allows deletion of these cells and the maintenance of tolerance. The absence of aire leads to autoimmune polyendocrinopathy, proof that aire is the center of an amazing ‘filtering’ system. These and other molecular mechanisms underlying tolerance are explored in this and the next paper in this series.”

Author

Roberto Perniola

Publication

Frontiers in Immunology

Date

February 2018

Description/Quotes:

This article “recapitulate the course of discoveries over Aire, and marks […] doubts and insights into its function.”

“Pathogenic AIRE variants cause the autoimmune polyglandular syndrome type 1, which is a rare and complex disease that is gaining attention in research on autoimmunity. […] Delineation of AIRE functions adds interesting data to the knowledge of the mechanisms of self-tolerance and introduces exciting perspectives of therapeutic interventions against the related diseases.

“The absolute heritable profile of the human related disease, APS1, suggests exciting implications on the topic of gene therapies.”

Aire expression can be manipulated by immunologic, virus-based, physical, and chemical methods. Nonetheless, enhancing Aire expression may impair unexpected forms of immune defense and get unwelcome surprises. As seen, genes encoding some cancer-associated ts-ags are Aire-dependent, so that it is not surprising that Aire−/− mice are able to provide a stronger immune response after melanoma challenge.”

“Translating these data to hypothetical therapies of human autoimmune diseases, the cited studies suggest that, while restoring AIRE expression is the goal of gene therapy in APS1 patients, ideal profile of a tailored, AIRE-based treatment should be restricted to selected cell lineages or single AIRE-dependent genes, to avoid the pitfalls of a generalized PGE* distortion.

“Of course, just an increasing knowledge of PGE and the related Aire role will help to refine any strategy aiming at restoring, promoting, or strengthening the mechanisms of central and peripheral self-tolerance.

“First Aire−/− mice were engineered in 2002 […]”

“About two decades ago, cloning of the autoimmune regulator (AIRE) gene materialized one of the most important actors on the scene of self-tolerance”

*promiscuous gene expression

Authors

Diane Mathis & Christophe Benoist

Publication

Nature Reviews Immunology

Date

July 2007

Description/Quotes

It is interesting to contrast this article which explore the first 10 years of AIRE research with the article, “Twenty Years of Aire”, to see how far our understanding of AIRE has come in 10 short years.

“In 1997, the autoimmune regulator (AIRE) gene was identified as the locus underlying susceptibility to the polyendocrine autoimmune disease known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). In the intervening 10 years, it has become increasingly clear that this rare disorder has provided us with an illuminative window on one of the most fundamental processes of the immune system — the establishment and maintenance of self tolerance.”

Authors

Mireia Mora, Felicia A. Hanzu, Marta Pradas-Juni, Gloria B. Aranda, Irene Halperin, Manuel Puig-Domingo, Sira Aguiló & Eduardo Fernández-Rebollo

Publication

PLOS | ONE

Date

July 2014

Description/Quotes

This article identifies the molecular defects and investigates the clinical and mutational characteristics of two siblings with APS-1. Although both siblings carried the same homozygous splicing mutation, one developed severe symptoms while the other developed only mild symptoms. 

“To date, more than a hundred different mutations of the AIRE gene have been identified in APS-1 patients, but only two major mutations (p.R257X and p.L323SfsX51) are responsible for 95% of the mutant alleles in APS-1 patients.  However, it is noteworthy that few AIRE mutations have been thoroughly studied and on the other hand, with only one previous publication about an AIRE mutation reported in Spain.”

Authors

Eystein S. Husebye & Mark S. Anderson

Publication

Immunity

Date

April 2010

Description/Quotes

This article clearly links the study of APS Type 1 to gaining a better understanding of Type 1 diabetes and new treatments.

“Autoimmune diseases like type 1 diabetes are complex in their pathogenesis. One approach to improving our understanding of type 1 diabetes is the study of diseases that represent more extreme examples of autoimmunity.  Autoimmune polyendocrine syndromes (APS) are relatively rare diseases that often include type 1 diabetes as part of the disease phenotype. Recently there has been tremendous progress in unraveling some of the underlying mechanisms of APS. Here we highlight the APS disorders with the perspective of the clues they can offer to the pathogenesis and treatment of type 1 diabetes.”

Authors

Steffen Meyer, Matin Woodward, Christina Hertel, Phillip Vlaicu, Yasmin Haque, Jaanica Kamer, Annalisa Macagno, Shimobi C. Onuoha, Dymtro Fishman, Hedi Peterson, Kaja Metskula, Raivo Uibo, Kirsi Jantti, Kati Hokynar, Anette S.B Wolfe APECED patient collaborative, Kai Krohn, Annamari Ranki, Part Peterson, Kai Kisand, & Adrian Hayday

Publication

Cell

Date

July 2016

Description/Quotes

By studying the naturally occurring autoantibodies that occur in APS Type 1 patients, which seem to actively limit type 1 diabetes, new therapeutic approaches to type 1 diabetes may be possible.

“[…] many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.”

Authors

Maureen A. Su & Mark S. Anderson

Publication

Nature Reviews Immunology

Date

April 2016

Description/Quotes

This article highlights how much we’ve learned about the function of the AIRE gene, and how much remains to be discovered.  AIRE may provide clues into providing new types of therapies for a variety of cancers.

“[…] there have been major advances of our understanding of autoimmunity through the study of monogenic forms of (autoimmune) disease(s).” 

AIRE was originally identified as the culprit mutated gene in patients with an autosomal recessive form of autoimmunity called Autoimmune Polyglandular Syndrome Type 1 (APS1).” 

“In addition to melanoma, other cancer types may also be modulated by Aire. In mouse models of primary and transplanted sarcoma, negative regulation of Aire-expressing mTECs enhanced anti-tumor immunity. As described above, Aire also regulates Treg TCR clones that were originally isolated from prostate cancer, suggesting a role for Aire in regulating T cell immune response against prostate cancer. Thus, Aire is likely to have a broad effect on multiple cancer types.”

“Recently, our group also provided evidence that modulation of Aire-expressing mTEC’s may be a tractable approach for enhancing tumor-specific immune responses.”

“Looking forward there is still much that needs to be learned about the biology by which this critical regulator of tolerance operates and how pathways it controls contribute to human disease.”   “Aire mediated TSA upregulation in mTECs also impacts the development of chronic graft versus host disease (cGVHD), a major complication of allogeneic hematopoietic stem cell transplantation.”

Author

Olle Kämpe

Publication

Journal of Internal Medicine

Date

April 2009

Description/Quotes

Research into understanding APS Type 1 Candidiasis may help patients on immunosuppressive drugs or patients with immunodeficiencies such as AIDS.

“Rapid progress has recently been made in our understanding of tolerance mechanisms as a result of studies of APS‐1.”

“The identification of modifying genes, environmental events or stochastic factors that cause such variable clinical presentations in a monogenic disease may help in the understanding of common autoimmune disorders.”

“Although most components of APS‐1, endocrine or nonendocrine, are attributable to an autoimmune assault and the autoantigens for most of manifestations has now been identified, the cause of mucocutaneous Candidiasis, a hallmark of the disease, still remains elusive. An effort to understand why almost all APS‐1 patients develop this superficial fungal infection, despite a normal response to other bacterial and fungal infections, may help patients on immunosuppressive drugs or patients with immunodeficiencies such as AIDS. This may also shed more light on the exact function(s) of the AIRE protein.”

Authors

Mireia Giménez-Barcons, Anna Casteràs, Maria del Pilar Armengol, Eduard Porta, Paula A. Correa, Ana Marín, Ricardo Pujol-Borrell & Roger Colobran

Publication

The Journal of Immunology

Date

October 2014

Description/Quotes

The study of AIRE gene expression is important in understanding APS Type 1, as well as Down syndrome (DS), since both conditions share a similar range of autoimmune disorders.

“Although it is widely accepted that autoimmunity requires a failure of immunological tolerance to self-antigens, how this originates in most cases remains unknown. However, solid evidence exists that genetic factors play a major role. Because the primary genetic anomaly in DS is well defined, analyzing autoimmune disease in DS can contribute to advancing our understanding of both autoimmunity and DS.”

“It is recognized that the spectrum of autoimmune diseases that DS subjects have is reminiscent of that seen in the rare autosomal recessive disease autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome, also called autoimmune polyendocrine syndrome type 1.”

“In this study, we confirmed that there was a significant, specific reduction in AIRE expression in the thymus of those with DS and that this resulted in clearly reduced pGE in these subjects.“ “Thus, our findings provide evidence for the fundamental role of AIRE and pGE in preventing the development of autoimmunity in DS individuals and support the concept that their predisposition to autoimmune disease is not due to premature immune senescence but to a qualitative failure of the thymus in the establishment of central tolerance.”

Authors

Flavia A. Lima, Carlos A. Moreira-Filho, Patrıcia L. Ramos, Helena Brentani, Leandro de A. Lima, Magaly Arrais, Luiz C. Bento-de-Souza, Luciana Bento-de-Souza, Maria I. Duarte, Antonio Coutinho, & Magda Carneiro-Sampaio

Publication

The Journal of Immunology

Date

Originally published August 2011 but noted that this information is current as of November 4, 2019.

Description/Quotes

The study of AIRE gene expression is important in understanding APS Type 1, as well as Down syndrome (DS), since both conditions share a similar range of autoimmune disorders.

“Although some similarities between DS and APECED prompted us to investigate AIRE in DS (and, in fact, we now know that AIRE expression is altered in both conditions), they result from different pathophysiological mechanisms. In APECED, we have an AIRE mutation causing a severe impairment of gene function, whereas in DS, there is a moderate decrease in AIRE expression interplaying with a global thymic gene hypofunction caused by trisomy 21. Nonetheless, it is striking that both conditions show important commonalities regarding organ-specific autoimmune disorders, mainly endocrinopathies, as well as unique autoimmune Ab pattern.”

Authors

Meng-Lei Zhu, Anil Nagavalli & Maureen A. Su

Publication

Cancer Research

Date

January 2013

Description/Quotes

APS Type 1 patients, because of AIRE deficiency, may have an activated immune response to melanomas, which is worth investigating. Dr. Su presented this work at an APS Type 1 breakout session at the 2019 National IDF Conference.

“Melanoma is the deadliest form of skin cancer and accounts for 5% of cancer deaths in the United States.”

“[…] AIRE-deficient patients are predisposed to vitiligo, an autoimmune disease of melanocytes that is often triggered by efficacious immunotherapies against melanoma. “Aire deficiency is associated with activated immune response against melanoma.”

Clinical and Patient Guidance

Authors

Eystein S. Husebye, Mark S. Anderson & Olle Kämpe

Publication

The New England Journal of Medicine

Date

March 2018

Description/Quotes

This article provides a comprehensive discussion of APS Type 1, including clinical features, genetics and disease mechanisms, and auto-antibodies, as well as a discussion of other inherited forms of Autoimmune Polyendocrine Syndromes (IPEX and APS Type 2).

“Work is currently under way to generate thymic epithelial tissue from stem cells. This approach could eventually be used to correct the expression of AIRE in patients with APS-1 and help reverse the immunopathological course that leads to multiorgan autoimmunity.”

Authors

Elise Ferre, Stacey Rose, Sergio Rosenzweig, Peter Burbelo, Kimberly Romito, Julie Niemela, Lindsey Rosen, Timothy Break, Wenjuan Gu, Sally Hunsberger, Sarah Browne, Amy Hsu, Shakuntala Rampertaap, Muthulekha Swamydas, Amanda Collar, Heidi Kong, Chyi-Chai Richard Lee, David Chascsa, Thomas Simcox, Angela Pham, Anamaria Bondici, Mukil Natarajan, Joseph Monsale, David Kleiner, Martha Quezado, Ilias Alevizos, Niki Moutsopoulos, Lynne Yockey, Cathleen Frein, Ariane Soldatos, Katherine Calvo, Jennifer Adjemian, Morgan Similuk, David Lang, Kelly Stone, Gulbu Uzel, Jeffrey Kopp, Rachel Bishop, Steven M. Holland, Kenneth N. Olivier, Thomas A. Fleisher, Theo Heller, Karen K. Winer & M.S. Lionakis

Publication

JCI insight

Date

August 2016

Description/Quotes

This groundbreaking research at the National Institutes of Health was developed through comprehensively examining a large cohort of North American patients. This research lead to the identification of a second triad of APS Type 1 manifestations, which when used, would lead to faster identification and treatment of the disorder.

“We admitted all patients to the NIH and obtained detailed medical histories; then, comprehensive clinical, laboratory, and radiographic evaluations were performed by a multidisciplinary team of specialists with an aim to systematically record all clinical manifestations in our patients and identify common and distinct features relative to other APECED cohorts.”

“By systematically defining early nonclassic triad APECED manifestations, we found that patients were likely to have been seen by dermatologists, gastroenterologists, dentists, ophthalmologists, pulmonologists, and hepatologists early in the course of their disease, often before they developed the widely recognized endocrine and fungal manifestations. In this patient cohort, incorporating urticarial eruption, intestinal dysfunction, and enamel hypoplasia into the diagnostic criteria of APECED would result in earlier recognition and diagnosis.”

Authors

Rachel I. Gafni & Michael T. Collins

Publication

The New England Journal of Medicine

Date

May 2019

Description/Quotes

This article discusses diagnosis and evaluation of hypoparathyroidism, medications for the treatment of hypoparathyroidism, monitoring and therapeutic targets, conventional therapy for hypoparathyroidism including emergency and long-term management guidelines & possible reno-protective therapies.

“PTH is critical for maintaining the level of circulating calcium within a narrow normal range through its actions on bone, kidney, and intestine. Its secretion is regulated primarily by the calcium-sensing receptor (CaSR) found on parathyroid chief cells; when ambient calcium levels are low, the CaSR is inactive and PTH synthesis and secretion are increased.  PTH then regulates calcium and phosphate levels by actions on the bone, kidney, and, indirectly, intestine.”

Authors

Sergio Setsuo Maeda, Carolina Aguiar Moreira, Victória Zeghbi Cochenski Borba, Francisco Bandeira, Maria Lucia Fleiuss de Farias, João Lindolfo Cunha Borges, Francisco José, Albuquerque de Paula, Felipe Augusto Brasileiro Vanderlei, Fábio Luiz de Menezes Montenegro, Rodrigo Oliveira Santos, Bruno Ferraz-de-Souza & Marise Lazaretti-Castro

Publication

Archives of Endocrinology and Metabolism

Date

February 2018

Description/Quotes

This article reviews the etiology, epidemiology, clinical manifestations, diagnosis, treatment, and complications of hypoparathyroidism, i.e. what are the chronic complications of hypoparathyroidism? and how should they be monitored?

Dr. Winer’s work on the use of parathyroid hormone (PTH) is cited: “Hypoparathyroidism persists as the last classic hormone deficiency in which the conventional treatment is not done with replacement of the missing hormone (D) (1-3). Studies with PTH (1-34) administered with a continuous infusion pump, compared with subcutaneous PTH (1-34) twice daily in adults and children, showed a more physiological control of serum calcium and reduction in urinary calcium. It is important to highlight that PTH (1-34) is only approved for the treatment of osteoporosis in adults and for 18 to 24 months, and has not been approved by regulatory agencies for the use in hypoparathyroidism. In January 2015, the FDA approved the use of PTH (1-84) for the treatment of hypoparathyroidism.”

“Serum calcium concentration is maintained within a narrow physiological range by complex controlling mechanisms involving the parathyroid hormone (PTH), active vitamin D (1,25(OH)2D), and calcium sensor receptors (CaSRs) acting in renal, intestinal, parathyroid, and bone tissues to maintain mineral homeostasis. When these homeostatic mechanisms fail or are not fully compensated, hypocalcemia occurs.”

The authors’ purpose is “to present an update on the diagnosis and treatment of hypoparathyroidism based on the most recent scientific evidence.”

“Over the past ten years, we have gained a greater understanding of hypoparathyroidism regarding its epidemiology, genetics, associated skeletal disease, and therapies. A major therapeutic challenge in hypocalcemia is effectively balancing calcium levels while avoiding hypercalciuria and other complications.”

Authors

Maria Luisa Brandi, John P. Bilezikian, Dolores Shoback, Roger Bouillon, Bart L. Clarke, Rajesh V. Thakker, Aliya A. Khan & John T. Potts, Jr.

Publication

The Journal of Clinical Endocrinology & Metabolism

Date

June 2016

Description/Quotes

This publication presents guidelines developed from the 1st International Conference on the Management of Hypoparathyroidism with extensive discussion of the use of PTH (1-34) and PTH (1-84) for the management of hypoparathyroidism. Dr. Winer’s work is cited extensively.

“Hypoparathyroidism is a rare disorder characterized by hypocalcemia and absent or deficient PTH. This report presents a summary of current information about epidemiology, presentation, diagnosis, clinical features, and management and proposes guidelines to help clinicians diagnose, evaluate, and manage this disorder.”

Authors

Jens Bollerslev, Lars Rejnmark, Claudio Marcocci, Dolores M. Shoback, Antonio Sitges-Serra, Wim van Biesen & Olaf M Dekkers

Publication

European Journal of Endocrinology

Date

August 2015

Description/Quotes

This article discusses diagnosis, treatment and monitoring strategies for hypoparathyroidism. Dr. Winer’s work is cited extensively.

“Hypoparathyroidism (HypoPT) is a rare (orphan) endocrine disease with low calcium and inappropriately low (insufficient) circulating parathyroid hormone levels[…] Standard treatment is activated vitamin D analogues and calcium supplementation and not replacement of the lacking hormone, as in other hormonal deficiency states. The purpose of this guideline is to provide clinicians with guidance on the treatment and monitoring of chronic HypoPT in adults […] We intend to draft a practical guideline, focusing on operationalized recommendations deemed to be useful in the daily management of patients.”

Authors

E. S. Husebye, B. Allolio, W. Arlt, K. Badenhoop, S. Bensing, C. Betterle, A. Falorni, E. H. Gan, A.-L. Hulting, A. Kasperlik-Zaluska, O. Kämpe, K. Løvas, G. Meyer & S. H. Pearce

Publication

Journal of Internal Medicine

Date

November 2013

Description/Quotes

This article includes recommendations on diagnosis of primary adrenal insufficiency, guidelines on chronic replacement therapy, guidelines for treatment of an adrenal crisis, and guidelines for follow-up of patients with primary adrenal insufficiency. Includes example of Swedish medical information card.

“Primary adrenal insufficiency (PAI), or Addison’s disease, is a rare, potentially deadly, but treatable disease.”

“The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison’s disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium’s investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow-up.”

“Patients with PAI require lifelong steroid replacement, both glucocorticoids and mineralocorticoids, and often an increased intake of sodium chloride to compensate for increase adrenal loss. Education on how to increase steroid doses during concurrent illnesses or injury is important, as well as training in intramuscular administration of HC during acute adrenal crisis. Patients should wear a Medic Alert Bracelet and carry a steroid card to inform medical personnel on chronic PAI status. Delays in the administration of HC in an emergency or stress situation by the patient or healthcare professionals can be fatal. The sad fact remains that many patients have to argue with the attending physician or emergency department staff to receive emergency treatment, and this must be overcome by improved information.”

Authors

Stefan R. Bornstein, chair, Bruno Allolio, Wiebke Arlt, Andreas Barthel, Andrew Don-Wauchope, Gary D. Hammer, Eystein S. Husebye, Deborah P. Merke, M. Hassan Murad, Constantine A. Stratakis & David J. Torpy

Publication

The Journal of Clinical Endocrinology & Metabolism

Date

February 2016

Description/Quotes

This article includes good charts on “Management of PAI (Primary Adrenal Insufficiency) in Specific Situations” and “Measures for Preventing Adrenal Crisis”

“This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency.”

“Patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticosteroids and associated autoimmune diseases, particularly autoimmune thyroid disease.”

Authors

Øyvind Bruserud, Daniela-Elena Costea, Saila Laakso, Ben-Zion Garty, Eirik Mathisen, Antti Mäkitie, Outi Mäkitie & Eystein S. Husebye

Publication

Frontiers in Endocrinology

Date

July 2018

Description/Quotes

This article discusses APS type 1 and oral cancers, noting that “[s]crutiny of history and clinical phenotypes indicate that chronic mucocutaneous candidiasis and smoking are significant risk factors.”

“Recently, we have come across several APS-1 patients diagnosed with oral tongue cancers, which seems to be a distinct entity associated with APS-1. Here we highlight their clinical presentation, diagnosis, treatment, and follow up. We also briefly discuss the biological aspects of oral malignancies in the context of APS-1.”

Authors

Linda Humbert, Marjorie Cornu, Emmanuelle Proust-Lemoine, Jagadeesh Batry, Jean-Louis Wemeau, Marie-Christine Vantyghem & Boualem Sendid

Publication

Frontiers in Immunology

Date

November 2018

Description/Quotes

This article provides recommendations for management of chronic mucocutaneous candidiasis (CMC).

“CMC is the most common infection occurring in APECED patients (77–100%), except in Iranian Jews (17%). CMC is also the most common first clinical manifestation of APECED syndrome (40–93%). Median age at diagnosis is usually <5-years-old (1.0–6.5years). According to the Finnish series, one-sixth of patients had developed CMC by 1.0 year, half by 5 years, 70% by 10 years, 94% by 20 years, and 97% by 30 years of age.”

Author

Janine A. Clayton

Publication

The New England Journal of Medicine

Date

June 2018

Description/Quotes

This article addresses management of dry eye and mentions use of “therapeutic contact lenses” but not Boston Prose Lens specifically.

“Dry eye disease can have serious deleterious effects on physical and psychological health, and the societal costs attributable to this condition are consequential in terms of direct costs of care and lost productivity. Management of dry eye could benefit from a more precise means of assessing the components of ocular surface health, including biomarkers of active disease and identification of the major drivers of symptom-related disease development.”

“Dry eye is also known as keratoconjunctivitis sicca, a term coined by Swedish ophthalmologist Henrik S.C. Sjögren, for whom Sjögren’s syndrome is named. Sjögren’s syndrome is characterized by dry eye and dry mouth and sometimes has multiple extraglandular manifestations.”

“Primary Sjögren’s syndrome is associated with aqueous-deficient dry eye, although it can also be manifested by other signs of dry eye, such as meibomian gland changes. In Sjögren’s syndrome, an autoimmune-mediated exocrinopathy leads to T-cell infiltration of the lacrimal glands, reducing tear production.”

Authors

Eystein S. Husebye, Mark S. Anderson & Olle Kämpe

Publication

The New England Journal of Medicine

Date

March 2018

Description/Quotes

This review article provides a comprehensive discussion of APS Type 1, including clinical features, genetics, disease mechanisms, and auto antibodies, as well as a discussion of other inherited forms of autoimmune polyendocrine syndromes (IPEX and APS Type 2).

“Work is currently under way to generate thymic epithelial tissue from stem cells. This approach could eventually be used to correct the expression of AIRE in patient s with APS -1 and help reverse the immunopathological course that leads to multi organ autoimmunity.”