PracticalDermatology

Atopic dermatitis (AD) is a chronic, heterogeneous dermatosis with complex pathophysiology that comprises a deficient skin barrier, immune dysfunction, and dysbiosis, and affects up to 20 percent of children and three percent of adults.^1,2 While there has been a nearly incredible revolution in the treatment of psoriasis, AD has been relatively left behind, until very recently.^3,4 As our therapeutic armamentarium continues to expand, we are increasingly put in the position of selecting the best treatment for a given patient, and often have to choose between similar medications. Twenty years ago, choosing a systemic therapy for psoriasis was essentially limited to methotrexate and cyclosporine. Thus, it was fairly easy to choose, as the two drugs arguably have similar efficacy, but very different risks.⁵ For example, methotrexate is a teratogen and can cause hepatotoxicity, while cyclosporine has renal toxicity and adverse interactions with various other drugs, including statins.^6,7 However, with the advent of biologic therapies, we now have an entire class of medications that, compared to conventional immunosuppressants, are generally both safer and more effective than these older agents. Indeed, in the past several years, we have witnessed an embarrassment of riches in psoriasis with each new drug, progressing from TNF-alpha inhibitors to IL-23 and IL-17 inhibitors, seemingly providing additional benefits over the last.⁸ The introduction of biosimilars into the market further expands the repertoire of psoriasis medications, making the decisions even more complicated.

In AD, the long therapeutic drought is finally coming to an end with the advent of new biologic agents, topicals, and small molecules (Table 1). Thus, as in psoriasis and other areas of medicine with multiple treatment options, we will face increasing pressure to select intelligently.

Selecting Intelligently

How to decide appropriate treatment? The American Academy of Dermatology (AAD) and the Joint Task Force in Allergy are two of a number of groups that provide a set of clinical guidelines for AD, but the guidelines are not updated with the constantly evolving medications for AD, including biologics and Janus kinase (JAK) inhibitors.^9,10 For mild to moderate AD, the AAD recommends initial non-pharmacological therapy, stressing patient education about using moisturizers and lifestyle modifications including altering bathing practices and avoiding potential allergens and triggers by being more cognizant of diet and environment.⁹ In addition, topical corticosteroids, topical calcineurin inhibitors, topical antimicrobials, antiseptics, and phototherapy may be used, as well.^9,11

However, in moderate to severe cases, which represent about one-third of children and one-half of adults with AD, systemic therapy may be required, as lifestyle modifications, topical treatments, and phototherapy may not sufficiently control the disease.^11–13 In addition to phototherapy and the often frowned-upon use of oral or intramuscular corticosteroids, systemic treatment for AD consists of the conventional immunosuppressive agents not approved for AD in the United States (i.e., cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil), and a newer agent, dupilumab, a monoclonal antibody (mAb) that targets the IL-4/IL-13 pathway, initially approved in 2017.^14–16 Over the past few years, there has been a tremendous increase in topical and systemic medications that have been approved or are in the pipeline for AD (Table 1).

The AAD, in collaboration with the Choosing Wisely campaign, recommends against the use of systemic oral antibiotics unless there is a clear sign of infection and avoids using oral or injected systemic steroids for long-term treatment, due to the significant side effects.¹⁷ Additionally, Drucker et al recently published a systematic review with meta-analysis evaluating the relative effectiveness and safety of systemic medications for moderate-to-severe AD. The authors’ analysis of 20 medications mostly included studies comparing a drug to placebo, and only a few comparing different doses of the same drug, or comparing one drug to another drug in a head-to-head fashion. Nonetheless, the authors found that compared to methotrexate and azathioprine, dupilumab, and higher-dose cyclosporine were more effective in the first 16-weeks of treatment at improving clinical symptoms and quality of life. Furthermore, pipeline JAK inhibitors upadacitinib and abrocitinib showed promise as they had clinical outcomes comparable to dupilumab.¹⁸ Another systematic review by Alexander and colleagues that compared systemic therapies for AD found that dupilumab and nemolizumab, a monoclonal antibody against the IL-31 receptor, were superior to other treatments in terms of long-term control of AD.⁴

Beyond the general guidelines, and more complex than the question of which agent is simply “better,” there is a more nuanced matrix that can help differentiate therapies when deciding on course of action for an individual. Ideally, there is a shared decision-making process for each patient. When comparing different medications for AD, it may be beneficial to consider four characteristics: Efficacy (onset and maximum effect), Accessibility, Safety, and Tolerability, or EAST.

Efficacy

In some ways this is the central question about a medicine: Will it be effective for the patient’s problem? There are many dimensions to this, including the facts that most drugs elicit a range of effects, and individual responses may vary. However, there is a gestalt for most familiar medications that can be gleaned from both experimental data and clinical experience, and, broadly speaking, it can be broken down into two useful aspects: how quickly the medication begins to work and the magnitude of the maximal effect.

For example, oral prednisone is fast acting and has a high maximal effect.¹⁹ On the other hand, mycophenolate mofetil, a B- and T-cell inhibitor that is also used in severe AD cases, has a much slower onset and lower maximal effect than does prednisone.²⁰

Accessibility

While the cost of the drug is important, this is a concept fraught with difficulty in American medicine. There is often an enormous disconnect between a listed cost and what the patient will actually pay for a medication, due to the myriad of players involved. Thus, a more practical concept is accessibility.

Continuing our example of prednisone and mycophenolate mofetil, both drugs are fairly accessible. According to GoodRx.com, a popular tool used for drug pricing information, even without insurance coverage, a typical prescribed dose of prednisone (40 x 10mg tablets) costs less than $10, while mycophenolate mofetil (60 x 500mg tablets) costs less than $24, and both drugs are part of Medicare and Medicaid forumularies.²¹ Paradoxically, newer branded medications like crisaborole, despite being much more expensive than older generic drugs, can often be more accessible due to specialty pharmacies, manufacturers’ incentives, and coupons.²² The rapid changes in drug pricing, regional differences, and the impact of an individual’s insurance makes this attribute highly individualized for each patient.

Safety

Safety can be the deal-breaker for many drugs. Systemic steroids like prednisone have a large and serious side effect profile, which includes but is not limited to: diabetes, weight gain, Cushing syndrome, behavioral changes, sleep disturbances, adrenal insufficiency, hypertension, cataracts, glaucoma, and avascular necrosis. Thus, the use of systemic corticosteroids is best avoided or limited to the short-term when possible.^14,19 Mycophenolate, on the other hand, has a more favorable safety profile, especially when comparing medium and even long-term use. Mycophenolate’s most common side-effects include nausea, vomiting, diarrhea, and other gastrointestinal disturbances.²³ Some of the safety issues will apply broadly, while others may be especially relevant to select patients. A patient with pre-existing diabetes, for example, would be particularly ill-suited for systemic prednisone, particularly when other options are available; likewise, cyclosporine would be contraindicated in a patient with renal impairment.

Tolerability

Tolerability is often lumped together with safety, but it warrants classification as a unique parameter. Issues like “injection site pain” or “stinging and/or burning with application” are not true safety issues, but nonetheless can have an outsized effect on adherence and the overall patient experience. A powerful modern example is the topical ointment crisaborole. Crisaborole has a relatively favorable safety profile when compared to topical corticosteroids but has been noted to cause application site pain in four to 31 percent of patients, which certainly affects tolerability.^24,25 All side effects, no matter their severity, have the potential to decrease patient adherence or even prevent initiation of treatment altogether. However, more nuanced understanding should enhance the shared decision making process.

A Practical Approach

While no absolute numbers exist for these parameters, each clinician can develop an individualized conception of these elements for treatments that should be considered. A helpful tool to visually compare medications is a Radar Chart. A blank Radar Chart with the arbitrary scale of 0-100 is included (Figure 1A). In figure 1B we have provided an example using a personal conceptualization of prednisone versus mycophenolate for AD. Again, it is important to note that different clinicians may have different impressions for these parameters, but working through them, and ideally sharing such a comparison with the patient, may be a helpful exercise to guide the discussion to a treatment decision, especially as new medications are added to the armamentarium.

Figure 1. A: Blank Radar Chart. B: Radar Chart comparing prednisone (red) and mycophenolate (blue).

1. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis: Section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-351. doi:https://doi.org/10.1016/j.jaad.2013.10.010

2. Nutten S. Atopic Dermatitis: Global Epidemiology and Risk Factors. Ann Nutr Metab. 2015;66(suppl 1(Suppl. 1):8-16. doi:10.1159/000370220

3. Noda S, Krueger JG, Guttman-Yassky E. The translational revolution and use of biologics in patients with inflammatory skin diseases. J Allergy Clin Immunol. 2015;135(2):324-336. doi:https://doi.org/10.1016/j.jaci.2014.11.015

4. Alexander H, Patton T, Jabbar-Lopez ZK, Manca A, Flohr C. Novel systemic therapies in atopic dermatitis: what do we need to fulfil the promise of a treatment revolution? [version 1; peer review: 3 approved]. F1000Research. 2019;8(132). doi:10.12688/f1000research.17039.1

5. Heydendael VMR, Spuls PI, Opmeer BC, et al. Methotrexate versus Cyclosporine in Moderate-to-Severe Chronic Plaque Psoriasis. N Engl J Med. 2003;349(7):658-665. doi:10.1056/NEJMoa021359

6. Lebwohl M. A clinician’s paradigm in the treatment of psoriasis. J Am Acad Dermatol. 2005;53(1 SUPPL.):59-69. doi:10.1016/j.jaad.2005.04.031

7. Wiggins BS, Saseen JJ, Page RL, et al. Recommendations for Management of Clinically Significant Drug-Drug Interactions with Statins and Select Agents Used in Patients with Cardiovascular Disease: A Scientific Statement from the American Heart Association. Circulation. 2016;134(21):e468-e495. doi:10.1161/CIR.0000000000000456

8. Sakkas LI, Zafiriou E, Bogdanos DP. Mini review: New treatments in psoriatic arthritis. Focus on the IL-23/17 Axis. Front Pharmacol. 2019;10(JULY):1-8. doi:10.3389/fphar.2019.00872

9. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: Section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116-132. doi:https://doi.org/10.1016/j.jaad.2014.03.023

10. Schneider L, Tilles S, Lio P, et al. Atopic dermatitis: A practice parameter update 2012. J Allergy Clin Immunol. 2013;131(2):295-299.e27. doi:https://doi.org/10.1016/j.jaci.2012.12.672

11. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for the management of atopic dermatitis: Section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71(2):327-349. doi:https://doi.org/10.1016/j.jaad.2014.03.030

12. Silverberg JI, Simpson EL. Associations of childhood eczema severity: A US population-based study. Dermatitis. 2014;25(3):107-114. doi:10.1097/DER.0000000000000034

13. Barbarot S, Auziere S, Gadkari A, et al. Epidemiology of atopic dermatitis in adults: Results from an international survey. Allergy Eur J Allergy Clin Immunol. 2018;73(6):1284-1293. doi:10.1111/all.13401

14. Drucker AM, Eyerich K, de Bruin-Weller MS, et al. Use of systemic corticosteroids for atopic dermatitis: International Eczema Council consensus statement. Br J Dermatol. 2018;178(3):768-775. doi:10.1111/bjd.15928

15. Megna M, Napolitano M, Patruno C, et al. Systemic Treatment of Adult Atopic Dermatitis: A Review. Dermatol Ther (Heidelb). 2017;7(1):1-23. doi:10.1007/s13555-016-0170-1

16. Paller AS, Kabashima K, Bieber T. Therapeutic pipeline for atopic dermatitis: End of the drought? J Allergy Clin Immunol. 2017;140(3):633-643. doi:10.1016/j.jaci.2017.07.006

17. Dermatology AA of. American Academy of Dermatology Ten Things Physicians and Patients Should Question. Choos Wisely, An Initiat ABIM Found. 2014;2013:10-11.

18. Drucker AM, Ellis AG, Bohdanowicz M, et al. Systemic Immunomodulatory Treatments for Patients With Atopic Dermatitis: A Systematic Review and Network Meta-analysis. JAMA Dermatology. 2020;156(6):659-667. doi:10.1001/jamadermatol.2020.0796

19. Yu SH, Drucker AM, Lebwohl M, Silverberg JI. A systematic review of the safety and efficacy of systemic corticosteroids in atopic dermatitis. J Am Acad Dermatol. 2018;78(4):733-740.e11. doi:https://doi.org/10.1016/j.jaad.2017.09.074

20. Grundmann-Kollmann M, Podda M, Ochsendorf F, Boehncke W-H, Kaufmann R, Zollner TM. Mycophenolate Mofetil Is Effective in the Treatment of Atopic Dermatitis. Arch Dermatol. 2001;137(7):870-873. doi:10-1001/pubs.Arch Dermatol.-ISSN-0003-987x-137-7-dst10044

21. Prescription Prices. Coupons & Pharmacy Information - GoodRx.

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23. Neuber K, Schwartz I, Itschert G, Dieck A to. Treatment of atopic eczema with oral mycophenolate mofetil. Br J Dermatol. 2000;143(2):385-391. doi:10.1046/j.1365-2133.2000.03667.x

24. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494-503.e6. doi:https://doi.org/10.1016/j.jaad.2016.05.046

25. Pao-Ling Lin C, Gordon S, Her MJ, Rosmarin D. A retrospective study: Application site pain with the use of crisaborole, a topical phosphodiesterase 4 inhibitor. J Am Acad Dermatol. 2019;80(5):1451-1453. doi:https://doi.org/10.1016/j.jaad.2018.10.054