Targeting the Clinical, Economic and Payer Considerations of Atopic Dermatitis - Episode 2

Targeting the clinical, economic and payer considerations of atopic dermatitis

Atopic dermatitis (AD), also known as atopic eczema, is a pruritic inflammatory skin disorder.1-3 It is distinguished by recurrent eczematous lesions with reddened, blistered, crusty or oozing skin; lichenification; and xerosis.1 Although the prevalence of AD in the United States is higher among children (approximately 11%-13%),4,5 recent estimates indicate that a considerable proportion of adults are affected (about 7%).6

Clinical burden of atopic dermatitis

The clinical presentation of AD is heterogeneous.1 AD may follow a relapsing-remitting course with acute flares or occur as chronic persistent disease.7,8 AD can present on any area of the body but most frequently occurs on the inside of the elbows, back of the knees, top of the feet and lower legs.9

The pathogenesis of AD is multifaceted, involves epidermal barrier dysfunction and immune system activation and is likely influenced by environmental factors.1 The strongest risk factor for AD is a family history of atopic diseases and especially of AD.1

AD is diagnosed based on clinical signs, historical features, morphology and the distribution of skin lesions. Currently, there are no biomarkers for AD.3 Pruritus is a prominent feature of AD and one that contributes to the substantial disease burden borne by patients.2,10 In one study of 380 adults with moderate to severe AD, most reported daily itching, and approximately 60% indicated that the itching was “unbearable” or “severe.”11

Disease severity can be difficult to determine, because the symptoms of AD can fluctuate over time and depend upon bodily location; darker skin can suggest less severe skin involvement, and assessment tools have different severity categories. Similarly, several severity assessment tools require the subjective judgment of patients (e.g., regarding intensity of itch and sleeplessness).2,7,12

There are four validated tools to measure AD severity; however, two of these are most often used in clinical trials and may require too much time to be of use to healthcare providers: the Scoring Atopic Dermatitis (SCORAD) index and the Eczema Area Severity Index (EASI). The SCORAD composite score is based on the extent and severity of AD and on patient-reported symptoms (pruritus and sleep loss).1,7 EASI is used to determine the extent and severity of AD and focuses on four body regions (head and neck, the trunk, and the upper and lower extremities).7,13 The EASI rates four key clinical symptoms of AD: erythema (redness),induration/papulation (thickness), excoriation (e.g., scratching) and lichenification.13

Healthcare and economic implications of AD


In the United States, a significant association exists between AD and immune-mediated comorbidities (e.g., ulcerative colitis, pernicious anemia).14 Adults in the United States with AD also have a higher a prevalence of cardiovascular (e.g., heart disease, high blood pressure), psychological (e.g., depression and anxiety) and other chronic conditions than do those without AD.15 Data from the 2013 U.S. National Health and Wellness Survey (NHWS) determined that adults with AD were more than two times more likely to report sleep disorders, depression and/or anxiety than matched controls without AD (P < .001 for all).16

Quality of life

Itch triggers and exacerbates a host of AD symptoms, diminishing quality of life (QOL) for patients with AD.1 A study using a self-administered internet-based questionnaire indicated that adult patients with moderate or severe AD had significantly more trouble sleeping, longer sleep latency, more frequent sleep disturbances and an increased need for over-the-counter (OTC) sleep medications than those with mild AD (P < .001 for all).17 A population-based study demonstrated that AD is associated with marked QOL impairment for adults in the United States that restricts patients’ lifestyle (51.3%), leads them to avoid social interaction (39.1%) and affects their activities (43.3%).18

Healthcare utilization and economic burden of AD

The costs associated with AD in the United States are approximately $7 billion per year (2020 U.S. dollars). Direct costs are approximately $1.7 billion, and indirect costs have been estimated at $1.04 billion. Intangible costs, estimated by patient willingness to pay for symptom relief, are approximately $4.37 billion.19-21

Adults with AD have increased healthcare resource use compared with those without AD, and higher disease severity is associated with greater utilization.22,23 An analysis of healthcare claims data from three different populations (commercial, Medicare and Medi-Cal) determined that, each year, adults with AD have average numbers of emergency department visits, outpatient visits and pharmacy prescriptions that are significantly greater than those for adults without AD (P < .05 for all).22 These results are consistent with an analysis of data from the 2013 NHWS, which demonstrated that adults with AD have average numbers of provider visits (P < .001), emergency department visits (P < .001) and hospitalizations (P = .004) that are higher than those of matched controls.23

Guidelines for the management of AD

Goals in the management of AD include improving skin, minimizing flares and reducing comorbidities and symptom burden (i.e., sleep disorders and itching).1,24 Interventions aimed at avoiding triggers, improving the skin barrier and reducing inflammation are central to meeting these goals.2

As mentioned previously, symptom severity and response to treatment can be measured using validated tools such as the EASI. The validated Investigator Global Assessment for AD (vIGA-AD), frequently used in clinical trials, is another tool to measure treatment efficacy. The vIGA-AD scale is used to measure improvement in clinical signs and has distinct categories (erythema, induration/papulation, lichenification, and oozing and/or crusting) to assess disease severity in AD.25

Guidelines for AD suggest a multifaceted approach. Basic nonpharmacologic measures (e.g., bathing, moisturizing and avoiding triggers) are recommended across all severities of AD. Pharmacologic treatment follows a stepwise progression based on disease severity.1,2

Nonpharmacologic therapy

Moisturizers are essential in AD to lubricate and soften the skin, reduce water evaporation, and attract and hold water.24 They can decrease the signs and symptoms of AD and reduce inflammation and severity.24 Severe flares or persistent disease may require wet-wrap therapy, whereby a wetted first layer of tubular bandages or gauze is applied over a topical agent, and a dry second layer is used as the outer barrier.24


Step-therapy recommendations for AD suggest topical therapies (e.g., topical corticosteroid) when proper skin care and moisturizers no longer suffice for lesion control.24 Topical agents are used to provide symptom management in acute flares and as maintenance therapy in moderate to severe AD. The potency and dose of TCS can be increased based on symptom severity.2 However, long-term daily use of TCSs is not recommended, because it can be associated with systemic adverse effects (e.g., hypothalamic-pituitary-adrenal axis suppression), skin atrophy, telangiectasia, striae, worsening acne and tachyphylaxis. Some of these adverse effects may persist for several months following discontinuation of TCS.2,24,26 Topical calcineurin inhibitors (TCIs) (e.g., Elidel, or pimecrolimus cream 1%; or Protopic, or tacrolimus ointment 0.03%, 0.1%) represent a steroid-sparing class of anti-inflammatory agents that can be used for flares or maintenance in moderate to severe AD.2 They are recommended for patients who have not responded to other topical therapies or for whom other topical therapies are not appropriate.24 However, they are generally less effective than midpotency TCSs, their prescription labeling carries a boxed warning about the risk of malignancy and burning or itching may be experienced during early use.24,27 Eucrisa, or crisaborole ointment 2%, a nonsteroidal anti-inflammatory PDE4 inhibitor, has a favorable safety profile2 but limited efficacy in patients with mild to moderate disease.12

Some patients with an insufficient response to topical therapy or severe disease may require phototherapy or treatment with systemic corticosteroids or other systemic immunosuppressants such as cyclosporine A, methotrexate, azathioprine or mycophenolate mofetil.2 Dupixent (dupilumab), a human monoclonal antibody that inhibits interleukin (IL)-4 and IL-13 signaling, is FDA approved for the treatment of patients 6 years and older with moderate to severe AD not adequately controlled with topical prescription therapies or for whom those therapies are not advisable.28 Although Dupixent demonstrates good efficacy, has a favorable safety profile and requires no clinical laboratory monitoring, it takes time to start working, and the subcutaneous route of administration may limit its use.12,29,30 Despite the availability of numerous therapeutic options, there remains an unmet need for additional safe and effective medications for patients with AD.

Formulary decision-making and payer considerations

The results of a study using 2015 data from the Truven Health Analytics MarketScan Commercial and Medicare Supplemental databases revealed that utilization of TCSs or TCIs for AD affects pharmacy budget, irrespective of treatment choice.31 There were marked differences in annual prescription costs per patient based on the mechanism of action (TCI versus TCS) and TCS strength.31 With the availability of new agents in recent years and novel therapies under development, formulary decisions in AD will become more complex.

Barriers to appropriate therapy

Barriers to safe and effective AD therapy remain high. Access to certain agents is limited, and payers have requirements for changing therapy.

Access and payer requirements

Access to new medications can be a challenge for healthcare providers, and it may depend on the patient’s insurer and prescription drug coverage.2 Additionally, payers may restrict prescriptions for newer agents, such as biologics and small molecules (e.g., Janus kinase, or JAK, inhibitors), to specialists such as dermatologists or allergists, because their use may require a knowledge base greater than primary care physicians can offer.32 Lack of healthcare insurance may also limit a patient’s access to specialists and the newer therapies they may prescribe. Moreover, the cost of newer agents or out-of-pocket costs may limit patient access to the most beneficial therapy.32

Step therapy may require physicians to try several regimens before they find one that adequately controls disease.32 This can result in a significant time delay for relief of AD symptoms. For example, payers often require a 30-day trial of topical TCS or TCI therapy before other therapies are considered.32 Payer step-therapy requirements can also restrict access of certain agents, causing a roadblock to the most safe and effective AD therapy for a particular patient.32


The affordability of TCSs prompts the off-label prescribing of these agents. However, medium- to high-potency TCSs are not intended for daily, long-term use.2 At the same time, lack of insurance coverage and the cost of TCIs and Dupixent may restrict their use.2,27 Less expensive options on formulary may not be as effective as newer, albeit costlier, therapeutics. The high cost of newer therapies may necessitate that payers institute prior authorization criteria or other limits on utilization.32

Balancing safety and efficacy

Systemic therapy may be necessary for severe disease, especially when it negatively impacts QOL. Older systemic medications are immunosuppressants and nonspecific. They require a high level of monitoring, including blood tests, and carry the risks related to systemic immunosuppression. They are not the best options for long-term treatment.33

Evolution to targeted therapy

The landscape in AD therapies is changing. Targeted agents offer improved safety and efficacy profiles and can modify the disease course, quickly resolve symptoms and enable patients to enter a maintenance phase.34 Importantly, new therapies in development for AD address some of the most important symptoms that impact QOL (i.e., itch and sleep disturbances). Emerging systemic therapies for AD include biologics and oral JAK inhibitors. Promising new topical agents such as JAK inhibitors, which inhibit key regulators of pro-inflammatory signals, are in clinical development.35

Clinical development of novel targeted agents: JAK pathway

JAK inhibition for AD

The JAK family includes JAK1, JAK2, JAK3 and tyrosine kinase 2. The JAK-STAT pathway regulates the differentiation of T helper 2 cells. In addition, several cytokines thought to play a role in the pathogenesis of AD (e.g., IL-4, IL-31) utilize the JAK-STAT pathway of signal transduction. The hyperimmune response in AD, specifically the upregulation of IL-4, plays a key role in skin barrier dysfunction. IL-31 is also implicated in the development of AD, as increased production is associated with nerve crosstalk (i.e., the itching sensation) and worsening pruritus.36

JAK inhibitors represent a new direction in the treatment of AD. JAK inhibition targets the itch-scratch cycle by quelling sensory neurons and improving the skin barrier by reducing inflammation.37 The inhibitors selectively bind to different JAK proteins.30

Oral JAK inhibitors under investigation for AD include Olumiant (baricitinib, which binds to JAK1/2) and Rinvoq (upadacitinib) and abrocitinib (which bind to JAK1).29,30 Concerns about the safety of oral JAK inhibitors approved for other indications (Xeljanz, or tofacitinib; Olumiant; Rinvoq) because of adverse effects such as serious infections, blood vessel disorders and malignancies have resulted in the FDA extending the review period for an AD indication. Of note, the prescribing information for Xeljanz, Olumiant and Rinvoq include boxed warnings regarding serious infections, malignancy and thrombosis; the boxed warning for Xeljanz also includes risk of mortality.12,38-40

In September 2021, the FDA approved Opzelura (ruxolitinib cream 1.5%) for the short-term and noncontinuous chronic treatment of mild to moderate AD in nonimmunocompromised patients 12 years of age and older with disease not adequately controlled with topical prescription therapies or when those therapies are not advisable. This is the first topical JAK inhibitor approved for this indication.41,42 Although the prescribing information for Opzelura carries the same boxed warning as that for oral JAK inhibitors, in the TRuE AD1 and TRuE AD2 clinical trials that supported the FDA approval, there were no safety signals attributable to systemic JAK inhibition.43,44 Safety concerns for this topical agent are not likely to be as great as those for oral JAK inhibitors.12


Ruxolitinib cream has a dual mode of action that targets the pruritic and inflammatory effects of AD with direct delivery to the skin.44 The efficacy and safety of ruxolitinib cream in patients at least 12 years old with mild to moderate AD were assessed in the two large, double-blind, vehicle-controlled phase 3 TRuE AD1 and TRuE AD2 trials.44-46 Patients were required to have AD for at least two years, an Investigator’s Global Assessment (IGA) score of 2 or 3, and 3% to 20% of their body surface area affected. A total of 1,249 patients were randomized (2:2:1) to receive 0.75% ruxolitinib, 1.5% ruxolitinib or vehicle cream twice daily for eight weeks.44 The primary end point for both studies was the percentage of patients achieving IGA treatment success, defined as clear or almost clear skin with at least a two-grade improvement from baseline at week eight.44 Significantly more patients given ruxolitinib in TruE-AD 1 and TruE-AD 2 (0.75% ruxolitinib, 50.0% and 39.0%, respectively; and 1.5% ruxolitinib, 53.8% and 51.3%) met the primary end point versus those given vehicle (15.1% and 7.6%, respectively) (P < .0001 for all).44 Ruxolitinib 1.5% cream was associated with a significant reduction in itch by 12 hours, with even greater reductions reported over eight weeks.44 Ruxolitinib cream also had a favorable safety profile.44 The percentage of adverse effects was similar across treatment groups and among both studies. The most common treatment-related adverse effect was application-site burning, which occurred at the highest frequency in the vehicle group. There were no safety signals attributable to systemic JAK inhibition. The long-term safety of ruxolitinib is currently being evaluated in 44-week extension periods for both studies.44

In August, the Institute for Clinical and Economic Review issued its final policy recommendations regarding the effectiveness and value of JAK inhibitors and monoclonal antibodies for the treatment of AD. The New England Comparative Effectiveness Public Advisory Council voted 12-1 in favor of ruxolitinib cream for mild to moderate AD compared with topical emollients alone.32

Other JAK inhibitors in development


Delgocitinib, a pan-JAK inhibitor (JAK1/2/3, TYK2), is approved in Japan as an ointment for AD.47 Two phase 3 trials, DELTA 1 and DELTA 2, are currently enrolling patients with moderate to severe chronic hand eczema.48,49


The efficacy, safety, tolerability and pharmacokinetics of topical ATI-1777, a JAK1/3 inhibitor, were investigated in a phase 2a, multicenter, randomized, double-blind, vehicle-controlled trial of 50 patients with moderate to severe AD.50 The primary efficacy end point was the percent change from baseline in the modified EASI (mEASI) score, which excludes body surfaces not treated in the trial, at week 4.50 ATI-1777 was associated with a 74% reduction in mEASI score compared with vehicle (41%) (P < .001).50

ATI-1777 had a favorable safety profile.The incidence of adverse effects was similar between the two groups. The most common adverse effects in the ATI-1777 group were increased blood creatinine phosphokinase and headache. There were no cases of thrombosis.50


AD is associated with considerable clinical and economic burdens. Itching and sleep disturbances are two of the most troubling symptoms that occur with AD, and they have a substantial impact on patients’ QOL. JAK inhibitors represent a new direction in AD therapy. Their mechanism of action directly targets the pruritic and inflammatory effects of AD. Topical JAK inhibitors, such as ruxolitinib cream, may offer these benefits without the systemic effects associated with oral JAK inhibitors.


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24. 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:10.1016/j.jaad.2014.03.023

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41. Ruxolitinib cream approved for short-term treatment of atopic dermatitis. AJMC®. September 22, 2021. Accessed September 27, 2021.

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43. Jakafi. Prescribing information. Incyte Corporation; 2021. Accessed October 4, 2021.

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50. Aclaris Therapeutics announces positive preliminary topline data from phase 2a trial of ATI-1777 for moderate to severe atopic dermatitis. Aclaris Therapeutics. June 8, 2021. Accessed October 4, 2021.