How to Tell the Difference Between Nummular Eczema and Ringworm
It’s often difficult to distinguish between nummular eczema and ringworm, so it’s always best to be evaluated by a dermatologist, say experts.
Published On: Feb 28, 2022
Last Updated On: Mar 29, 2022
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.
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.”
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 your particular 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.
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.”
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.11-13 These 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.
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.”
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
Figure 1: From Opzelura™ Prescribing Information.
References:
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.
5. Janus Kinase (JAK) inhibitors: Drug Safety Communication – FDA Requires Warnings about Increased Risk of Serious Heart-related Events, Cancer, Blood Clots, and Death for Jak Inhibitors that treat certain chronic inflammatory conditions. Approved uses also being limited to certain patients. In: US Department of Health and Human Services Food and Drug Administration, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death. Accessed February, 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.
11. National Eczema Association. Breaking News: FDA Approves Opzelura™ (Ruxolitinib) Cream. 2021. https://nationaleczema.org/opzelura-approval/. Accessed February, 2022.
12. National Eczema Association. Breaking News: FDA Approves Rinvoq® (Upadacitinib). 2022. https://nationaleczema.org/rinvoq-approval/. Accessed February, 2022.
13. National Eczema Association. Breaking News: FDA Approves Cibinqo® (Abrocitinib). 2022. https://nationaleczema.org/cibinqo-approval/. Accessed February, 2022.
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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