As reported in the Journal of Allergy and Clinical Immunology, team of UK researchers administered an estimated threshold dose of peanut in a blind challenge. Then participants with a confirmed allergy “underwent 3 open peanut challenges in random order: with exercise after each dose, with sleep deprivation preceding challenge, and with no intervention.” They concluded: Exercise and sleep deprivation each significantly reduce the threshold of reactivity in patients with peanut allergy, putting them at greater risk of a reaction. Adjusting reference doses using these data will improve allergen risk management and labeling to optimize protection of consumers with peanut allergy.
By Henry Ehrlich
We have covered this breakthrough drug for years from before FDA approval when a presentation by Dr. Emma Guttman-Yassky at a New York Allergy & Asthma Society dinner treated the audience to “before” pictures of atopic dermatitis that made patients’ legs look like rotisserie lamb and “after” pictures that looked normal. At that time, Dr. Guttman-Yassky heralded an approaching “golden era for atopic dermatitis.” Now following a couple of years on the market, we are starting to see what a blockbuster looks like in the real world.
Dr. Peter Lio wrote about dupilumab—now Dupixent—for us in December 2016. He said, “The dream of patients and providers alike–aside from preventing it in the first place or a total cure, of course!–is a medication that would work quickly to calm the itch and inflammation, to truly allow the skin to truly heal. It would do so safely, without toxic side effects to the liver or kidneys and without an increased risk of cancer and infection. It would be easy to use instead of greasy creams or cumbersome wraps. Finally, it would not simply suppress the inflammation, but would help block the escalating itch-scratch cycle and not result in a rebound flare up when stopped.”
He described the drug and its action in this way: “It is composed of monoclonal antibody–proteins that are part of our immune system normally– and, as such, is sometimes referred to as a ‘biologic’. It is specifically designed to bind to (and thus inhibit or block) two important chemical messengers in the body: interleukin-4 (IL-4) and interleukin-13 (IL-13). These messengers, called cytokines, are very important in that they seem to be overproduced in eczema. Their message, in large part, seems to be: ‘Make more inflammation and itch! Make an allergic reaction!. Thus, it follows that by very carefully quieting them down, the resulting eczema quiets down. Perhaps most importantly, it does so WITHOUT shutting down the entire immune system or poisoning the body.”
Dr. Lio has recently published two journal articles that point to problems that arise in the real world of a drug post introduction. The first is an editorial from JAMA Dermatology, published online in December of last year entitled “Considerations in Weaning or Withdrawing Dupilumab Therapy—Nothing is Forever”. It seems strange that having waited their whole lives for relief from their eczema, patients should be anxious to find an exit strategy, but that is the case, for two primary reasons. One is that they must get the shots every two weeks. Based on a description by a friend of her child’s routine on shot day, it’s not a quick in-out. The other consideration is the astonishing cost, which is north of $30,000 annually.
Delineating the line between research and real world, Dr. Lio writes, “Dupilumab was studied for 52 weeks at continuous dosing every 2 weeks to establish its safety and efficacy, but inevitably for patients who are doing well while receiving treatment (and even for those who are not), the question arises, ‘Do I have to take this medicine forever?’” Dr. Lio describes atopic dermatitis as a “waxing and waning disease. The waning cycle leads people to wonder if they are cured or if at least may require less frequent dosing for maintenance.
Given experience with biologics for other diseases, the portents are not good. Patients tend not to do as well after stopping and restarting, and they may develop antibodies to the medicine. With dupilumab specifically, researchers “found that continuing treatment with the original dosage (300 mg weekly or every 2 weeks) resulted in a better maintenance of response than a less frequent dosage and significantly better than placebo for all end points. Moreover, the less frequent dosage regimens produced some dose-dependent reduction in efficacy but no previously unreported safety events…The authors* thus concluded that continued treatment with dupilumab using the more frequent treatment regimens (ie, every 2 weeks) ensures the most consistent maintenance of treatment effect and appears to confer no greater risk than (and likely fewer risks) than less frequent administration.”
Dr. Lio’s second article, published online in Dermatology in April 2019, was co-written with two colleagues from the University of Arizona, is called “Dupilumab and Alopecia: Causative or Therapeutic.” This one had particular resonance for me because I had recently spoken to someone who experienced hair loss with Dupixent as she was trying to cope with topical steroid withdrawal and red skin syndrome. She felt the mild relief wasn’t worth the added indignity.
According to Dr. Lio and his co-authors, the door swings both ways on this. “Our literature review yielded 6 recent case reports on ‘dupilumab’ and ‘alopecia, with four describing alopecia developing after initiation of dupilumab and two reporting resolution of pre-existing alopecia.” The hair loss seems to constitute a drug reaction.
Clearly, this drug is just getting started.
Peter A. Lio, MD is an Assistant Professor of Clinical Dermatology & Pediatrics at the Northwestern University Feinberg School of Medicine, and a Diplomate of the American Board of Dermatology. Dr. Lio received his medical degree from Harvard Medical School, completed his internship at Boston Children’s Hospital and his dermatology training at Harvard. He served as a full-time faculty at Harvard (Beth Israel & Children’s Hospital Boston) from 2005-2008 before returning home to his native Chicago to join Northwestern and Children’s Memorial Hospital. He is also a trained acupuncturist and a leader in the Chicago integrative health care community.
Dr. Lio will be speaking at the 6th East-West Integrative Medical Symposium for Immunology & Wellness at the New York Medical College in Valhalla, NY on June 20, 2020.
*Worm M, Simpson EL, Thaçi D, et al. Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis: a randomized clinical trial [published online December 26, 2019].JAMA Dermatol. doi:10. 1001/jamadermatol.2019.3617 7.
By Dr. Paul Ehrlich
Penicillin was discovered by Alexander Fleming in England in 1928 and by the 1940s it had achieved its deserved status as a wonder drug. US government laboratories perfected safe mass production in time to play a critical role in the successful prosecution by the Allied armies in World War II. But after millions of doses, the first case of anaphylaxis was reported in 1944 as we are told in an epic new paper in the New England Journal of Medicine by Mariana Castells, MD and PhD, and her co-authors David A. Khan, MD, and Elizabeth J. Phillips, MD.
This expert analysis has particular meaning for me. I was born in 1944. Five years later as I was preparing for my birthday party, which my cousin Henry attended in utero, I came down with something and my father, Leonard Ehrlich, a pediatrician, gave me a shot of penicillin. I broke out in a rash at which point Dr. Lenny, as he was known to generations of patients, pronounced me allergic.
Fast forward 20 years. I was a medical student at NYU and saw a flyer for a study of penicillin safety, with a hundred dollar participation fee. A hundred bucks was a hundred bucks and I already had mouths to feed so I went along. When I saw that an injection was involved and balked the physician in charge, Dr. Bernard Levine, said, “this is a hospital. If anything happens we’ll take care of you.” So I got the shot, nothing happened, and a crisp hundred was laid in my greedy hand. And my data presumably contributed to Dr. Levine’s discoveries in penicillin allergy diagnosis.
Dr. Castells and her colleagues tell us that the dangers of penicillin allergy are real, although quite rare, especially for oral dosing. One UK study found “one case of fatal anaphylaxis from oral amoxicillin in 35 years and 100 million treatment courses.” However, the drugs that are used in place of penicillin preparations are not as effective and more dangerous in some instances, as well as more expensive.
The authors conclude:
The incidence of both IgE-mediated and non–IgE-mediated reactions has not increased worldwide in the past 50 years, and a penicillin-allergy label has serious consequences for both individual and public health (Figure 4). Although a large number of patients are labeled as having penicillin allergy, more than 95% of them can safely receive penicillin when they are appropriately and safely evaluated. Penicillin allergy is lost over time, and using sensitive and specific tools to identify patients with true reactions should be a health priority implemented through delabeling algorithms and programs. Over time, it would be expected that delabeling patients who no longer have penicillin allergy will control the use of alternative and more expensive antibiotics and reduce the associated morbidity and mortality and the surge of organisms that are resistant to penicillin and beta-lactams. Protection of patients who are truly allergic to penicillin by means of accurate diagnosis, proper labeling, and if necessary, desensitization should be the next steps toward improved safety and quality of care in personalized medicine. Allergists should have a central role in facilitating outpatient and inpatient testing programs aimed at correctly identifying patients with penicillin allergy. Through appropriate history taking and risk stratification to identify patients without IgE-mediated allergy, as well as low-risk patients, all health care providers can play a central role in alleviating the enormous individual and public health burden related to the penicillin-allergy label.
Mom told you that you had a rash after penicillin when you were little? Maybe it’s time to revisit.
Testing graphic from WBUR.org. To see their take on the same story click here.
By Dr. Paul Ehrlich
With the age of prescription therapy for food allergies rapidly approaching, it’s not too early to start figuring out what patients will prefer among the options presented. Allergists and their patients have confronted similar dilemmas before, although simple preference doesn’t solve the problem. For example, we have been offering shots for a hundred years, and no one is terribly fond of them. To many, sublingual immunotherapy (SLIT) sounds like a dream, but experience teaches us that in the real world patients don’t like them in nearly equal measure. Taking a medicine every day is burdensome, and many patients don’t like the way the medicine feels and tastes in their mouths.
Thus, it was fascinating to read about Dr. Matthew Greenhawt’s presentation to the ACAAI meeting in Houston about patient and caregiver feelings concerning two modes of therapy that are rapidly nearing availability—Palforzia oral immunotherapy (OIT) and the Viaskin “peanut patch,” also called epicutaneous immunotherapy or EPIT. A total of 200 children aged 7-11 and 206 caregivers were surveyed with questionnaires replete with emoticons to express their feelings in addition to straight answers. Compliments to Matt and his team for their imagination in assaying patient emotions as part of the package.
Unsurprisingly their greatest concerns were over the prospect of medical emergency, but they were also deeply disturbed by things like touching, tasting, and smelling peanuts. Questioned about the prospective treatments, many rejected the oral approach. Many more were drawn to the idea of the patch.
Looking at the numbers, I began to think about my own experience over many years. The two key senses—taste and smell—have figured heavily in the lives of many patients whom I first met as children, and treated on into adulthood, and in many cases treated their own children. While there was no such thing as active treatment all those years, some of them did manage to outgrow their allergies, including to peanut. I would test them for IgE and do skin prick testing and urge them to try their allergens or do an office food challenge. But for some, the chance to eat the allergen just wasn’t enough to overcome that sensory aversion, although some do arrive at some remarkable strategies over time. The key is to associate food with the pleasure it is meant to give rather than regard it as medicine.
It’s early days for food immunotherapy, but it’s not so early that we can’t start figuring in the dimension of time. Longitudinal data for some of the earliest studies show that many subjects drop out. Medication fatigue is a real thing with all chronic disease management. It’s likely to factor heavily as OIT, the patch, and other non-curative treatments hit your allergist’s office. Those early aversions and fears at the front end have their analogues on the back end.
But maybe that’s not a bad thing. In a recent talk, one of the pioneers of private practice OIT observed that patients he had treated as little kids would come to him as they reached adolescence and inform him they were quitting. He was okay with that. He had helped them deal with their allergies long enough to come of age and could make their own decisions. They could negotiate the risks for themselves. I liked hearing this.
With a range of treatment options on the horizon, the allergist’s responsibility remains the same. To understand patient and caregiver needs and fears, to provide treatment when appropriate while explaining all the risks and offering lots of encouragement, and be just as considerate and well-reasoned when rejecting a treatment. One thing is sure: all those fears and aversions covered in Matt’s study are going to be a constant. We may have seen it all before, but it’s always new to the patient.
This website has long been concerned with people not taking their medicine, particularly for asthma. Thus we were instantly drawn to an editorial in JACI In Practice entitled “The Hidden Story of Nonadherence with Asthma Therapy: For a Few Dollars More?” by Dr. Job F.M. van Boven, PharmD, PhD from the Netherlands and Kenneth R. Chapman, MD, from Canada, which among other things critiques both medical practice, patient behavior, and health care policy in wealthier countries, focusing on a study in Australia, covered in the same issue. So we wrote to one of the authors to see if he would answer a few questions.
AAC: Thank you, Dr. van Boven, for taking time for our readers. First, how did you come to write this editorial? Did the editors of In Practice send you the Australia study? Did they send it to both you and Dr. Chapman, or did the two of you decide to collaborate?
Dr. van Boven: It is my pleasure, thank you. Regarding your question, it was actually the editor-in-chief of In Practice, prof. Michael Schatz, who invited the both of us. Indeed, he shared the article with us and subsequently asked us to write the editorial together and put the Australian article on cost-related underuse of asthma medication in a broader perspective. Given our complementary knowledge on this subject, this collaboration worked out very well.
AAC: A few years ago, we covered a study done in the Netherlands that showed roughly three quarters of patients failed to complete their courses of allergy shots (the results for sub-lingual immunotherapy were even lower). Is nonadherence a particular concern of the Dutch medical community?
Dr. van Boven: I remember that SCIT/SLIT adherence study, published in JACI, was it? Indeed, nonadherence is a concern in the Dutch medical community, yet I wouldn’t want to say we are unique in that sense. Nonadherence is a pressing global issue. The World Health Organization estimates that worldwide only around 50% of medications are taken correctly. As a result, people may end up in hospital more frequently than necessary, not only increasing the clinical burden but also the economic burden.
AAC: Returning to your editorial, you wrote that nonadherence because of things like fear of steroids is well studied but that cost is not. Why is cost less studied? I read years ago that it’s a factor in Canada where your co-author lives. Is that still the case? Policy makers in the US look to imports from Canada to relieve our own disastrous medication costs, which Canadians can’t like. And of course, your editorial was a response to the Australia study. How high are the costs to consumers in some of these countries, which have much more comprehensive medical coverage?
Dr. van Boven: I think the reason that costs are less studied is that this factor is hard to measure. The costs of medicines vary from drug to drug, by a country’s health system, health plan, and even over time. The same goes for the exact amount of co-payment that patients have to bear. In the Netherlands, medical coverage is quite extensive and asthma drugs generally have no co-payments in place yet on an annual basis, the first €350 of healthcare costs (including medications but also specialist visits or hospital visits for any reasons) need to be paid by the patient him/herself. In Belgium, our neighboring country, co-payment for asthma medication is around €5 per prescription. This makes international comparative studies difficult. Also, as we argue in our editorial, when asking people face-to-face, it may be difficult to distinguish “costs” from other reasons, such as not believing in, or fearing the side effects of, the drug. Reasons for nonadherence could be multiple and also change over the course of a regimen.
AAC: I like your analysis of the “penny wise, pound foolish” elements of cost for standard controller asthma medications, which posits that non-adherence drives patients into higher-cost emergency medical treatment. Do you have any figures on how much of a burden this places on health care budgets in different countries and how does it affect patient outcomes?
Dr. van Boven: In the Netherlands, there are around 8,000 asthma exacerbations annually that often require a multi-day hospital stay (5 days on average). Total expenses on hospital care for asthma cover 37% of the total yearly spending on asthma of €427 million. It is hard to say what will be the exact percentage of nonadherence-related hospitalizations that is potentially preventable, but each hospitalization is a severe burden on asthma patients’ quality of life. Looking beyond asthma medication nonadherence alone, the OECD estimates that in Europe 200,000 deaths and €125 billion could be related to medication non-adherence. For the USA, these numbers are equally worrisome with an estimated 125,000 preventable deaths and $289 billion of costs.
AAC: You also mention the advent of biologics, which are much more expensive than standard controller medications. You point out that because asthma is poorly controlled because of non-adherence, patients may be prescribed these much more expensive drugs, just as they often end up in the emergency department. Aren’t there protocols about the use of these new drugs, or can we just expect prescriptions to skyrocket because people don’t like the cheaper drugs?
Dr. van Boven: You are correct that, in most countries, these biologics cannot just be prescribed without meeting several prerequisites, before prescription and/or reimbursement is allowed. Usually, one of these prerequisites is ruling out uncontrolled asthma due to inhaler nonadherence. However, in daily clinical practice we often don’t have reliable, objective methods available to assess adherence and we therefore often rely on patient self-report, or pharmacy refill records at best. Fortunately, there are exciting developments around “smart” inhalers that connect to smartphone apps and help patients to better self-manage (e.g. by sending reminders and motivational messages), but also provide insights to the clinician on when and how the inhaler was actually used. This could help them make an informed decision on when to prescribe biologics or when to put actually more efforts on improving adherence first. Another, still very preliminary, method is to measure long-term inhaled drug concentrations in human hair. In this way, we may be able to establish, with one single test, whether or not a sufficiently high drug concentration was reached over the last months. In our Center, we are currently working on both smart inhalers as well as the hair method.
AAC: Your editorial is polite but firm in its critique of the weaknesses of asthma care in the real world. Do you expect much response from your colleagues and the larger community of health care practitioners, researchers, and policy makers?
Dr. van Boven: After publication of the editorial, I got some responses from Dutch and Canadian healthcare professionals. For example, our national pharmacist association noticed that an increasing number of people are not filling their prescriptions, in particular the ones that are not fully reimbursed. They expect that 75% of these unfilled prescriptions are not filled due to cost reasons. Extrapolating the Australian results directly to other countries remains however difficult. The thing is that health systems, prices and reimbursement policies vary from country-to-country and even change over time or between sub-populations.
AAC: Could you offer a few words of advice to patients about their use of asthma medication? And could also give some advice to medical practitioners about their patients’ use of the medicines?
Dr. van Boven: To patients: make sure you get proper education on how and when to use your inhaler. All healthcare professionals (doctors, nurses, pharmacists) should be able to provide this. If you experience difficulties, don’t worry; this is completely normal. Using an inhaler is complex and over 70% of people don’t get it right the first time. So if you are in doubt, ask a qualified health professional to help out.
To medical practitioners: To maximize chances of high adherence, try to involve the patient in the initial choice of inhaler (i.e. by shared decision making), tailor it to their needs, skills and preferences and make sure to provide proper education on when and how to use the inhaler. Often, a one-off educational session is not enough, checking inhaler technique and adherence should preferably be a repeat protocol! Inhaler technique should be visually checked (ask the patient to show you) and adherence should be checked as objective as feasible in your setting and optimized with personalized interventions, tailored to the underlying reason(s). The latter advice is especially relevant when a patient has uncontrolled asthma and before you consider the prescription of additional therapy.
AAC: Finally, whose idea was it to use a Clint Eastwood reference in the title?
Dr. van Boven: Haha, Dr. Chapman came up with the first part of the title, yet the Clint Eastwood inspired subtitle was actually my idea.
Job F.M. van Boven PharmD, PhD is Assistant Professor of Drug Utilization Research and Principal Investigator at the Groningen Research Institute for Asthma and COPD (GRIAC) of the University Medical Center Groningen, the Netherlands. Having interest and wide experience in both medication adherence and health economic methods, his mission is to find novel, cost-effective ways to make better use of our respiratory medications in order to maximize both patients’ and societal benefits. Having completed visiting fellowships in Spain, the USA and Australia, he thereby benefits from a large global respiratory network and perspective. He is the founding director of the Medication Adherence Expertise Center of the northern Netherlands (MAECON).
On Halloween morning, this popped up on our Twitter feed:
“One of my clinical hates is when patients are told that they have been saved from anaphylactic death by paramedics or ED staff – and ‘oh and by the way – your next reaction is going to be worse!’ It understandably creates great stress and angst and is not factually correct.”
Dr. Smith has contributed to this website before, discussing the False Alarm Hypothesis to account for the rise in food allergies. Another time we tracked him down after reading his work on fatal anaphylaxis. So after seeing his Halloween Tweet, we asked him to catch up and ask a few questions about his “clinical hate.”
AAC: Welcome back to our website. How often do you hear this story about escalating reactions?
Pete: Once every couple of weeks. This is too much, as it really compounds an already distressing situation.
AAC: You say this is one of your clinical hates. What are some others, and what do you hate about them? How do they affect your patients?
Pete: Okay, hate is a strong work – “peeve” might be better. I don’t like the upper airways being forgotten (it is such an easy thing to manage) and also the eyes. Seeing someone spend over $400 on glasses because of blinking and squinting when the problem is allergic conjunctivitis is frustrating. Having patients being diagnosed with EoE and discharged on a PPI with no follow up is also frustrating.
AAC: The field of allergies is replete with mythology that passes for fact just because no one ever bothers to find out the truth. (The number of food allergy fatalities is a major example.) This one is insidious because it generates anxiety, as you said. Why is it so hard to dispel? Do you have any ideas about how to get the word out?
Pete: Patients often see the dose required to elicit a reaction decrease before an allergy is diagnosed or may see an escalation in symptoms with venom reactions before they seek medical review. There are many co-factors that determine if you have a severe reaction or not. Sites like yours get the word out. Awareness of research and publications help. For example, risk factors that multiply reactions and Now we have sleep deprivation as well
AAC: You are a busy practitioner in what if I’m not mistaken is the most allergic, asthmatic nation in the world. We came across a new paper showing that cost of asthma medication is a big factor for non-compliance. Can you reflect for a moment on why this is (apart from the taste for barbecued food) and what can be done about it? What are some of the other factors you see in your practice?
Pete: Compliance is an issue for many reasons. 20% of patients do not obtain their medications because of the word steroid. If you have allergies – your immune system is too effective and your body makes steroids to counteract this – but you can make less if you focally treat the afflicted area such as the lungs in the case of asthma. It is important to understand why medications are being used. We have reported that 40% of eye drops and 20% of nasal sprays* purchased over the counter are alpha-agonists that may provide temporary relief but may allow rebound effects that will make things worse. Other compliance factors may be side effects such as throat symptoms (made worse by not using a spacer and not rinsing) or nose bleeds (more common with poor technique).
AAC: Finally, the False Alarm Hypothesis is one of the most interesting things we have covered on this website. Can you tell us how it has been received among your colleagues? I know there was one study in Europe that seemed to bear out some of your observations. Can you tell us about that and perhaps some others?
Pete: It was a very heavily accessed paper in JACI in 2017. A study in South Africa also looked at this and found trends to high glycation foods. A paper was presented a couple of weeks ago in Florence at the PAAM meeting – some research came in from Naples that reinforced the AGEs-in-diet paper.
AAC: The False Alarm Hypothesis was so novel and interesting. You came to a team at Mount Sinai to investigate the underlying science for reasons you explained in our earlier interview. Do you farm out other ideas?
Pete: The Mt Sinai team had already shown that isoflavones/genestin in soy stopped the development of food allergy in an animal model. They had a working food allergy model, but were not aware of advanced glycation end products. It made sense to work with a team with an existing model. I share ideas though.
AAC: Thanks for your time.
*An example of such a nasal spray is oxymetazoline hydrochloride, sold as Afrin among other brand names. As we reported in Asthma Allergies Children: a parent’s guide, it “provides profound relief as swollen blood vessels in the nasal passages shrink, restricting the painful flow of fluids into the nose and sinuses.But when the effect wears off it makes the patient feel miserable. The vessels dilate to more than their previous diameter, literally becoming engorged; the congestion increases.” After prolonged use, it “makes the nasal blood vessels and tissues look like raw hamburger.”
Dr. Pete Smith is a Professor in Clinical Medicine at Griffith University in Queensland Australia. He trained in Pediatrics and did his PhD in molecular immunology at Flinders University South Australia and has worked as a Senior Lecturer at the Institute of Child Health London and an Honorary Consultant in Allergy at Great Ormond St Hospital London. He consults in Clinical Medicine in Southport Queensland and is Medical Director of Allergy Medical Group in Brisbane and Sydney. Current research includes AGEs and allergy, molecular ion channels in hypersensitivity and allergy, molecular activation pathways in allergic rhinitis and clinical studies in food allergy and rhinitis. He can be found on Twitter @ProfPeteSmith.
A recent article in JACI-In Practice says that not taking medicines for chronic disease as directed accounts for some 125,000 deaths in the US. This involves some 3500 asthma fatalities. “The Hidden Story of Nonadherence with Asthma Therapy: For a Few Dollars More?” (Van Boven & Chapman) attributes poor adherence to “asthma’s symptom variability, its error-prone delivery systems, and reliance on patient self-monitoring…” The authors cite several categories of nonadherence: According to the WHO, we should consider 3 broad categories of nonadherence: “(1) erratic (more commonly known as forgetfulness), (2) unwitting (eg, using reliever as preventer, poor self-management, and poor inhaler technique), and (3) intelligent nonadherence (eg, nonintake due to fear of steroids or medication dependence).” The problem is no better in countries with universal health care systems than our own.
Within that last one is the high cost of medicines. Another article in the same issue discusses this in detail. (Laba et al) A study in Australia shows that 25% of patients don’t fill their prescriptions due to cost. Per capita asthma fatalities are much higher in Australia than in the US.
By Henry Ehrlich
In recent decades, new allergic conditions have appeared and proliferated at a pace more rapid than the capacity of doctors to classify them, let alone treat them. Eosinophilic esophagitis and mast cell activation syndrome are just a couple of examples of “new” diseases that defied classification for years and continue to elude definitive treatment. Another one that has been occupying a great deal of my time is an offshoot of moderate-to-severe atopic dermatitis (AD). Eczema is an old disease. It’s the conditions pursuant to treatment that are new. Over-reliance on the frontline medicine, topical steroids, results in topical steroid addiction (TSA), topical steroid withdrawal (TSW), and TSW’s most visible and debilitating symptom, Red Skin Syndrome, (RSS).
I have been thinking about these conditions while interviewing patients of Dr. Xiu-Min Li being treated with traditional Chinese medicine and bringing them back from the brink of despair. Red-skin syndrome is debilitating, disfiguring, and demoralizing. They describe pants stuck to their legs with blood; buying a dust-buster to remove dead skin from their beds in the morning; opiate dependency from trying to cope with the pain. One mother says she has no memories of her child’s first two years except his blood and pain, while another had to turn care of her child over to grandparents for a period of time. Once you go red, you’d rather be dead.
A thread that ran through their stories was frustration at doctors’ low receptivity to the conditions that were plainly on display and their continual resort to prescribing stronger steroids. It’s not only the doctors’ fault. Patients are so hungry for relief that they go overboard in their use of steroids. In 2014 we featured an account of a talk by James Treat, MD of the Perelman School of Medicine at the University of Pennsylvania. We wrote in summary of Dr. Treat’s talk: “While many of us are steroid averse, sometimes to a fault, eczema brings out the opposite tendency. To wit, if it works people will continue to use the medicine too long. There’s a hierarchy of steroids and while it may be advisable to use a very strong one to gain control, the treating physician should closely monitor progress, and the dosages should be stepped down. Dr. Treat said this is a particular problem for teenage girls who want to avoid having their health supervised and will use what works to keep their skin clear until their immune systems are dangerously compromised.
I can certainly sympathize with those adolescent girls; I have resorted to that behavior and incurred RSS myself, albeit of a very mild variety. As anyone with chronic eczema can tell you: anything to stop the itch.
A New Era of Understanding and Treatment?
A few years ago at a conference a prominent academic dermatologist opined that AD had lagged behind psoriasis in attracting pharmaceutical money (you can see the results every day on TV) but that was going to change. The biologic dupilumab (Dupixent) has since hit the market.
In the meantime, there remain the challenges of preventing and managing a major epidemic. Another speaker at that meeting was Dr. Peter Lio, frequent contributor to this website, who, along with Neha Chandan, MPH and a fourth-year medical student, has published a review article in the August issue of Practical Dermatology that should help doctors understand TSW and RSS more fully, and guide them in preventive and therapeutic treatment. They write, “Topical Steroid Withdrawal (TSW) is a poorly understood clinical adverse effect of inappropriate, prolonged, or frequent use of TCS (topical corticosteroids), generally those of mid- to high-potency. The mechanism behind this phenomenon remains unclear. A fine balance exists between using TCS effectively and avoiding adverse side effects of these agents, including topical steroid addiction (TSA) and TSW. Because TSA tends to precede withdrawal, prevention through proper treatment of AD is key. When TSW is suspected, rather than continuing to escalate treatment with steroids, one may consider the use of other therapeutic options.”
Not a moment too soon. A few months ago, we published an interview with Kelly Barta, CEO of ITSAN (International Topical Steroid Addiction Network) which has 12,000 members worldwide. The interview contained an estimate that 3-million patients in the US alone may have TSW.
Our friend Tonya Winders, President & CEO of Allergy & Asthma Network, tells us they have been working on a number of AD initiatives, including shared decision making for patients and doctors, in collaboration with the American College of Allergy, Asthma, and Immunology, and developing a nursing AD educator role. Her organization has also published a model publication called Understanding Atopic Dermatitis: Knowing Your Skin from the Inside Out, which gives you everything you need to know about causes, management, and treatment. For more on AAN, click here.
The study of eczema from the patient point of view is about to take a major leap forward on September 23 at a meeting in Washington, DC, and online billed as “The First Patient-Focused Drug Development Meeting Dedicated to Eczema. Called “More Than Skin Deep: Understanding the Lived Experience of Eczema Patients.” They will tell their stories to an audience of FDA staff, drug and medical device developers, and of course other patients. This format is particularly pertinent in light of the running theme from my interviews that doctors don’t seem all that open to the full history, nor to explore beyond the standard tools—steroids and more steroids.
This theme rang a bell. Dr. Renata Engler, a distinguished allergist who spent most of her monumental career in the US Army, told me for a book I wrote about Dr. Li, “The system is currently failing a lot of patients. There’s a tendency to abandon those who don’t fit into comfortable evidence-based slots…Our community consigns patients to hopelessness or treatments that are worse than the disease. Steroids haven’t answered the mail for everyone.”
Dr. Engler also said: “We have lost connection with patient stories. Patients who don’t fit are marginalized. Doctors should expand their medical toolbox for patients who don’t fall within guidelines.”
By Henry Ehrlich
Congratulations to Gwen Smith and the team from Allergic Living for the “Food Allergy Anxiety Guide.” This 90-page e-magazine will surely be the definitive guide to all aspects of the subject for years to come. As Gwen writes in her introduction, “The purpose of this e-magazine is to discuss the fears and the ‘what ifs’ with honesty, without sugar-coating, and to begin to understand this phenomenon as its own anxiety disorder.” Mission accomplished. It is an authoritative and polished product, complete with podcast, and should be on the desktops of patients, parents, and practitioners.
I wrote to Gwen and asked her a couple of questions:
AAC: What was the impetus for starting the project and how long did it take?
Gwen: I have a long interest in the anxiety issues surrounding food allergies. But the impetus for this full-on ‘Food Allergy Anxiety Guide’ stems directly from our decision earlier this year to transition to a digital publication. Doing so related to the future direction of publishing, but it also provided me an opportunity to stand back and assess: What could a digital Allergic Living be that was truly useful to the community? Coming from a current affairs (radio) and news magazine background, I’m always interested in taking apart and packaging big topics.
This led to my idea of a “big topic” special edition guide, and I had a sense from our community that a natural such subject/need was food allergy anxiety. We tested the idea on our social media channels by asking: “If you are stuck in food allergy stress, tell us your story.” (The Consulting Editor on this issue is Gina Clowes; she asked the same on Allergy Moms.) The outpouring in emails and posts was incredible, and people’s stories were so affecting. The need here, just as quality-of-life surveys have shown, is clear.
The edited-down reader quotes (preview publicly available here) are what led me to go slightly overboard and create a 90-page interactive publication. I felt compelled to do something exceptional on this topic. It’s almost more a book than a magazine. I honestly think this is the best work we’ve done in a dozen years of publishing. The reason is the importance of the topic and the fact that our writers and podcast moderator were able to get top food allergy therapists to give actionable strategies to show that you don’t have to stay locked in stress and fears.
We pulled it together four months. We burned lot of midnight oil. But we got there.
AAC: Wow. Tight timeframe. Were there any particular challenges?
Gwen: Even with Allergic Living’s big audience, getting enough people to know about the Guide and to understand it’s a significant and unique piece of work on the food allergy anxiety topic is taking a great deal of work. It’s also a bit of a challenge to communicate that while the Guide discusses anxiety, the real focus is on the steps toward stress control and better quality of life.
There were some hiccups at the beginning, but fortunately we got those sorted out quickly. Transitions always seem to come with learning curves.
What was NOT a challenge – finding people to speak on this topic. There are many wanting to talk, wanting to find a way through.
The finished product is worth the cost: $7.95. It’s not a one-time thing. Readers should go back again and again for the advice, for the inspiration, and for the exposure to multiple points of view. Print out pieces of it and show them to your uncomprehending friends and relatives. Get a grip. You are not alone.
Long-time readers of this website will remember an article by Dr. Eva Untersmayr linking use of antacids to adult onset of an allergy to Beluga caviar in an individual patient. He had eaten the delicacy at a party with no ill effects, but several months later had a severe reaction after eating more. The Dr. Untersmayr and her colleagues learned that he had been taking antacids during the first ingestion, reducing the crucial acid environment of his stomach. Poorly digested larger protein components found their way into the intestines and the blood, where the immune system went on alert and cranked out allergic antibodies in case it ever happened again. The same pattern was observed for patients with dyspeptic disorders treated using anti-ulcer medication. When Dr. Untersmayr popped up again recently as a co-author of an article in the journal Nature Communications entitled “Country-wide medical records infer increased allergy risk of gastric acid inhibition” which elaborates on the connection between anti-ulcer drugs and allergy, not just to food but to all kinds. She has generously agreed to answer some questions about the new article. – Henry Ehrlich
AAC: Eva, welcome back and thanks for volunteering your time. First, your methodology in this study was fascinating. You were able to access the medical records of 97% of the population of Austria between 2009 and 2013 because the country has near-universal health insurance. As an American I marvel at that all by itself. Simply put, you compared prescriptions of anti-allergy medicine to patients who had previously been taking H2 agonists—antacids–and proton pump inhibitors, or PPIs. How did you arrive that this approach? Also, I know it’s not as easy as it sounds. How did you construct the study? And what protections are there for patient privacy?
Eva: Henry, thank you very much for the invitation and your questions. You are right, our approach sounds straightforward, but it was made only possible within a network of excellent collaborations. The reason why we designed the study that way was to evaluate the impact of this medication on the entire Austrian population. We are very lucky to have compulsory health insurance ensuring nearly complete health care coverage, even paying for most of the medication Austrians are prescribed by medical doctors. In the health insurance databases, in- and outpatient data on medical services covered by the health insurance is available. And of course the study was performed in strict agreement with data protection and patient privacy law. Therefore, a pseudonymized data set was used and only after approval by our ethics committee of course. And in the end the analysis means a lot of statistical calculations and comparisons, which were done by the expert in our team.
AAC: The idea that digestion is impaired by these drugs so that allergenic protein components sneak through is familiar enough. But your study shows that they also activate Th2 mechanisms, which are more generally allergic, as indicated by patients needing medicines that don’t work on food allergies. How do these medicines affect the larger immune system? Could you particularly highlight their effects on the gut and oral microbiome?
Eva: I am not so sure that the concept of digestion impairment and higher risk for allergy development is familiar to everyone working in the field of allergy or gastroenterology. I still get a lot of questions from the audience when I present even our older data at scientific meetings. But you are right, our current data shows that the effect goes beyond food allergy, as we investigated use of anti-allergy medication, which is most frequently used for respiratory allergies and far less frequently in case of food allergies. One mechanism, which we also highlight in our paper, could be the direct effect on the immune response as immune cells have H2 receptors, PPIs can induce mast cell activation and the aluminum-containing Sucralfate might act as an adjuvant. Moreover, anti-ulcer drugs have an enormous effect on microbiota, which is even more prominent than the effect of antibiotics when considering the entire population due to longtime intake of this medication. So there are different layers of mechanisms that might explain our results.
AAC: These changes take place very quickly, don’t they? You mention as few as six days.
Eva: The change in the gastric milieu takes place very quickly. You are right that approximately 5-6 days of PPI intake elevates the gastric pH to around 5. But long-term use of anti-ulcer drugs seems to especially increase the risk for need of anti-allergy medication, which we could also prove in our current study.
AAC: I was particularly struck by how many young boys are on these drugs. Why? Is it because they eat a lot of junk? If so, why are their doctors prescribing these things and not focusing on improving their diets?
Eva: There is not really a difference between anti-ulcer drug prescription between boys and girls in childhood. Around puberty girls are more likely to get prescription for this medication and the female gender dominates until very old age.
AAC: Finally, the paragraph on “imprinting the next generation for allergy” was very troubling. I know that reflux is a big problem during pregnancy. I kind of hate to ask because mothers of food allergic kids are constantly worrying about what they did wrong, but I have to. How does antacid use “imprint” the next generation? Is this an epigenetic change or something else?
Eva: We and other groups have demonstrated this link in previous studies, both in experimental models and in human data. When the mother takes anti-ulcer medication during pregnancy, the child is more prone to become allergic due to skewing the immune response. Moreover, as mentioned above, anti-ulcer drugs affect the microbiota composition and we know how important our microbes are for immune health and how much the mother’s microbiota influences the colonization of the child. But I think much more research is needed until we fully understand all the mechanisms involved here. As an advice for pregnant mothers-to-be suffering from reflux (like I did with my second child): Lifestyle changes are also a good option and can prevent the need for medication. Do not eat too late and try to sleep with your upper body slightly elevated.
AAC: In your previous article, you wrote, “There is evidence that patients and doctors are trading long-term health for short-term comfort. In Europe, and I suspect elsewhere, the sales figures of acid-suppressive drugs are continuously on the rise and they are being used for long periods of time.” Do you have the feeling that patients and their doctors are taking better care of their digestion? Are they eating better? Are they using alkaline water instead of antacids and PPIs? Or is it business as usual?
Eva: Unfortunately I do not see a big difference in caring for a functional gastrointestinal digestion. Nevertheless, it is very important to raise awareness, to constantly inform medical doctors and patients. We once launched an awareness campaigns together with one of our health insurance companies here in Austria and we could really see an impact of this campaign on anti-ulcer drug prescription habits. Making important information available is very helpful!
AAC: Your biography says that you are a trained acupuncturist. The only doctors I know who address digestion as part of treatment for food allergies are also trained in Asian medicine—one in Chinese medicine and one in Ayurvedic medicine. Do you think that Western doctors have something to learn from these disciplines?
Eva: I am personally very keen on a broad approach in medicine. There are so many fields to learn from. Asian traditional medicine is one example, but we also should not forget traditional medical knowledge from our cultures, where much more attention was given to how, when and what to eat.
AAC: Thank you for your time.
Eva: Thank you Henry for your interesting questions and for highlighting our research!
Eva Untersmayr, MD, PhD, is Associate Professor and head of the Gastrointestinal immunology research group at Institute of Pathophysiology and Allergy Research at the Medical University of Vienna. She is a Clinical Immunologist especially interested in the connection between digestion, food allergy and the immune system of the gastrointestinal tract. Her work was continuously funded by several grants of the Austrian Science Fund, the Austria National bank, the EC Horizon 2020 and other funding agencies. Following her medical studies, Dr. Untersmayr also trained as an acupuncturist in Austria.
Fotocredits, © MedUni Wien, Felicitas Matern”