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Wednesday, August 17, 2016

Cellular and molecular immunologic mechanisms in patients with atopic dermatitis

Atopic dermatitis is one of the most common chronic skin diseases among both adults and children.  Although it is often thought of as a skin disease, it also affects many organ systems. There remain a lot of gaps in our knowledge of atopic dermatitis, but researchers are developing a greater appreciation for its complexity of atopic dermatitis and introducing new treatments for this frustrating disease.

From an immunologic point of view, atopic dermatitis appears to be a collection of many different variants.  These endotypes are just recently beginning to be described, but involve the various arms of the immune system.  Defects in the innate immune system skew the skin towards inflammation; polarization of T-cells (Th2, Th17, and Th22) lead to further inflammation.  Other cell types, like dendritic cells, eosinophils, and mast cells, play important roles in the development of atopic dermatitis.  The interplay between immune cells and skin barrier proteins, like filaggrin, is also being explored.  Filaggrin influences cell differentiation, prevents water loss, and maintains the integrity of the skin barrier.  With defects in filaggrin, allergens penetrate deeper into the skin and bacteria like staphylococcus aureus are more likely to colonize the skin.

To make things even more complicated, as time progresses, so too does the disease, and patients can have an “atopic march” towards asthma, allergic rhinitis, and other allergic diseases.  Additionally, patients with atopic dermatitis have changes in the bacteria that colonize their skin and gut.  They have less microbial diversity, particularly when there is greater inflammation.  The role of these bacteria are being increasingly fleshed out with basic science and clinical research.

These insights are helping to guide new therapies.  In particular, dupilumab, an antagonist of the IL-4 receptor alpha chain, is showing promise in the treatment of atopic dermatitis.  And in those that don’t respond to dupilumab, there’s interest in other therapies like the IL-6 receptor antagonist tocilizumab.  As Werfel and colleagues note, it is difficult to find the best treatment for atopic dermatitis without knowing the pathophysiology behind the disease and its various endotypes (J Allergy Clin Immunol 2016; 138(2): 336-349).  In the future, with better knowledge, it may be possible to personalize appropriate treatment by identifying the correct endotype for each patient.

Tuesday, August 9, 2016

Multidisciplinary interventions in the management of atopic dermatitis

Atopic dermatitis is the most common skin disease in children, affecting up to 1 in 5 children in the United States.  But it doesn’t do it justice to call it just a skin disease.  The itching and scratching leads to a breakdown of the skin, disruptions in sleep, conflicts with parents, and an inability to concentrate at school.  Studies have shown that children with atopic dermatitis have a higher risk of developing mental health disorders like attention-deficit hypersensitivity disorder, anxiety, depression, conduct disorder, and autism.

Because atopic dermatitis does not have a single cause and has such far-ranging effects, management can be a challenge.  As LeBovidge and colleagues describe, multidisciplinary interventions are being investigated as a way to help these children (J Allergy Clin Immunol 2016; 138(2): 325-334).  Evaluation by an allergist or dermatologist can help to determine triggers, and education by nurses can help improve adherence and technique of applying emollients.  Psychologists can help redirect unhelpful compulsive behaviors like scratching into more helpful activities, such as re-application of moisturizers.  And nutritionists can ensure that children, especially those that have food allergies that require restriction of certain foods, receive enough Vitamin D and other nutrients.

Several institutions have embraced this multidisciplinary approach, but randomized controlled trials are limited.  Some group-based models have shown an improvement in control but others found no difference in disease severity, quality of life, or medical therapy use.  New models of collaboration between specialists and primary care providers are being developed in order to improve the quality of care.  It is hoped that improving the quality of care will decrease the economic burden of the disease.

Atopic dermatitis may be a skin disease, but its effects are felt in more than just the skin.  In order to get the disease under better control, new ways of delivering care will have to be developed.  Professionals in various fields, including allergists, dermatologists, nurses, nutritionists, and psychologists, are aligning with parents to break the itch-scratch cycle that causes such misery to the millions to have atopic dermatitis.

Multifactorial skin barrier deficiency and atopic dermatitis: Essential topics to prevent the atopic march

Some things are so evident that we take them for granted.  Take our skin for example.  We live in our skin and, for the most part, don’t give a second thought about it.  But skin is more than meets the eye.  It is vital for immunity, not only because it protects us from the outside but also because it fine tunes how our immune system responds to the various stimuli it encounters.  For those who have atopic dermatitis, a type of allergic disease that affects the skin leading it to become dry, irritated, and thickened, we see one result of a poor skin function.  In this month’s issue of JACI, Egawa and Kabashima discuss the role of skin barrier dysfunction in atopic dermatitis (J Allergy Clin Immunol 2016; 138(2): 350-358).

To understand the skin, we have to think about it in layers.  The topmost layer, called the stratum corneum, is a little like a wall, with flattened cells called corneocytes working like bricks and intercellular lipids functioning as mortar.  Together, they maintain the integrity of the skin.  But in atopic dermatitis, the wall is weakened.  Mutations in filaggrin, a protein important in making the corneocytes, have been associated with an increased risk of developing atopic dermatitis.
With the growing knowledge of genetics and immunology, there are beginning to be great insights into how atopic dermatitis starts to take hold.  In addition to filaggrin mutations, there’s a host of newer mutations that lead to the irritation, peeling, and thickening of the skin.  Mutations in genes encoding some proteins, like LEKTI and KLKs, have to do with the way that skin desquamates, or sheds, whereas others, like CLDN1, influence the tight junctions that maintain the integrity of the skin barrier.  And, in addition to these structural proteins, the immunologic messengers, particularly type 2 cytokines like IL-4, IL-13, IL-31, and IL-33, are found to be key in the development of atopic dermatitis.

As Egawa and Kabashima note, the skin is a very complex organ, and one that we are just starting to understand from an immunologic perspective.  Its importance cannot be overstated, not only because it brings us closer to figuring out what causes diseases like atopic dermatitis, but also because it opens the door towards finding new, effective medications and therapies that can target proteins like filaggrin.  In turn, this can improve the lives of the millions who live with atopic dermatitis, and the diseases that are associated with it.

Monday, July 11, 2016

Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation

You are more than just one human being.  That may sound like an inspirational quote, but it’s actually a scientific fact: there are literally millions of bacteria living on, in, and around you that play crucial roles in the ways that your body and your mind work.  And now, thanks to newer technology, we have the ability to see how these ‘old friends’ – bacteria have likely been around since the emergence of humans – interact with our own cells to change how our immune system works.
In this month’s issue of the Journal of Allergy and Clinical Immunology, Garn and colleagues provide an overview of how these microbes influence our metabolism and can lead to inflammation, based on the insights from the International von-Behring-Röntgen-Symposium (J Allergy Clin Immunol 2016; 138(1): 47-56).  While our knowledge of the microbiome keeps on growing, the fact is that there remains so much to be researched.  For example, how does our modern age of hygiene, where we have eliminated so many of the old infectious agents with which we have co-evolved, impact chronic inflammation?  How do resident microbes interact with food to cause inflammation, or resolve it?  What role does biodiversity (which plummets while on antibiotics) play in maintaining the balance between promotion and resolution of inflammation?  And how do these microbes educate our immune systems during infancy and childhood?  Unfortunately, these questions remain mostly unanswered but there are some promising leads.  For example, a study involving 560 babies of families from Baltimore, New York City, and St. Louis demonstrated that exposure to allergens in the first few months of life may be associated with a reduced risk of recurrent wheeze, while exposure to microbes may reduce both the risk of atopy and atopy plus wheeze.

Extracellular RNA, DNA, and proteins that may come from microbes have been shown to mediate inflammation.  These molecules alter the cytokines released by our own cells, and can lead to upregulation of inflammatory responses.  While research is extremely preliminary, the influence of the microbiome on allergic, autoimmune, gastrointestinal, and neuropsychiatric disease is becoming more and more appreciated, possibly opening doors to new management strategies.  So embrace your inner germs and realize that you’re more than just one, sole human being.

Friday, July 8, 2016

Inflammatory mechanisms in patients with chronic obstructive pulmonary disease

C-O-P-D (chronic obstructive pulmonary disease) is a series of four letters that strikes terror in the hearts (and lungs) of millions throughout the world.  It’s a condition in which there is chronic inflammation within the lungs that leads to their destruction, causing problems in breathing.While the consequences of COPD have been long known, the immunology behind it is still largely unknown.  In this month’s issue of the Journal of Allergy and Clinical Immunology, Dr. Barnes reviews the inflammatory mechanisms behind COPD (J Allergy Clin Immunol 2016; 138(1): 16-27).
As he mentions, one of the difficulties behind figuring out how immune dysfunction causes COPD is that COPD doesn’t seem to be a single disease.  Different types of immune cells and mediators seem to be involved in different ways in different patients, and our knowledge continues to grow about how we can tease apart all these endotypes and phenotypes.

However, some common themes are emerging.  Patients with COPD have lower levels of anti-oxidants, leading to excess reactive oxygen species (ROS), which, in turn, trigger the inflammatory response.   These ROS may also promote lung cancer by activating growth factors and damaging DNA directly.  The other major common theme is that there is systemic inflammation that “spills over” to cause an increased risk of heart disease, diabetes, lung cancer, and pneumonia.

Currently, we don’t have treatments to help reverse the damage from COPD, and most of our efforts remain in prevention and control of symptoms.  But with greater knowledge on the roles immune system, we may be able to help people, who have been diagnosed with COPD to regain control of their lungs, and their lives.

Thursday, July 7, 2016

Intranasal triamcinolone use during pregnancy and the risk of adverse pregnancy outcomes

It’s not surprising that expecting mothers carry a lot of weight in their bellies.  But they also carry a lot of weight on their shoulders.  What to do, and what not to do, complicates nearly every decision when there’s a second person to think about, even the relatively minor act of using a nasal steroid spray to treat allergic rhinitis.  Fortunately for them, Dr. Berard and colleagues conducted a study to help address these concerns (J Allergy Clin Immunol 2016; 138(1): 97-104).
They looked at nearly 300,000 pregnancies in Montreal between 1998 and 2008 to find pregnant women who took intranasal triamcinolone as well as other intranasal steroids.  They then looked at the number of major abnormalities at birth, spontaneous loss of pregnancies, and underweight newborns, and compared the rates to those who did not use intranasal triamcinolone. 
For the most part, the results are comforting.  They suggest that there is no link between using intranasal triamcinolone (and, by extension, all nasal steroid sprays) and major birth abnormalities or spontaneous fetal loss.  However, out of 296 pregnancies, there were 5 cases of respiratory defects in babies born to mothers who used triamcinolone during the first trimester.  This was a statistically significant finding.  Of note, no link between respiratory defects and other nasal steroid sprays could be found.
The implications of this study are also covered in an accompanying editorial by Drs. Namazy and Schatz, who praise the importance of the study, the first of its kind trying to determine the safety of nasal steroids during pregnancy (J Allergy Clin Immunol 2016; 138(1): 105-106).  They also mention that controlling allergic rhinitis during pregnancy may be helpful in preventing snoring, which is linked to hypertension during pregnancy.Namazy and Schatz try to make sense of why triamcinolone may be correlated with respiratory defects.  It may be due to unmeasured confounders, but that is unlikely since these confounders were present in both the triamcinolone and non-exposed groups.  Or perhaps it’s a biologic effect of triamcinolone, since animal studies of intramuscular triamcinolone have shown similar defects.  Or, it may just be due to pure chance.

Regardless, the authors suggest that, to be on safe side, intranasal steroids like fluticasone or mometasone should be used instead of triamcinolone during the first trimester.  

Thursday, June 9, 2016

Allergen Immunotherapy: No Evidence of Infectious Risk

Nearly three million Americans this year will be administered subcutaneous allergen immunotherapy for a variety of different reasons, including allergic rhinitis, asthma, allergic conjunctivitis, and venom allergy.  Altogether, these are over 16 million allergy shots.  Despite low risks of a large local reaction (0.7-4%) or systematic allergic reaction (0.2%), it has been shown to be relatively safe, cost-effective disease-modifying treatment.  However, recent proposed changes by the United States Pharmacopoeia requiring that vials of allergens be mixed in a strictly sterile fashion threaten the availability of allergen immunotherapy.

To investigate whether this is a real concern, Balekian and colleagues looked through the records of over 3000 patients who collectively received more than 130,000 injections over the preceding 10 years from Massachusetts General Hospital and Brigham and Women’s Hospital (J Allergy Clin Immunol 2016; 137(6): 1887-1888).  They could not find evidence of any local or systemic bacterial infection due to allergen immunotherapy.

Their research supports the community of allergists who maintain that current practices to guarantee sterility and safety are enough to prevent bacterial infection.  They conclude that the proposed changes won’t make a difference in infection rates, but will prevent people who need allergen immunotherapy from receiving them.