Addiction to and Withdrawal from Topical Corticosteroids in Atopic Dermatitis and Other Diagnoses

JANUARY 21st, 1 2024 VERSION OF PAPER

Article type: Original article

Title: Addiction to and Withdrawal from Topical Corticosteroids in AtopicDermatitis and Other Diagnoses

Marvin J. Rapaport, MD1, Shannon Forest, BA2

David Geffen School of Medicine, UCLA; and 2Department of English, UCLA

Corresponding author: Shannon Forest, PhD Student and Instructor Department of English, UCLA, 149 Humanities, Los Angeles, CA 90095 Email: sforest@g.ucla.edu.

Funding sources: The authors have no funding sources to declare.

Attachments: Author checklist, research protocol, releases for identifiable patients

Keywords: general dermatology; pediatric dermatology; Atopic Dermatitis; psoriasis; eczema; topical steroid addiction; topical steroid withdrawal; RedSkin Syndrome; topical steroids; corticosteroids; seborrheic dermatitis; contact dermatitis Conflict of Interest Disclosures: The authors have no conflicts of interest to disclose.

Key Findings:

Question: Why has the 200-year old clinical definition of Atopic Dermatitis abandoned the classic pattern of presentation and shifted to include an entirely different group of symptoms in recent literature?

Findings: This is a retrospective study of all patients initially referred to the lead author with eczematous and erythematous rashes demonstrating novel or irregular patterns. Lead author consulted with over 8500 patients from referral until ultimate cure, all were chronic users of topical steroids and were rigorously evaluated for rashes, photosensitivity, allergens, and lymphoma.

Meaning: All patients were cured through total cessation of steroid usage, without relapse, because all patients, across an array of initial referral diagnoses, had the same underlying condition: TSA/RSS/TSW resulting from chronic TCS use. Ninety percent presented with atopic dermatitis, ten percent other dermatologic diseases (often unknown until steroid addiction was cured and the underlying problem became evident).

Abstract: Importance: In the last 70 years, Atopic Dermatitis and a wide variety of other eczematous problems have invariably been initially treated with topical corticosteroids. However, due to the worsening and spreading of skin eruptions, practitioners increased the amount, strength and steroid vehicle. Ongoing repeat evaluations failed to reveal any other reasons for the worsening conditions. Often multiple hospitalizations and serious misdiagnoses of an array of infections and other maladies were blamed. Increased steroid strength and type calmed the problem for a short period of time, only to repeat in worsening severity within weeks. Doctors have misdiagnosed patients with “bad eczema,” instead of TSA. Momentary and inadvertent cessation of steroids allows patients to demonstrate new problems of TSW.

Objective: To question the skyrocketing numbers of alleged AD cases repeatedly recorded in epidemiological studies on the grounds of this misidentification, and to provoke a reconsideration of the ingrained and problematic prescribing practices around TCSs.

Design: This is a retrospective cohort study assembled from case series of over 8500 patients, all of whom were personally seen by lead author between his founding of the Contact and Photo Dermatitis Clinic at UCLA in 1975until the writing of this paper, January 2024.

Setting: Patients were studied in university clinic, private practice settings, and via telemedicine.

Participants: When first seen, the patterns of skin disorder were severe and hindered regular functioning due to itching, burning, and sleeplessness.Patients referred for assistance in diagnosis and treatment exhibited ongoing, severe and chronic skin eruptions despite intensive treatment with various therapies.

Exposure: The sole parameter was total cessation of corticosteroid use.

Main Outcomes and Measures: The primary outcome was remission 86 of the aforementioned symptoms including itching, burning, sleeplessness, depression and anxiety. Evaluation included detailed history and physical exam, full tray patch testing, CBC, metabolic panel, serologic studies, and skin biopsy and/or bacterial culture.

Results: All patients were ultimately cured following cessation of steroids, utilizing symptomatic support. Depending upon an array of factors, total cure took 3–5 years with normal skin and no rebound symptoms.

Conclusions: The reported surge in “severe AD” patients is in fact due to medical mismanagement with potent TCSs and increasingly expansive definitions of AD that include the symptoms of TSA not the disease itself.The dermatologic use of potent and super potent TCSs therefore must be reexamined.

Abbreviations: AD, “Atopic Dermatitis”; TSW, “Topical Steroid Withdrawal”;TSA, “Topical Steroid Addiction”; TCSs, “Topical Corticosteroids”; IM, “Intra-muscular”; NO, “Nitric Oxide”; ITSAN, “International Topical Steroid Awareness Network”; CBC, “Complete Blood Count”; RAST“radioallergosorbent test”; OTC “Over the Counter”; IL “interleukin”; EASI,“Eczema Area and Severity Index”; ACD , “Australasian College of Dermatologists.”

Rapaport & Forest 6 Addiction to and Withdrawal from Topical Corticosteroids in Atopic Dermatitis and Other Diagnoses

Marvin J. Rapaport, M.D. Clinical Professor of Dermatology, Retired

David Geffen School of Medicine, UCLA, Shannon Forest, PhD Candidate andInstructor, Department of English, UCLA [The authors would like to thankJohn McGlasson for his diligent and incisive insight on the final draft of this paper.]

Introduction

Over the last few years, dermatology journals have published a parade of articles concerning what they describe as a rise in unusually severe cases of atopic dermatitis (AD), including an array of associated medical problems previously described. 1–8 These associated problem are described in Table 1.Yet some recent research (by the lead author and others) suggests that these patients are not struggling with “severe AD” at all, but rather a relatively new, distinct dermatologic condition: Topical Steroid Addiction (TSA). What follows is a retrospective study of over 8500 of these so-called “severe AD”patients. Findings are deduced from detailed medical histories and physical examination records of every patient and are contextualized through scientific commentary and analysis of shifting AD diagnostic guidelines since the invention of super potent steroids in the 1970s. The severity of the problem has exponentially increased. A recent review article in the NewEngland Journal of Medicine discusses this purported 158 surge in atopic dermatitis (AD) cases: it estimates that AD affects 15–20% of children and up to 10% of adults worldwide, making it the skin disorder with the highest disease burden. In Australia, for example, the prevalence of AD in young children increased from 10 to 30% between 1995 and 2010 — a threefold increase over a mere 15 years.9 The article states that this surge of AD cases, concentrated in high-income and industrialized nations, might be due to environmental factors such as increased air pollution and hygiene products, yet provides no data to support this claim. Indeed, the case of Australia confounds this hypothesis: since the installation of national ambient air quality standards in 1998, air quality has only improved in Australian cities, and the worst-performing urban areas still have an air quality of “good” or“very good” on the air quality index — a rating that indicates “little or no risk to human health.”10

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Therefore, there must be another more obvious and ubiquitous cause: 168namely, the therapy, chronic and prolonged overuse of topical corticosteroids (TCSs). In 43 years of practice, the lead author has not seen a huge surge in AD itself, but rather in TSA symptoms due to chronic TCS use, which are also used to treat twelve other dermatologic diseases.11 All diagnoses demonstrate the same patterns during the addictive and withdrawal phases until remission. No patients demonstrated worsening of the underlying disease, all showing another, unified group of symptoms and signs indicative of TSA alone. Tables 2a, 2b and 3 demonstrate the aforementioned misinterpretation of “AD.”

Methods

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This a retrospective study of findings compiled from the lead 188 author’s observation and documentation of patients since his founding of the Contact and Photo Dermatitis Clinic at UCLA in 1975. Concomitantly, the lead author saw a much larger cohort of patients in his private practice, totaling over8500. All records are on file. All patients referred to the clinic for diagnostic evaluation and medical care exhibited eczematous, erythematous, or exfoliative dermatitis clinically and were treated for an extended period. The patterns of erythema and rash fit no previously described disease. The referral and “working” diagnoses included contact dermatitis, photo-dermatitis, severe eczema, lupus erythematosus, exfoliative dermatitis and lymphoma. Existing treatment protocols prescribed by referring doctors included large amounts of topical corticosteroids of various and increasing strengths, oral and IM corticosteroids, and often methotrexate, Cell-Cept or Imuran. The long-term result of these treatments was always measurably worsening symptomology despite any short-term relief. All patients were seen by the lead author (MR). Evaluations included detailed history and physical, full tray patch testing, CBC, metabolic panel, serologic studies and often a skin biopsy. If the skin manifested any oozing, a bacterial culture was taken. All patients in the clinic were prescribed a single therapy after initial evaluation and testing: the total cessation of all corticosteroids including any nasal or pulmonary inhalers. Only symptomatic medications for relief, such as antihistamines, sleep medication, anti-anxiety medication and baths were prescribed. Almost all patients required consistent communication andcounseling. Steroid cessation was the sole parameter among these patients. Patients’ failure to resolve symptoms with prior treatments served as acontrol. In addition, the removal of steroid nasal and pulmonary inhalers did not result in any symptom flaring, in fact, symptoms ceased, demonstrating steroid addiction in nasal and pulmonary mucosa.

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Participants continued to be evaluated in the university clinic. 211 In addition, a larger contingent was seen at the lead author’s private practice. As patients referred to the clinic presented with increasingly severe symptoms as new and increasingly potent TCSs became available, the severity of TSW symptoms during steroid cessation also increased. Total body erythema during treatment and depressive symptoms necessitated an addition of cyclosporin to the treatment regimen as well as referrals to patient support groups and, in some cases, clinical psychiatrists.

Results

Fashions in therapy may have some justification, fashions in diagnosis have none.

Medicine depends upon an accurate diagnosis for successful treatment of disease. Changes in diagnostic criteria must therefore face a high level ofscrutiny. Table 2a and 2b list several key differences between how AD patients were described — repeatedly and by numerous authors — in the 200 years prior to 1980 as opposed to their description in the last 40–50 years. In the 19th-C, the English physicians Robert Willlan and Thomas Bateman used the term eczema to refer to an “eruption of minute vesicles” that form “thin flakes or crusts” that are caused by irritation of the skin. Ferdinand Rittervon Hebra (1816–1880) later used the term prurigo to describe AD as a lichenous rash localized to the face, for infants, and the flexural folds, after infancy, and cites again the cause as being skin irritation. While the termatopic dermatitis was only coined by Fred Wise and Marion Sulzberger in1933, the clinical description of the underlying disease did not change in 200years.13,14 In contrast, Dr. Sonja Ständer, the author of the article mentioned above, states that many cases of AD are extremely severe and“areas of eczema coalesce into larger regions of generalized redness of the skin (erythroderma).” Ständer is certainly not alone in the inclusion of erythroderma in “AD” criteria; major institutions that provide patientinformation are also following this trend.15 However, older sources tell a different story. In the authoritative Rook’s Textbook of Dermatology (1968)and elsewhere, erythroderma is listed as a “very uncommon” pattern of atopic dermatitis that “may occur in the first few days of life” but which“settle(s) in time to the more usual patterns.”16 Our central question is this:How can it be that the pattern of eczema presentation has changed thisdrastically in the last forty years? The differences in the literature across time are so stark as to suggest two distinctly different diseases.

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This is precisely the case. We argue that the diagnosis for the cases 256Ständer describes should be TSA, not “severe AD.” Our contention is based on the data in Table 4, namely the introduction of “potent” and“super potent” TCSs in the 1980s — their widespread adoption and frequent combination with systemic CSs as patients’ dermatologic disease patterns invariably worsen. While physicians search elsewhere to explain worsening symptoms — the cause is in fact the treatment itself. The Introduction of Topical Corticosteroids AD has not changed, but treatment has. The major, and often sole treatment for patients with AD is topical corticosteroids(TCSs). While hydrocortisone was first brought to market in 1952, TCSs of higher strength classes became available in the 1970s and 80s (see Table 4).These topicals were phased-in gradually — a process followed by an increasing reported prevalence of AD and documented new side-effects such as erythroderma. Invariably, a severe burning sensation occurred, especially with water contact and bathing. Children were adamantly afraid of bathing. This was never seen in Atopic Dermatitis descriptions prior to the 1970s.Thus the rapid increase in access to TCSs — facilitated by urbanization, reductions in poverty, and increased utilization of healthcare, all factors correlated with increased prevalence of “AD” in recent epidemiological studies17,18 — may in fact be driving this surging number. In addition, this increase has been coupled with the appearance of extraordinarily severe cases of “AD” that often present with unbearable itching and burning, fear of infection, severe swelling, ceaseless oozing, and hospitalization. These patients often opt-out of work and school.19 How is it possible that the introduction of a valuable therapy coincided with an exponential increase in the same disease?

It is well-known that TCSs cause vasoconstriction followed by rebound vasodilatation.20 The TSA patient exhibits this physiological phenomena; erythroderma is always present. In aTSA crisis, the body’s ability to modulate vasodilatation fails, precipitating“withdrawal” (TSW). This mechanism is detailed below. Because this pattern of side-affects occurred across multiple diagnoses and not merely AD, TCSs— the only unifying factor — must be the culprit. Side-effects of TCSs includes ymptoms newly absorbed by “revised” definitions of atopic dermatitis, such as erythroderma, especially if widespread and affecting the face and genital area, which is the hallmark of TSA/RSS.21–24 Side effects can be systemic or localized and range from mild to severe. The lead author has also seen five cases of extreme steroid-induced internal problems: two adrenal gland shutdown cases in older patients and three osteonecrosis cases in teenagers.Figure 1 shows a schema of addiction and withdrawal that is consistent across all underlying diagnoses treated with TCSs.

Mechanism of Addictionand Clinical Presentation

Doctors often accept that “bad eczema” is the cause of flares and therefore prescribe increasingly potent TCSs. Their use is often coupled with oral and intramuscular steroids, of which specialists in other areas have recently begun to comment are overprescribed.25 This worsens vascular addiction. Most patients are told by their physicians that their condition will persist throughout their life. Allergists find positives for various allergens and patients retroactively attribute flares to allergen exposures. Avoidance of supposed allergens fails to ameliorate symptoms.

Are bound rash indicates that the skin has become vascularly addicted to TCSs ;it is a vasodilatation response to the release of Nitric Oxide (NO), a chemical released by the skin vasculature. As the body releases NO to dilate vessels, stronger and stronger TCSs are needed to constrict them and reduce erythema.11,26 When the application of TCSs ceases, the skin becomes flooded with NO, resulting in withdrawal symptoms — such as widespread erythema, especially on the face and neck, burning sensation of the skin, atrophy, edema, nummular patches, and vesiculation. This cascade wreaks havoc on atopics already at a statistically greater risk of depression leading to suicide in some.

After suffering for many years, some patients — or their parents — find information about TSA and TSW, often through ITSAN(International Topical Steroid Awareness Network), a nonprofit founded by the lead author (now retired from board) that advocates for regulatory changes regarding steroid use and labelling, sponsors support groups, and provides resources for patients going through TSW. Others find information through groups on social media platforms. According to ITSAN, these groups number over a dozen and total over 50,000 active members from 35+countries. Patients often end TCS application at this discovery stage; some do so in consultation with a physician, who can prescribe medications to manage withdrawal symptoms (see Protocols II and III in Figure 1), and others do so without medical management (Protocol I). All had a complete history, PE CBC, and metabolic panel; most had a rheumatoid panel and ask in biopsy from the erythematous areas. All parameters were normal, except spongiosis on biopsy. Figure 2 shows examples of TSW presentation and cure protocols across various age groups. Follow-up visits and contactoccurred with most patients up to 8–10 years. No recurrences of flares or rashes occurred after cessation of steroid use.

In the last few years, at least twenty new small molecules and biologicals for the treatment of AD have been in various trial stages. Several have been approved by the FDA since2017.28 The clinical studies had two key variables in common: a) subjects averaging 37 years of age — which suggests that they are not truly ADpatients at all; and b) a lack of limitations on the ongoing use of TCSs throughout the duration of the trial.29,30 These two factors suggest that many of the patients in clinical trials are addicted to TCSs. It is therefore unclear whether the drug impacts AD or TSA, and fluctuations in symptoms may be due to changes in TCS application throughout the duration of the trial, not the efficacy of 325 the drug. This allows for misinterpretation of findings and data. Almost all the published studies report only slight differences in only two subjective parameters: namely, itch and sleeplessness.31,32 No objective complaints were described or clinically assessed. The dropout rate in all of the studies was typically high. Lead author believes that steroid usage was a majorfactor here. CITE studies and EASI scores were utilized in an attempt at objectivity, but their relevance has not been clearly determined. Researchers were given no parameters on experimental control of steroid use. The recently FDA-approved dupilumab, a humanized monoclonal antibody which targets the α subunit of the interleukin (IL)-4 and IL-13 receptors, is a newly popular treatment. However, there is very little information on thedrug’s mechanism of action and its impact on symptoms. A 2014 dupilumab study reports a 50% reduction in EASI scores — a subjective measure of eczema severity — but fails to report on symptoms with objective parameters and does not control for the amount of TCSs used by patients.

Public outcry over the lack of guidance around TCS usage recently prompted the publication of new guidelines by the British Association of Dermatologistsand the National Eczema Society of the UK in early 2021 which describes“rebound erythema” as the first symptom.33 Others, such as the AustralasianCollege of Dermatologists (ACD), have denied that withdrawal occurs entirely. In 2017, the ACD made the highly specious claim that TCS are“underutilized” due to fear of side-effects and that the recommendation “use sparingly” is “nonsensical and has no value.” They go on to state that what patients (and parents, in the case of pediatric use) often perceive as steroid-related side-effects are in fact “misinterpretation(s) of active eczema.” This untenable opinion ignores evidence to the contrary, such as a series of case studies by Dr. Belinda Sheary which identified patterns of addiction and withdrawal among Australian children whose parents ceased TCS application. These children’s symptoms eventually improved.34 Further, theACD guidance discourages patients from considering the side-effects of CSs and from seeking help for addiction symptoms. The American Academy of Dermatology, for its part, has not released revised guidance on TCS prescribing practices, though it did publish a met analysis in 2015 that reluctantly admitted to a risk of TSW — despite underrating the quality of evidence that supports this finding — and a 2022 report on comorbid conditions and AD. Further, denial of TSA and its problematic absorption into the clinical definition of atopic dermatitis itself (among other conditions) — exemplified by the recent AD article mentioned in the introduction — possibly prompted drug companies to develop new drugs with unclear efficacy.

There have been no reports or published papers of patients cured by any of these new medications. In fact, marketing language directed at the public, patients, and prescribing doctors (listed in Table 5) —whether in print advertisements, on television, or in offices — describe only marginal and subjective improvements with respect to these medications.Drug trials and marketed approval go back at least 8 years without any patients successfully cured despite extraordinarily high treatment costs.Table 6 compares prices of the medications discussed above to cyclosporin, which is relatively inexpensive and leads to cure.

Therapy

Figure 1 is a complete schema of the lead author’s approach to treatment of all patients of TSA evolving into RSS and TSW. In all protocols all patients stopped using corticosteroids entirely; topical, systemic, nasal, and pulmonary sprays. Utilizing Protocol I, patients refused medical care andassistance. Their symptoms are handled by scientific and unscientific methods such as diets, acupuncture, light therapies etc. In Protocol II, patients seeking medical care usually have“tolerable” symptomatology and function in life and work with some 371 difficulty, utilizing symptomatic medications for itch, burn, sleep, and anxiety. Psychological assistance is often needed. In Protocol III, the lead author prescribed cyclosporin to ameliorate symptoms. This was resorted to when the symptomatic support for the patient was far from sufficient in allowing them to function in life.They were unable to go to school, work, or perform basic life tasks. These patients often exhibited depression and even suicidal ideation. A search for a safe but systemically potent medication included the medications CELL-CEPT, Imuran, methotrexate, and others, plus cyclosporin. The last medication appeared to be the safest and most appropriate seventeen years ago and was chosen as the only safe and efficacious medication for this group of patients.

Initially, the desired usage, dosage, and duration of treatment evolved over one to two years and was determined by trial and error. The regimen that afforded cure was: a) cyclosporin type — modified or nonmodified — but no switching of company products; b) 300mgs/ day to start, with the possibility of tapering by 25–50mgs/day in 3–4 weeks; c)maintenance of this dosage until erythema cleared (usually 12–30 months);d) tapering by 25–50mgs every 2–3 weeks / end of therapy typically one and a half to three years; e) blood testing for renal function every four to six weeks, blood pressure every four weeks. As of this writing over 950 patients have been cured using cyclosporin. All exhibited normal skin, no further flares of rash, and no further symptoms of disfunction.

In regards to the new medications, we cite several problems in study designs, publication parameters, and FDA approval. In addition, the cost to patients for all of the medications is exceptionally high compared to cyclosporin. None of the medications demonstrated results of cure like cyclosporin. Suspected limitations in these drugs’ evaluation included a) several medications underwent only one two evaluations; b) large number of dropouts; 394 c)corticosteroids were concomitantly used in almost all studies; d) multiple venues were used with many physicians “donating” patients; e) final paper was written by the drug companies. Finally, during 2023, insurance companies in Utah began disapproving payment for Dupixent. No reason has been cited.1,28,29,32,35–43

Conclusion

The alleged epidemic of AD is typically attributed to environmental factors without conclusive evidence suggesting causation. This mistaken attribution obscures a more obvious cause: “AD” has become more prevalent and more severe because the basis on which we diagnose AD has shifted to include symptoms of TSA, and because steroids proliferate everywhere — they are prescribed chronically and even formulated into innumerable OTC drug-store creams and hygiene products. A small patch of eczema on the back of a child’s knee might have once been disregarded, but now it results in a prescription for TCSs that, when inappropriately used, may precipitate a cascade of vasoconstriction followed by problematic vasodilatation. We suggest that the reported deluge of “severe AD” patients is in fact due to medical management, not the disease itself. Thus we offer another epidemic in place of the “AD” epidemic: one of vascular addiction to TCSs.

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Figures

Figure 1. Addiction and Withdrawal Phases — Composite of Multiple “AD”Patients.

Figure 2. Clinical Presentations of TSW. Panels 1a/b: mother applied steroidsfor 16 months; cured in 24 months with Protocol I (see Figure 1). Panels 2a/b:steroids used for 17 years; cured in 36 months with Protocol II. Panels 3a/b:steroids used 22 years; cured in 42 months with Protocol III.