Published in Dermatology Journal Scan / Research · March 22, 2022 Chemoprevention of Cutaneous Squamous Cell Carcinoma in Solid Organ Transplant Recipients Using Topical Sirolimus Journal of the American Academy of Dermatology
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In this study, solid organ transplant recipients (not on systemic sirolimus) with history of nonmelanoma skin cancer were treated on one arm and dorsal hand with topical sirolimus and the other arm and dorsal hand with control vehicle for 5 weeks. The number of keratotic lesions decreased in the treated arm by 31% compared with a 6% increase in the control arm. At 24-month follow-up, the treated side demonstrated 81% reduction in intraepithelial neoplasms but not a statistical difference in squamous cell carcinomas.
Topical sirolimus may decrease the burden of keratotic lesions and intraepithelial neoplasms in solid organ transplant recipients.
Immunosuppression in solid organ transplant recipients (SOTR) greatly increases the risk of keratinocyte cancer (KC), indisputably a significant burden in terms of morbidity, mortality and cost. Switching calcineurin inhibitors to sirolimus is a major strategy that has resulted in a two-fold reduction in the risk of SCC, but is poorly tolerated with many serious adverse events.
Journal of the American Academy of Dermatology
Chemoprevention of cutaneous squamous cell carcinoma and its precursors in solid organ transplant recipients using topical sirolimus: a randomized, double-blind, placebo-controlled pilot trial
J Am Acad Dermatol 2022 Feb 24;[EPub Ahead of Print], S Chong, HY Wong, A Althabteh, C Cox, P Stevenson, S Brown, A Griffin, N Isbel, G Siller, HP Soyer, H Schaider, E Roy, S Campbell, AC Green, K Khosrotehrani
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Published in Dermatology Journal Scan / Research · March 22, 2022 Correlations Between Hormonal IUDs and Androgenic Skin Conditions Journal of the American Academy of Dermatology
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This retrospective study included 1224 women to compare new instances of dermatologic conditions between those with hormonal (levonorgestrel) and non-hormonal copper intrauterine devices (IUDs). The results revealed an increased odds of diagnosis of acne vulgaris in the year following implantation versus women with placement of a non-hormonal copper IUD. Women with hormonal IUD placement were less likely to be diagnosed with androgenic alopecia, rosacea, and hirsutism.
This study showed that women with hormonal IUD implantation were significantly more likely to be diagnosed with acne vulgaris following hormonal IUD implantation than those with non-hormonal copper IUD implantation.
Long-acting contraceptives are utilized by 10.4% of American women aged 15-49, often in the form of hormonal implanted intrauterine devices (IUDs) which utilize levonorgestrel to prevent pregnancy. Levonorgestrel is androgenic and may play a role in diseases and symptoms influenced by androgens. IUDs are associated with cases of new and worsening acne vulgaris, but no levonorgestrel-specific risk of adverse dermatological conditions has been established. This study aimed to evaluate associations between hormonal IUDs and adverse dermatologic events.
Journal of the American Academy of Dermatology
Correlations between hormonal IUDs and androgenic skin conditions: a retrospective cohort study
J Am Acad Dermatol 2022 Feb 24;[EPub Ahead of Print], A Munjal, R Tripathi, C Wu, S Radke, JG Powers
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Bidirectional Association Identified for NAFLD and Psoriasis
Risk for developing psoriasis significantly increased for NAFLD patients, and risk for NAFLD significantly increased for psoriasis patients
MONDAY, March 21, 2022 (HealthDay News) -- There is a bidirectional association between nonalcoholic fatty liver disease (NAFLD) and psoriasis, especially for patients younger than 40 years, according to a study published online Feb. 16 in Frontiers in Immunology.
Shuo-Yan Gau, from Chung Shan Medical University in Taichung, Taiwan, and colleagues retrieved data from Taiwan's National Health Insurance Research Database to examine the bidirectional association between NAFLD and psoriasis. Patients with new-onset NAFLD and psoriasis were enrolled in two cohorts; propensity score-matched controls with no NAFLD or psoriasis were included for each comparison cohort.
The researchers observed a significantly increased risk for developing psoriasis for patients with new-onset NAFLD (hazard ratio, 1.07), while for younger patients with NAFLD, the risk was increased 1.3-fold. For new-onset psoriasis patients, the risk for developing NAFLD in the future was increased 1.28-fold compared with those without psoriasis; the risk was higher for patients in younger psoriasis subgroups younger than age 40 years versus those in older subgroups (adjusted hazard ratio, 1.55).
"Future studies should consider the mechanism influencing the pathogenesis and correlation between NAFLD and psoriasis and focus on the difference between different psoriasis severity subgroups and to what extent the severity difference would affect the bidirectional association," the authors write.
Published in Dermatology Journal Scan / Research · March 19, 2022 Safety of Propranolol for Infantile Hemangioma in Infants <5 Weeks Corrected Age Pediatric Dermatology
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This single institution, retrospective study identified 24 infants <5 weeks corrected age (<45 weeks corrected gestational age) with infantile hemangiomas (IH) treated with propranolol. Overall, 22 patients showed improvement of their IH and 3 patients stopped propranolol between 3 days and 4 weeks after initiation due to side effects including fussiness, feeding difficulties, and sleep disturbances. No serious adverse events were reported.
Propranolol appears to be an effective and safe treatment option for IH in infants <5 weeks corrected age; however, evidence-based guidelines are required for appropriate monitoring.
These authors examine the safety and efficacy of propranolol use in very young infants, <45 weeks corrected gestation age, with hemangiomas. In this cohort of 24 infants, there were no serious adverse events. The most common side effects included sleep disturbance, irritability and cool hands and feet.
Very young infants often need oral propranolol to stop the growth of function or appearance threatening hemangiomas before peak proliferation occurs, sometimes between 5-7 weeks of life. Unfortunately, this propranolol is administered with worry and hesitation under 6 weeks of life. This and other reports provide reassuring evidence of the safety in this group. Notably, past initiation protocols suggested hospital admission and monitoring for this young group, and 21 of these infants had propranolol initiated in an outpatient setting with most starting at 1mg/kg/day. As evidence like this grows, outpatient propranolol initiation in select young infants may become more commonplace.
Abstract
BACKGROUND/OBJECTIVES
Propranolol is used to treat problematic infantile hemangiomas (IHs), but its safety in infants <5 weeks corrected age has not been established. The objective of this study was to assess the safety and efficacy of propranolol for treatment of IH in infants <5 weeks corrected age, or 45 weeks corrected gestational age (CGA).
METHODS
We performed a single institution, retrospective review of patients treated with propranolol prior to the age of 6 months between 2017 and 2021. Patient characteristics, location of hemangioma(s), weight at initiation of treatment, dosing information, side effects, response, and duration of treatment were documented.
RESULTS
Of 200 patients with IH treated with propranolol, 24 started treatment prior to 45 weeks CGA. Mean CGA at initiation of treatment was 42 weeks. Sixty-seven percent were female and 75% were white, non-Hispanic. Mean duration of treatment was 255 days. Twenty-two patients (92%) had clear benefit from treatment at a dose of 1-3 mg/kg/day. The most common side effects were sleep disturbance (21%), irritability (17%), and cool hands/feet (13%). There were no serious adverse events.
CONCLUSIONS
In this cohort of 24 patients with corrected age <5 weeks (CGA <45 weeks), propranolol was safe and effective for the treatment of infantile hemangiomas. Larger, prospective studies are indicated to investigate propranolol in this age group.
Pediatric Dermatology
Safety of propranolol for infantile hemangioma in infants less than five weeks corrected age
Pediatr Dermatol 2022 Mar 03;[EPub Ahead of Print], JE Gatts, MC Rush, JF Check, DM Samelak, TW McLean
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Comparing Treatment Effectiveness of Local Hyperthermia at 44°C and Cryotherapy for Plantar Warts
Acta Dermato-Venereologica
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In this prospective study, 1000 patients with plantar warts were treated with either local hyperthermia at 44°C (n = 515) or cryotherapy (n = 485). At 3-month follow-up, complete response was achieved in 50.9% of the hyperthermia group and 54.3% of the cryotherapy group. The recurrence rate at 6 months was 0.8% in the hyperthermia group, compared with 12% in the cryotherapy group. Pain scores were significantly lower for local hyperthermia than for cryotherapy group (P < .001).
Local hyperthermia is comparable in efficacy to cryotherapy for the treatment of plantar warts and may offer reduced pain during treatment and lower rates of recurrence.
Local hyperthermia was less painful and equally effective compared with cryotherapy but took more time (30 minutes for 3 consecutive days, then repeated for 2 consecutive days after 2 weeks). We suppose that this might be reasonable for a select group of patients, but it will certainly depend on the cost of the device used for heating and the ability to have staff or the clinician spending time with the patient (or whether the patient can be left alone with the device). Perhaps we will hear more about this, and others have studied hot water soaks as home treatment; however, this is interesting because warts continue to be a significant problem for patients for which a "perfect" solution continues to elude us!
Abstract
Cryotherapy is one of the most common treatments for warts; however, pain during treatment and relatively high recurrence rates limit its use. Local hyperthermia has also been used successfully in the treatment of plantar warts. The aim of this study was to compare the clinical effectiveness of local hyperthermia vs cryotherapy for the treatment of plantar warts. This multi- centre, open, 2-arm, non-randomized concurrent controlled trial included 1,027 patients, who received either cryotherapy or local hyperthermia treatment. Three months after treatment, local hyperthermia and cryotherapy achieved complete clearance rates of 50.9% and 54.3%, respectively. Recurrence rates were 0.8% and 12%, respectively. Pain scores during local hyperthermia were significantly lower than for cryotherapy. Both local hyperthermia and cryotherapy demonstrated similar efficacy for clearance of plantar warts; while local hyperthermia had a lower recurrence rate and lower pain sensation during treatment.
Acta Dermato-Venereologica
Local Hyperthermia Versus Cryotherapy for Treatment of Plantar Warts: A Prospective Multi-centre Non-randomized Concurrent Controlled Clinical Trial
Acta Derm Venereol 2022 Feb 28;102(xx)adv00655, W Huo, YL Gao, HY Wang, GJ Bi, S Qiao, YF Cai, RQ Qi, Y Yang, J Lan, ZR Yao, XP Han, JZ Zhang, TW Gao, S Yang, H Gu, RN Wu, HG Lu, FQ Zeng, X Chen, Y Qiao, XH Gao
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IL-36 and generalized pustular psoriasis: L'chaim!
By Warren R. Heymann, MD, FAAD March 9, 2022 Vol. 4, No. 10
In 1910, Leo Ritter von Zumbusch meticulously detailed the clinical course of "psoriasis pustulosa generalisata" (referred to herein as generalized pustular psoriasis, GPP) in a brother and sister, pondering if this was a variant of psoriasis or psoriasis combined with another entity. He concluded that the disorder "is a previously unrecognized form of psoriasis." (1)
Pustular psoriasis may be subdivided into variants. Localized forms include palmoplantar psoriasis and acrodermatitis continua of Hallopeau. GPP includes pustular psoriasis of pregnancy (impetigo herpetiformis), exanthematic (an acute pustular eruption without systemic symptoms that resolves in days), annular (with pustules along the advancing edge), and the von Zumbusch subtype (a diffuse, generalized pustular eruption associated with systemic symptoms, such as fever, joint pains, headaches, and leukocytosis). The von Zumbusch subtype has a higher risk of mortality, especially if there are associated comorbidities such as hepatic failure, renal insufficiency, or cancer. Complications include hypocalcemia, septicemia, hyperthermia, liver damage, acute renal failure, and malnutrition. (2)
As Cowen eloquently asserts in his editorial "It is time to focus on pustular psoriasis," there is no FDA-approved treatment for either localized or GPP. Fortunately, our understanding of GPP has taken a quantum leap forward over the past decade. (3) Cowen states that in 2009, a severe, neonatal-onset form of pustular psoriasis with systemic inflammation termed deficiency of the IL-1 receptor antagonist, or DIRA (OMIM 612852) was described. These children respond quickly and dramatically to treatment with recombinant IL-1 receptor antagonist therapy such as anakinra. (3,4) Two years later, an analogous form of variable-age–onset pustular psoriasis (known as DITRA) caused by deficiency of the IL-36 receptor antagonist, IL-36Ra, which is encoded by the IL36RN gene (OMIM 614204) was detailed. "Subsequent sequencing studies have demonstrated that variants in IL36RN may be responsible for 19% to 41% of GPP and have also linked pathogenic variants in CARD14, AP1S3, SERPINA3, and myeloperoxidase with GPP. These discoveries have prompted a renewed effort to disentangle the pathogenesis of pustular psoriasis from plaque disease and, more specifically, to clarify the role of IL-1 family member cytokines (IL-1, IL-36) in the management of idiopathic pustular psoriasis, which still represents the majority of pustular psoriasis cases." (3)
JAAD Case Rep 2017 Oct 6;3(6):495-497.
The following excerpt from the abstract by Madonna et al offers a concise, lucid summation of the significance of IL-36 in psoriasis: "Psoriasis is an immune-mediated inflammatory skin disease that involves mainly T helper (Th)17, Th1 and Th22 lymphocytes, which cause hyper-proliferation of the epidermis with aberrant differentiation of keratinocytes, and local production of chemokines and cytokines. These fuel a self-amplifying loop where these products act on T cells to perpetuate cutaneous inflammatory processes. Among the various inflammatory mediators involved, interleukin (IL)-36 cytokines are important for the recruitment and activation of neutrophils and Th17 cells in psoriatic skin. More specifically, IL-36s induce chemokines and cytokines that interfere with differentiation/cornification programs in the epidermis, as well as promote pathological angiogenesis and endothelial cell activation. IL-36 cytokines belong to the IL-1 family, and comprise IL-36α, IL-36β, and IL-36γ agonists as well as IL-36 receptor antagonist and IL-38 antagonists. IL-36 cytokines are up-regulated in psoriatic epidermis, and their expression is strongly induced by TNF-α and IL-17. Contrarily, IL-38 antagonist is downregulated, and its impaired expression may be relevant to the dysregulated inflammatory processes induced by IL-36." (5)
Noe et al performed a retrospective longitudinal case series of 95 patients with GPP. The authors found that 70.5% of patients were women with a mean age of 50.3 years. On initial presentation, more than one-third of patients were hospitalized, and two-thirds were treated with more than 20 systemic therapies (antibiotics, antiviral, antifungals, systemic steroids, immunosuppressives, apremilast, biologics, and phototherapy). Over time, 35.8% of patients reported hospitalizations for disease flares. (6)
Spesolimab is a humanized anti–interleukin-36 receptor monoclonal antibody, being studied for the treatment of GPP flares. In a phase 2 trial, 53 randomly assigned patients with a GPP flare in a 2:1 ratio received a single 900-mg intravenous dose of spesolimab (35 patients) or placebo (18 patients). Seven patients (5 in the spesolimab group and 2 in the placebo group) had IL36RN mutations. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (P<0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (P=0.02). Drug reactions were reported in 2 patients (1 with DRESS syndrome). Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12 (the most reported being urinary tract infection in 3 patients and influenza in 3 patients). Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab. The authors concluded that this phase 2 randomized trial of spesolimab resulted in a higher incidence of lesional clearance of GPP at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effectiveness and risks of spesolimab in patients with pustular psoriasis. They also note that the long-term administration of spesolimab is being investigated with a subcutaneous formulation to prevent flares of GPP (Effisayil 2 trial). (7) (The reader should note that the spesolimab study was funded by Boehringer Ingelheim, as are the Effisayil trials. I have no conflicts of interest — financial or otherwise — regarding this study.)
The potential severity of the von Zumbusch variant of GPP may warrant a greater risk-to-benefit ratio than other forms of pustular psoriasis. In Jewish numerology (gematria), the number 18 ("chai") means life (think of "L'chaim — to life!" from Fiddler on the Roof) — 36 is twice life. Perhaps advances in anti-IL-36 directed therapy will also mean two lives for patients with GPP — their former life of affliction replaced with a new one of disease control.
Point to Remember: IL-36 plays an important role in the pathogenesis of pustular psoriasis. Targeting this cytokine therapeutically may have the capability to alter the course of this potentially life-threatening disease. Further studies are necessary to determine the risk/benefit ratio of this approach.
Our experts' viewpoints
Joel Gelfand, MD, MSCE, FAAD James J. Leyden Professor of Dermatology and of Epidemiology Vice Chair of Clinical Research and Medical Director, Dermatology Clinical Studies Unit Director, Psoriasis and Phototherapy Treatment Center University of Pennsylvania Perelman School of Medicine
GPP is a severe life-threating skin disease but despite the serious nature of this condition there have been no large-scale detailed epidemiological studies of this disease in the U.S., with the last major study on this topic occurring in 1991 at a single institution. (8) We recently published a 20 U.S. center epidemiological study and concluded the following (6):
GPP is quite rare in the U.S. For example, five study sites (25%) did not have 5 GPP cases during the 10-year study period. This finding is striking as all sites were academic referral centers.
More than 20 different systemic therapies have been tried in the U.S. demonstrating that none have risen to the top as being consistently effective, and thus there is significant unmet medical need.
GPP is more common in women (70%) and the disease is highly burdensome. At presentation more than a third of patients were hospitalized and over time 36% of patients were hospitalized for a flare of GPP. Interestingly, women had a decreased risk of an emergency department or hospital encounter (odds ratio, 0.19; 95% CI, 0.04-0.83) for a GPP flare. This observation is a new finding which requires replication.
Mark Lebwohl, MD, FAAD Dean of Clinical Therapeutics Professor of Dermatology Kimberly and Eric J. Waldman Department of Dermatology Icahn School of Medicine at Mount Sinai
Despite breakthroughs in psoriasis, treatment of generalized pustular psoriasis (GPP) remains a major challenge. The skin of affected patients with GPP loses many of its functions. As a result, patients can come in febrile or hypothermic because of the loss of temperature control; hypotension and renal failure can occur because of loss of fluid through the skin; hypoalbuminemia frequently occurs because of loss of protein through the skin; patients develop a microcytic anemia because of loss of iron; and electrolyte imbalances such as hypocalcemia are common. Patients often develop lower limb edema as a result of high output cardiac failure, and the most common cause of death is sepsis because of loss of the skin's protective barrier against bacteria. As a result, GPP remains a life-threatening condition. Treatments in the past have been too slow and insufficiently effective.
There are no approved therapies for GPP in the United States. While systemic steroids are still commonly used in patients with GPP, the evidence is clear that use of systemic steroids for this condition is associated with increased fatality. In a large study by Ryan and Baker, nearly a quarter of patients treated with systemic steroids for GPP died, most often as a consequence of the steroid therapy. (9) Retinoids, methotrexate, cyclosporine, and TNF blockade can be effective but are often too slow for this life-threatening condition. Newer biologics have recently been approved outside the U.S., but the endpoints in studies leading to their approval demonstrate how difficult GPP is to treat. In some studies, the definition of treatment success is any improvement at all. Moreover, studies still use PASI scores even though induration, a key component of the PASI score, is not present in GPP; and those studies do not evaluate the presence or absence of pustules, a key element of GPP. Spesolimab thus represents a major breakthrough in the treatment of pustular psoriasis. It targets the specific cytokine known to drive GPP, IL-36, and it works quickly and in a high proportion of treated patients.
Dr. Gelfand had disclosed financial relationships with the following to the AAD at the time of publication: Abcentra, Amgen, BMS, Boehringer Ingelheim, Celgene Corporation, Daavlin Company, Dr. Reddy, Eli Lilly and Company, FIDE, GlaxoSmithKline, Happify, Healio, Janssen Pharmaceuticals, Inc, NEMA Research, Inc, Neumentum, Inc., Neuroderm LTD, Novartis Pharmaceuticals Corp., Ortho Dermatologics, Pfizer Inc., Regeneron, Sanofi US Services, Society for Investigative Dermatology, Sun Pharmaceutical Industries Ltd., Trevi Therapeutics, UCB, vTv Therapeutics.
Dr. Lebwohl had disclosed financial relationships with the following to the AAD at the time of publication: AbbVie, Aditum Bio, Allergan, Inc., Almirall, AltruBio Inc., Amgen, AnaptysBio, Arcutis, Inc., Arena Pharmaceuticals, Aristea Therapeutics, Arrive Technologies, Avotres, Inc., BiomX Ltd., BirchBioMed, BMD Skincare, Inc., Boehringer Ingelheim, Brickell Biotech, Inc., Cara Therapeutics, Castle Biosciences, Inc, Corrona, Inc., Bristol-Myers Squibb, Dermavant Sciences, Dr. Reddy, Eli Lilly and Company, EMD Serono, Evelo Biosciences, Inc., Evommune, Inc., Facilitation of International Dermatology Education, Forte Biosciences, Foundation for Research & Education of Dermatology, Helsinn Healthcare, Hexima Ltd., Incyte Corporation, Inozyme Pharma, Janssen Research & Development, LLC, Kyowa Kirin, Leo Pharma Inc, LEO Pharma, US, Meiji Seika Pharma Co., Ltd, Menlo Therapeutics, Mindera, Mitsibushi Pharma, Neuroderm LTD, Ortho Dermatologics, Pfizer Inc., Regeneron, Seanergy Maritime Holdings Corp., Theravance Biopharma, UCB, Verrica Pharmaceuticals Inc.
Full disclosure information is available at coi.aad.org.
Ring J, Locher W. Leo Ritter von Zumbusch. In Pantheon of Dermatology, Löser C, Plewig G, Burgdorf WHC (eds). Springer, 2013, pp 1222-1232.
Shah M, Al Aboud DM, Crane JS, Kumar S. Pustular Psoriasis. 2021 Aug 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 30725687.
Cowen EW. It Is Time to Focus on Pustular Psoriasis. JAMA Dermatol. 2021 Dec 8. doi: 10.1001/jamadermatol.2021.4634. Epub ahead of print. PMID: 34878490.
Cowen EW, Goldbach-Mansky R. DIRA, DITRA, and new insights into pathways of skin inflammation: what's in a name? Arch Dermatol. 2012 Mar;148(3):381-4. doi: 10.1001/archdermatol.2011.3014. PMID: 22431779; PMCID: PMC3464919.
Madonna S, Girolomoni G, Dinarello CA, Albanesi C. The Significance of IL-36 Hyperactivation and IL-36R Targeting in Psoriasis. Int J Mol Sci. 2019 Jul 5;20(13):3318. doi: 10.3390/ijms20133318. PMID: 31284527; PMCID: PMC6650959.
Noe MH, Wan MT, Mostaghimi A, Gelfand JM and the Pustular Psoriasis in the US Research Group. Evaluation of a Case Series of Patients With Generalized Pustular Psoriasis in the United States. JAMA Dermatol. 2021 Dec 8. doi: 10.1001/jamadermatol.2021.4640. Epub ahead of print. PMID: 34878491.
Bachelez H, Choon SE, Marrakchi S, Burden AD, Tsai TF, Morita A, Navarini AA, Zheng M, Xu J, Turki H, Anadkat MJ, Rajeswari S, Hua H, Vulcu SD, Hall D, Tetzlaff K, Thoma C, Lebwohl MG; Effisayil 1 Trial Investigators. Trial of Spesolimab for Generalized Pustular Psoriasis. N Engl J Med. 2021 Dec 23;385(26):2431-2440. doi: 10.1056/NEJMoa2111563. PMID: 34936739.
Zelickson BD, Muller SA. Generalized Pustular Psoriasis: A Review of 63 Cases. Arch Dermatol. 1991;127(9):1339–1345. doi:10.1001/archderm.1991.01680080075005
Ryan TJ, Baker H. Systemic corticosteroids and folic acid antagonists in the treatment of generalized pustular psoriasis. Evaluation and prognosis based on the study of 104 cases. Br J Dermatol. 1969 Feb;81(2):134-45. doi: 10.1111/j.1365-2133.1969.tb15995.x. PMID: 4304162.
All content found on Dermatology World Insights and Inquiries, including: text, images, video, audio, or other formats, were created for informational purposes only. The content represents the opinions of the authors and should not be interpreted as the official AAD position on any topic addressed. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment.
This literature review characterized the relationship between acute generalized exanthematous pustulosis (AGEP) and results of patch testing to culprit medications. A total of 93 drugs causing AGEP were identified, which resulted in 259 positive patch test reactions. Beta-lactam antibiotics, other antibiotics, and iodinated contrast media were among the many agents that cumulatively accounted for almost 60% of all reactions. The sensitivity, techniques, and safety of patch testing in AGEP were also discussed.
This review suggests that, although mild recurrence may be noticed occasionally, patch testing is mostly safe and can be regarded as the first-line diagnostic test to be performed to determine the causative drug in patients with AGEP.
One of the most difficult decisions we may have to make is "which drug may or may not" be causing this eruption. I too often am faced with eczematous rashes that on biopsy are reported as a dermatitis but have a comment listing drug induced mentioned as a consideration. That is bad enough but when we see patients with a severe cutaneous adverse reaction (SCAR) to a drug, such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN), we are tasked with trying to define the culprit drug. Unfortunately, we have not perfected any lab test or skin test that can tell us the answer 100% of the time. One thing we as dermatologists can do though that may help is applying patch tests to at least a few medications that are commercially available through Chemotechnique Diagnostics or Smart Practice Dermatology/Allergy. After reviewing the literature, we may prepare medications in petrolatum, water, or alcohol also, but these are not standardized. A very limited number of dermatologists may also attempt to identify the causative agent using Intradermal skin testing or the Lymphocyte Tranformation Test (LTT). As Dr. de Groot points out in his excellent review using AGEP as an example, it is clear that overall from this and other articles that we face about a 50% accuracy rate. He notes that 93 drugs were identified that have together caused 259 positive patch tests in 248 patients suffering from AGEP. Patch testing has been shown in other articles to be helpful to assess drug imputability in AGEP with positive tests reported with more than 20 different drugs (1,2), and even though testing is not close to delivering 100% reliability, it is usually quite safe and has been accurate to different degrees with regard to different reactions and with different medications (3,4). This is better than nothing, but we must also realize a very important caveat and that is that false negatives may be misleading. This is not serious with eczematous reactions if the patient is rechallenged with the suspect drug that has falsely been labeled as "not the one."
This article by Dr. de Groot, who tirelessly and continually teaches us so much dermatology, not only helps us understand what is known about testing for AGEP and other SCARs but also provides informative tables and an amazing list of references for those who wish to study testing for drug allergy. This demonstrates that more needs to be done to help us with such a dilemma.
LaBerge L, Pratt M. MD Immediate and Delayed Hypersensitivity to Systemic Corticosteroids: 2 Case Reports. Dermatitis. 2012;23(6):288–290. 10.1097/DER.0b013e318277ca22
Barbaud A, Collet E, Milpied B, et al. A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions. Br J Dermatol. 2013;168:555–562. https://doi.org/10.1111/bjd.12125
Abstract
The literature on positive patch test results in acute generalized exanthematous pustulosis (AGEP) is reviewed. 93 drugs were identified that have together caused 259 positive patch tests in 248 patients suffering from AGEP. The drug classes causing the highest number of reactions are beta-lactam antibiotics (25.9%), other antibiotics (20.8%), iodinated contrast media (7.3%) and corticosteroids (5.4%), together accounting for nearly 60% of all reactions. The highest number of reactions to individual drugs was to amoxicillin (n=36), followed by pristinamycin (n=25), diltiazem (n=14), amoxicillin-clavulanic acid (n=13), clindamycin (n=11) and iomeprol (n=8); 59 of the 93 drugs each caused a single case only. The "Top-10" drugs together caused over 50% of all reactions. The sensitivity of patch testing (percentage of positive reactions) in patients with AGEP is largely unknown, but may generally be around 50%, which also applies to pristinamycin. Patch testing in AGEP appears to be safe, although mild recurrence of AGEP skin symptoms or other rashes may occur occasionally. Clinical aspects of AGEP, including epidemiology, etiology and pathophysiology, clinical features, histology, treatment, and prognosis are briefly presented, as are diagnosing the disease and identifying the culprit drugs with patch tests, intradermal tests, in vitro tests, and challenge tests. This article is protected by copyright. All rights reserved.
Contact Dermatitis
Results of patch testing in Acute generalized exanthematous pustulosis (AGEP): a literature review
Contact Derm 2022 Feb 20;[EPub Ahead of Print], AC de Groot
Correlation of Basal Cell Carcinoma Subtype With Subclinical Extension During Mohs Micrographic Surgery
Journal of the American Academy of Dermatology
TAKE-HOME MESSAGE
In this multicenter prospective study involving 17 Mohs surgeons, 1686 cases of basal cell carcinoma (BCC) undergoing Mohs micrographic surgery (MMS) were analyzed. The objective was to correlate the histological subtype of BCC with the likelihood of subclinical extension as defined as the number of MMS stages required to clear the tumor. Morpheaform, infiltrative, metatypical, mixed, and superficial BCCs had a high risk of subclinical extension, with an average number of MMS stages of 1.8 or higher. Basosquamous, micronodular, nodular, and unspecified subtypes had an average number of MMS stages of 1.6 or lower. A change between BCC subtype at the index biopsy and the BCC subtype at the final MMS stage was most likely to occur with superficial BCC.
While superficial BCC is not deemed "appropriate" for MMS, it was as likely to exhibit subclinical extension as the "aggressive" subtypes of BCC.
Multiple options exist for the treatment of basal cell carcinoma. Mohs surgery is the most exacting method of tumor removal. Mohs surgery is particularly useful in the removal of lesions which may have subclinical extension (SCE).
This study was a detailed, prospective, multicenter investigation of lesions treated by Mohs surgery. The primary endpoint was to determine the types of basal cell carcinoma that were likely to exhibit SCE. The authors demonstrated that morpheaform, infiltrative, metatypical, mixed, and superficial BCC required a higher mean number of stages for complete tumor removal. Keratotic, micronodular, nodular, and unspecified lesions were less likely to have SCE. The authors note that superficial BCC may have SCE and that Mohs micrographic surgery should be considered.
The difference in stages between high-degree SCE and low-degree SCC was highly statistically significant, but the absolute difference (1.9 per case vs 1.6) was small. In this study, the authors did not distinguish SCE between a deep positive margin and a superficial epidermal margin. It is not clear that epidermal SCE for a superficial BCC on area L has the same implication as deep muscle SCE for an infiltrative BCC on the nose.
The Mohs AUC have functioned very well to define BCCs that are appropriate for Mohs surgery. The majority of BCCs, including superficial BCC, are appropriate in areas H and M. It remains unclear that Mohs micrographic surgery is appropriate for lesions of superficial BCC in area L, as many appropriate treatments are available. A few buds of BCC on a peripheral margin on the back are not prognostically equivalent to single-cell invasion of muscle or fascia, and they need not be treated equivalently.
Abstract
BACKGROUND
Traditionally "aggressive" histologic subtypes of basal cell carcinoma (BCC) are more likely to quantitatively exhibit subclinical extension (SCE), requiring more stages during Mohs micrographic surgery and therefore larger margins upon excision. However, the tendency for SCE has never been compared between histologic subtypes of BCC in a prospective manner.
OBJECTIVE
To prospectively correlate the histologic subtype of BCC with the likelihood of subclinical extension as defined by the number of MMS stages required to clear tumor.
METHODS
In a prospective, multi-center study involving 17 Mohs surgeons in 16 different practices across the United States, 1,686 cases of BCC undergoing MMS were collected. Patient demographics, tumor characteristics, number of MMS stages required for tumor clearance, and specific BCC subtypes noted on both index biopsy and final MMS stage were recorded.
RESULTS
Analysis of the average number of MMS stages for each histologic subtype required to clear tumor revealed two distinct degrees of SCE (P < 0.0001): high (higher than average) risk of SCE (1.9 stages, 1.0 SD), and low (lower than average) risk of SCE (1.6 stages, 0.9 SD). Subtypes of BCC within the high category were morpheaform (2.1), infiltrative (1.9), metatypical (1.9), mixed (1.8), and superficial (1.8). The low category included BCC subtypes of basosquamous (1.6), micronodular (1.6), nodular (1.6), and unspecified (1.5). Three hundred twenty-four cases (22.0%) manifested histologic subtype (HS) drift, or a change in subtype from index biopsy to final MMS stage. Superficial BCC was the only subtype that showed an increase in prevalence from index biopsy to final MMS stage (16.0% to 25.8%, P < 0.0002).
LIMITATIONS
Histologic subtypes from index biopsy may not be representative of all histologic subtypes present, resulting in sampling bias.
CONCLUSION
Subclinical extension of superficial BCC was as likely as SCE of BCC subtypes which are considered "aggressive" and are deemed "appropriate" for MMS by the AUC. Our study also found that when HS drift occurs, the most likely subtype to extend subclinically is superficial BCC.
Journal of the American Academy of Dermatology
Correlation of Basal Cell Carcinoma Subtype with Histologically Confirmed Subclinical Extension During Mohs Micrographic Surgery: A Prospective Multi-Center Study
J Am Acad Dermatol 2022 Feb 26;[EPub Ahead of Print], GFS Lim, OA Perez, JA Zitelli, DG Brodland
Skin Graft Donor Site Healing among Elderly Patients with Dermatoporosis - A Case Series
Toni Seppälä, Vahur Grünthal, Virve Koljonen
Int J Low Extrem Wounds. 2022 Mar 15 15347346221087081 [Epub ahead of print]
We reviewed donor site wound healing among morbid ≥65-year-old patients after split-thickness skin graft (STSG) harvesting. Patients were treated for a pretibial laceration or hematoma in Kymenlaakso Central Hospital, Finland, between 2015 and 2019. Twelve morbid patients with a mean Charlson Comorbidity Index of 7.1 (range 4-12) and a mean age of 80.6 years (range 69-91) were studied. Nine patients were female. Eight had a chronic cutaneous fragility syndrome, eg, dermatoporosis. All donor site areas were located on the thigh and were less than 2% TBSA. One donor site infection occurred. STSG integration on the pretibial wound bed was successful with all patients, and none of the patients needed further operative treatment. Graft thickness varied between 0.010 to 0.014 inches. STSG donor sites healed within the normal range of 21 days in 50% of patients. Among two patients, healing took 25 days, and among four, 37 to 97 days. All donor sites healed via local wound care without the need for regrafting. 4Our study indicates that harvesting STSG from elderly and morbid patients with poor skin condition is safe and does not result in significant complications. Prolonged donor site healing can occur, which can be managed with regular local wound care.
What Does a Black Box Warning Mean for Eczema Treatments?
All medications have drug labels and packaging inserts that provide important information on safe and proper medication use. This information includes how to use medications, who should not use them, things to avoid when taking certain medications and the risks of possible side effects (also known as adverse events).
All medications carry some risk of side effects, which can range in severity from relatively minor to more serious. Medications with a risk of serious side effects can be issued a boxed warning, also known as a "black box" warning by the U.S. Food and Drug Administration (FDA).1 Several drugs used to treat atopic dermatitis (AD) have a boxed warning label (Table 1). In this article, we will discuss what these labels mean and how you can discuss this information with your healthcare provider when considering and selecting treatment options.
What is a boxed warning and why does the FDA use it?
A boxed warning can be issued by the FDA for newly approved or existing drugs to highlight one of the following situations for healthcare providers and their patients if:2,3
• There is potential for a serious adverse event when compared to the potential benefit from the drug; risks and benefits must be carefully weighed;
• A serious adverse reaction can be prevented or reduced by appropriate use of the drug (e.g., patient selection, careful monitoring, avoiding using certain other medications at the same time, monitoring the dose of the drug, or avoiding use in a specific clinical situation);
• The FDA approved the drug with certain restrictions for use and distribution.
The FDA collects drug safety data for all phases of clinical trials, including Phase IV, after a drug has been approved and is being used in the real world by different types of patients.1 While many common but tolerable or manageable side effects (such as headache, upset stomach, et cetera) may be readily apparent during Phase I-III clinical trials, other more severe effects may be rare and, if they do not become apparent in the early phases, may become apparent in Phase IV when large numbers of people use the medicines.
If evidence of serious adverse events associated with a medication increases, the FDA may consider continued monitoring or a boxed warning and, if higher numbers of these events occur over time, may remove the drug from the market altogether.1
The FDA started using the boxed warning label in 19791 and has currently (as of September 2019) placed the warning label on over 400 different medications, including those delivered topically, orally, by injection or through other delivery methods. Figure 1 depicts an example of a boxed warning label for Opzelura, a topical Janus Kinase (JAK) inhibitor approved for use in atopic dermatitis (AD).2,4
Dr. Kendall Marcus, director of the division of dermatology and dental products at the FDA, provided some insight into these warnings, "Boxed warnings are prominently placed as the first section in the prescribing information for healthcare providers and contain a summary of the essential scientific information needed for the safe and effective use of the drug."2,3 Dr. Marcus went on to say, "The prescribing information must be updated when new information becomes available that causes the labeling to become inaccurate, false or misleading.3 The FDA has stated that if the criteria for including a boxed warning are no longer met, it is reasonable to modify or remove the boxed warning based on clinical data."
Boxed warnings and medications for atopic dermatitis
Several medications used in the treatment of AD carry a boxed warning, including the new FDA-approved topical and oral JAK inhibitors (Table 1). However, medications that carry a boxed warning can be important treatment options – highlighting an important opportunity for patient-healthcare provider discussions regarding potential risks of a therapy alongside the anticipated benefits.5,6
Table 1:Some drugs used to treat AD that have boxed warning labels.
Dr. Eric Simpson, of Oregon Health and Science University, said, "The black box is there for a reason – either a perceived or real risk as determined by the FDA – but the dangerous side effects mentioned on the label are often rare. A lot of times whether to still use a drug with a boxed label depends on the context. The most important thing is to discuss whether benefits outweigh risks in a particular situation taking into account disease severity, other medical problems, age and other treatment options that may be available. Then together, patients and healthcare providers can make informed decisions about whether these highly effective medications are right for the circumstance." Examples of the importance of context can be illustrated by looking at two different drug classes used for AD treatment, calcineurin inhibitors and Janus Kinase (JAK) inhibitors.
Topical calcineurin inhibitors
The topical anti-inflammatory calcineurin inhibitors (TCI) tacrolimus and pimecrolimus were approved as topical ointments and creams for treatment of AD in 2000 and 2001, respectively.7 These medications added much needed non-steroidal topical treatment options for AD. They can be used for short-term and longer-term non-continuous use to treat mild, moderate or severe AD in non-immunocompromised adults and children over 2 years-old who have not responded to other topical treatments. However in 2005, several years after the drugs had been approved for AD, the Pediatric Advisory Committee of the FDA added boxed warnings for these TCIs that remain today. The warning states, "Long-term safety of topical calcineurin inhibitors has not been established. Although a causal relationship has not been established, rare cases of malignancy (e.g., skin and lymphoma) have been reported."7
Data supporting this boxed warning were largely established from cell culture studies, animal models and data from prolonged systemic use in transplant patients. Since 2005, however, studies conducted with cohorts of thousands of AD patients in the U.S. have not found increased rates of skin cancer or lymphoma. A few cases of skin cancer after TCI use have been reported in older adults (>55 years old), but the case reports did not include details of earlier treatments or other factors that could have been associated with these cancers.7
A 2015 publication analyzing pediatric AD patients enrolled in the Pediatric Eczema Elective Registry (PEER) with a history of AD and pimecrolimus use showed no statistically significant association between the treatment and malignancy.8 An updated literature review published in 2019 with increased data collected over time concluded that "the benefits of TCIs outweigh their potential risks when used in the appropriate patient populations for the recommended duration of time."9 Another definitive long-term (10 years) study was recently published (2020) on the use of tacrolimus in children. The study concluded, "This finding provides no support for the hypothesis that topical tacrolimus increases long-term cancer risk in children with AD."10
It is important to understand what data led the FDA to issue the boxed warning and how subsequent published studies add to the broader understanding of risks in the real world. The incidence of the side effects, what kind of patients they occurred in and at what drug doses also be considered. Dr. Peter Lio, of Northwestern University, stated, "Black box labels by themselves do not tell us how likely risks are for a given patient. Further, risks on black box warnings often seem to be dose-related to some degree. In fact, tacrolimus, pimecrolimus and the newer ruxolitinib cream (a topical JAK inhibitor) have language to the effect of limiting use. The prescribing information for ruxolitinib cream says to use it for 'up to 20% body surface area' and 'do not use more than 60 grams per week.' It seems likely that when used in relatively small quantities, the absolute risk for some of the boxed warnings to AD patients is low."
Janus kinase (JAK) inhibitors
Though oral JAK inhibitors have been approved for the treatment of inflammatory diseases, such as rheumatoid arthritis, for several years, the FDA has recently approved a topical JAK inhibitor (ruxolitinib [Opzelura™] cream) and two oral JAK inhibitors (upadacitinib [Rinvoq™], and abrocitinib [Cibinqo™]) for treatment of AD.11-13These drugs represent the latest new therapies supported by decades of research to identify and target the immune pathways that contribute to AD. They provide patients and healthcare providers with additional options for different severities of disease.14,15
As these drugs were in the process of being reviewed by the FDA for use in AD, the FDA began revising the boxed warning label for the entire class of JAK inhibitors.5 Rare side effects seen after systemic use of drugs like tofacitinib (Xeljanz®) to treat rheumatoid arthritis resulted in even topical JAK inhibitors receiving the boxed warning. Dr. Raj Chovatiya, PhD, of Northwestern University said, "The JAK Inhibitor class of topical and oral medications have been given a label for risks including mortality, infections, malignancy, major adverse cardiovascular events and blood clots. These warnings are based on data from a long-term, randomized, post-marketing study (Phase IV) assessing safety of tofacitinib versus tumor necrosis factor alpha (TNFa) inhibitors in patients with rheumatoid arthritis.16 While most of these adverse events appear to be uncommon in AD patients treated with JAK inhibitors, some were still observed in rare instances – often without clear relation to the medication itself. Thus, while JAK inhibitors appear to be highly efficacious with favorable safety in AD patients, more data and more time is needed to better understand this over the long run."17,18
More studies are needed to understand similarities and differences between AD patients and patients using JAK inhibitors for other diseases like rheumatoid arthritis. While common immune system pathways may be shared across different inflammatory diseases, affected patients may have different co-occurring conditions that affect overall risk of side effects (such as cardiovascular disease in rheumatoid arthritis patients).17,18 Though studies in AD patients are limited to clinical trials, so far, the adverse events represented on boxed warnings have only very rarely been seen.19,20 This is an example of a type of drug class whose benefits may outweigh the risks in AD patients with the recommended dosing, avoiding or limiting use in patients with higher risks for side effects and with monitoring over time.
Shared decision making – a conversation about medication risks and benefits
The concept of "shared decision making," a growing movement in patient-centered care, is broadly defined as patients and caregivers working with healthcare providers to better understand their condition and treatment options to align on healthcare decisions together.
While understanding the risks and benefits of medications is a component of all shared decision making conversations, the presence of a boxed warning elevates the importance of this discussion in arriving at a treatment decision. Dr. Marcus said, "Boxed warnings will typically include steps to take to prevent, reduce, monitor for or manage clinically significant adverse reactions or risks, therefore allowing for the safe and effective use of the drug."
So, what would that conversation with your healthcare provider look like? Dr. Peter Lio and Dr. Raj Chovatiya both weighed in on positive doctor-patient conversations around these issues. First, we asked both doctors to comment on what factors they consider when evaluating a medication with a boxed warning, and how the presence of this warning impacts the conversation they have with patients.
Dr. Lio: "Sometimes a patient's eczema can be effectively treated with gentle, safer treatments and medicines, but if those treatments are not adequately treating the disease, we consider more powerful treatments, even in the face of some risk. Untreated or under-treated eczema has its own set of side effects and risks, so for some patients the risks of taking a particular medication are outweighed by its potential benefits.
Since there have been so few approved drugs to treat eczema, the dermatology healthcare community does use medications with black box warnings frequently. In general, the more powerful the treatment, the more likely there are side effects. As physicians, we never want to be dismissive or undermine an FDA warning. Reading the scientific data and Prescribing Information for how to use the drug to treat a disease like eczema influences our recommendation of a certain medication.
We want to be honest, open and accurate about the safety and risks of these medications for our patients and their families. I often say, 'Let's discuss the burden of the disease, the different treatment options, what we have so far tried and what treatment goals we are trying to achieve by using this medicine, plus what dose we will be prescribing.'"
Dr. Chovatiya: "I leave extra time for questions and discussion so a patient will feel comfortable in the decisions we make together.Many patients with AD do not have adequate control of their disease, underscoring the need for additional effective treatments. As our armament of topical and systemic therapies for AD becomes richer, so will the individual shared decision making conversations that accompany each potential treatment option. Black box warnings are an important mechanism used to highlight certain serious risks that may be associated with a particular drug or treatment class. While these adverse events are generally rare overall and/or associated with only certain risk factors, they are still important to discuss alongside efficacy, safety and patient preference (e.g., feasibility, cost, route of delivery) when helping an individual with AD select the most appropriate therapy.
Eczema is not a one-size-fits-all disease, and neither are treatments and their associated risks. When we feel comfortable with the balance of risks and benefits, I work my hardest to make sure that we do everything possible to get the best treatment on board – with 'best' meaning very different things from case to case. As an example, a patient who has not had previous success with other therapies, may decide that a therapy with a boxed warning might in fact be the 'best' to help them achieve disease control."
Some medications with boxed warnings might require monitoring for potential side effects. We asked the doctors about the different approaches they use.
Dr. Lio: "For most patients, I am happy to say, even the 'scariest' medications can be used safely and can bring great relief. Each medication has different considerations. For example, for our topical treatments, the key thing is to keep an eye on how much medication is being used. For me, I will look at the number of refills obtained between visits. Topical ruxolitinib only comes in 60 gram tubes so the recommended dose would be a full tube every week! It would be nearly impossible for the majority of patients to get a fresh tube every week. Therefore, patients are using less than the dose that led to the warning label for this medication.
For the oral agents, we do things like blood testing to check the kidneys, liver, platelets, blood count, etc. For medications like cyclosporine (sometimes used off-label for AD) we also check for elevated blood pressure. In addition to this monitoring, patients can reach out to healthcare providers if they are experiencing harmful side effects so adjustments can be made to the treatment plan."
Dr. Chovatiya: "First we do a thorough assessment of past medical history and review of systems. This is the most important way to monitor for any changes in health status while on therapy. Each medication has unique considerations and physicians are expected to closely read and understand the prescribing information and monitor for changes in medical labels to follow the best clinical practices. Depending on the drug in question, lab monitoring can be a helpful strategy. In the case of JAK inhibitors, we can include assessment of blood count, liver function, and lipids at various points throughout therapy, as well as baseline assessment of tuberculosis and viral hepatitis status."
Selecting a treatment approach is an important decision, and one that can raise a number of questions. We asked the doctors for their suggestions/recommendations for patients and caregivers as they think about whether to use treatments that have boxed warnings.
Dr. Chovatiya: "AD is associated with an immense burden for patients and choosing the right treatments over time is a major part of this. There really is no right or wrong answer, and each conversation is highly dependent upon someone's disease severity, comorbidities, previous treatment approaches, etc. Boxed warning or not, I want to encourage patients to take the appropriate time to understand and feel comfortable with both how well a drug works and how safe it is. Patients should be open with providers when it comes to personal concerns and points of view. There is no such thing as a bad question – if you're thinking about asking it, odds are many other patients have felt the same way."
Dr. Lio: "No medication should be used forever and I like to make sure we're checking in frequently, re-evaluating and changing the treatment approach to meet the current needs of the patient and address the current state of the disease."
Conclusions
We are at an exciting time in the treatment of AD, with several newly FDA-approved options available, and many more in the development pipeline. Despite the presence of boxed warnings for some existing and new treatments, these medicines add much needed tools to the toolbox needed to treat AD. This article highlights the importance of data and context as healthcare providers and patients work together to formulate treatment plans that take into account the risks and benefits of the medication, patient heterogeneity, individual preference and risk tolerance.
Take Home Points
All medications come with the risk of potential side effects that can range from mild to moderate or severe.
The FDA is responsible for the safety of people taking approved medications for their intended use and errs on the side of caution when warning of severe side effects, even if rare.
Warnings about the most severe potential adverse effects appear as boxed labels ('black box') on the medication and in the Prescribing Information.
Understanding what dose, delivery method, duration of use and patient characteristics (age, sex, health history, other medications, etc.) are indicated in a boxed warning can help you and your health care provider weigh the risks and benefits of taking the drug.
Many new drugs are in development for use for AD and their risks and benefits, as determined in clinical trials, may change as the drug begins being broadly used.
Determining your individual comfort level with the risks of each medication balanced against the potential benefits will help you and your healthcare provider align on a treatment strategy for managing AD.
1. Smith RG. US Food and Drug Administration Black Box Warnings. J Am Podiatr Med Assoc. 2020;110(1):Article10.
2. Cornell Law School Legal Information Institute. Specific requirements on content and format of labeling for human prescription drug and biological products described in §201.56(b)(1). In: Electronic Code of Federal Regulations. https://www.law.cornell.edu/cfr/text/21/201.57. Accessed February, 2022.
3. US Department of Health and Human Services. Guidance for Industry: Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Prodects – Content and Format. In: Food and Drug Administration, Rockville, MD, 2011. https://www.fda.gov/media/71866/download. Accessed February, 2022.
4. Delong C, Preuss CV. Black Box Warning. In: StatPearls. Treasure Island (FL) 2022.
6. Winterfield L, Vleugels RA, Park KK. The Value of the Black Box Warning in Dermatology. J Drugs Dermatol. 2015;14(7):660-666.
7. Ring J, Mohrenschlager M, Henkel V. The US FDA 'black box' warning for topical calcineurin inhibitors: an ongoing controversy. Drug Saf. 2008;31(3):185-198.
8. Margolis DJ, Abuabara K, Hoffstad OJ, Wan J, Raimondo D, Bilker WB. Association Between Malignancy and Topical Use of Pimecrolimus. JAMA Dermatol. 2015;151(6):594-599.
9. Hanna S, Zip C, Shear NH. What Is the Risk of Harm Associated With Topical Calcineurin Inhibitors? J Cutan Med Surg. 2019;23(4_suppl):19S-26S.
10. Paller AS, Folster-Holst R, Chen SC, et al. No evidence of increased cancer incidence in children using topical tacrolimus for atopic dermatitis. J Am Acad Dermatol. 2020;83(2):375-381.
14. Ballard A. Jak Inhibitors are Coming and they are the Biggest Eczema Development in Years. National Eczema Association, 2021. https://nationaleczema.org/jak-inhibitors-research/. Accessed February, 2022.
15. Cartron AM, Nguyen TH, Roh YS, Kwatra MM, Kwatra SG. Janus kinase inhibitors for atopic dermatitis: a promising treatment modality. Clin Exp Dermatol. 2021;46(5):820-824.
16. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022;386(4):316-326.
17. Rajasimhan S, Pamuk O, Katz JD. Safety of Janus Kinase Inhibitors in Older Patients: A Focus on the Thromboembolic Risk. Drugs Aging. 2020;37(8):551-558.
18. Rajasimhan S, Pamuk O, Katz JD. Authors' Reply to Moura et al.: "Safety of Janus Kinase Inhibitors in Older Patients: A Focus on the Thromboembolic Risk". Drugs Aging. 2021;38(6):539-541.
19. Traidl S, Freimooser S, Werfel T. Janus kinase inhibitors for the therapy of atopic dermatitis. Allergol Select. 2021;5:293-304. 20. Tsai HR, Lu JW, Chen LY, Chen TL. Application of Janus Kinase Inhibitors in Atopic Dermatitis: An Updated Systematic Review and Meta-Analysis of Clinical Trials. J Pers Med. 2021;11(4).
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These authors examine the safety and efficacy of propranolol use in very young infants, <45 weeks corrected gestation age, with hemangiomas. In this cohort of 24 infants, there were no serious adverse events. The most common side effects included sleep disturbance, irritability and cool hands and feet.
Very young infants often need oral propranolol to stop the growth of function or appearance threatening hemangiomas before peak proliferation occurs, sometimes between 5-7 weeks of life. Unfortunately, this propranolol is administered with worry and hesitation under 6 weeks of life. This and other reports provide reassuring evidence of the safety in this group. Notably, past initiation protocols suggested hospital admission and monitoring for this young group, and 21 of these infants had propranolol initiated in an outpatient setting with most starting at 1mg/kg/day. As evidence like this grows, outpatient propranolol initiation in select young infants may become more commonplace.