Treatments for mild-to-moderate recalcitrant plaque psoriasis: Expected clinical and economic outcomes for first-line and second-line care
Published Web Locationhttps://doi.org/10.5070/D32116k54p
Treatments for mild-to-moderate recalcitrant plaque psoriasis: Expected clinical and economic outcomes for first-line and
1. Medical Education and Research Alliance (Med-ERA)145 West 58th Street New York, NY 100192. Wake Forest University School
of Medicine 3. Stanford University School of Medicine 4. Harvard Medical School 5. Private Practice, Potomac, MD
Albert Marchetti MD, Steven R Feldman MD PhD, Alexandra Boer Kimball MD MPH, Richard Rox Anderson MD, Laurence H Miller MD,
John Martin MPH, Peter An
Dermatology Online Journal 11 (1): 1
The cost effectiveness of treatments for psoriasis has been evaluated previously by several different investigators. Such evaluations should be updated as new products or data become available. To this end, a comparison of expected treatment-related clinical and economic outcomes is undertaken from the payer perspective using a disease-intervention model, decision analyses, and newly emergent information. The model is based on academy guidelines and recommended clinical practice. Model inputs (clinical and cost data) are culled from the medical literature and advisory clinical assessment surveys. Comparable therapies are various topical pharmacotherapies and phototherapies, including the 308-nm excimer laser (XTRAC, PhotoMedex, Montgomeryville, PA). Analytic results indicate that clinical and economic outcomes are influenced by treatment selections but are muted by the rotational nature of treatment regimens. Multiple analyses are required to reveal individual product performance. On the basis of these analyses, the addition of the 308-nm excimer laser to the rotational mix of treatments commonly utilized as second-line therapies for mild-to-moderate plaque psoriasis is expected to add incremental clinical benefit for patients without incremental cost for payers, because the laser can replace both more costly and less costly alternatives for appropriately selected patients who require a different therapeutic modality to maintain or improve their responsiveness.
The prevalence of psoriasis in the United States has been reported to be between 0.5 percent and 4.6 percent , with a generally accepted range of 1-2 percent, or about 3.35-6.5 million Americans . More than 3 million psoriasis-related health-care visits occur annually to care for these patients . Estimated direct medical costs have ranged from $463  to $4,593 (inflation-adjusted dollars)  per patient per year and are expected to rise with the use of immunosuppressive or biologic therapies for severe, extensive or recalcitrant disease.
Although its etiology is incompletely defined, psoriasis is a disease of immunologic derangement that leads to abnormal epidermal-cell kinetics . The physical illness is characterized by elevated scaly plaques that vary in size, degree of inflammation, and distribution . Eruptions tend to appear symmetrically on the body and have a predilection for elbows and knees but also commonly occur on ears, abdomen, intergluteal fold, sacrum, and genitalia. Nail and scalp involvement is noted often as well. Itching, burning, and pain are accompanying symptoms. Severity relates to the size, thickness, scaling, and inflammatory intensity of individual lesions and with the extent of body surface involved and the presence of systemic symptoms . Relapse and remittance are common occurrences over the natural history of a disease that rarely, if ever, resolves spontaneously or is cured. 
Primary treatment goals for patients with psoriasis are: (1) reduce the size, thickness, and extent of plaque, papules, and erythema; and (2) improve quality of life (physical, mental, emotional, and social functioning) . The measure of response to therapy (i.e., reduction in symptoms) is generally based on a physician global assessment (PGA) or psoriasis area and severity index (PASI) score . A reduction of 50 percent from pretreatment baseline scores is generally accepted as a positive physical response; a reduction of 75 percent or more is generally accepted as a superior response approaching clearance.
Several factors influence therapeutic selections for patients with mild-to-moderate disease . First and foremost, the nature of individual lesions (e.g., thick versus thin plaques) as well as the location and extent of distribution of plaques drive treatment decisions. Thereafter, therapeutic success, duration of remission, frequency of relapse, and appearance or desired avoidance of side effects dictate choices. Finally, patient preference must be considered because some therapies are cosmetically inelegant (e.g., topical ointments and creams) or stain skin, clothing, bed linens, and bathtubs (e.g., anthralin); others are time consuming (e.g., broadband ultraviolet A and B phototherapies) or somewhat intolerable (e.g., intralesional injections, especially for nails).
According to treatment guidelines from the American Academy of Dermatology (AAD) , therapeutic intervention for localized mild-to-moderate plaque psoriasis should begin with patient education and the use of topical corticosteroids with or without coal tar or calcipotriene. Thereafter, anthralin or tazarotene, alone or in combination with steroids, can be used following first-line treatment failure or subsequent loss of response to first-line therapy. Alternatively, if control is difficult to achieve or disease is widespread, phototherapy, with and without drugs such as psoralen or retinoids, may be required. In actual practice, therapies are often rotated to take advantage of unique features and benefits, to minimize the development of adverse events, or to avoid tachyphylaxis that may be associated with individual alternatives. Moreover, more potent systemic therapies, such as methotrexate, cyclosporine, and the biologics, are sometimes required for severe psoriasis, but these treatments are not included in the current analysis of mild-to-moderate disease. (For quick reference, the benefits and limitations of potential treatment selections for mild-to-moderate psoriasis are summarized in Table 1.)
Health economic assessment
With recommended clinical practice and academy guidance as the directives, a health economic study was conducted from the payer perspective to evaluate the clinical and economic impact of therapies for patients with mild-to-moderate plaque psoriasis, with a particular focus on second-line comparators, especially the excimer laser.
The objectives of the research were to compute and compare the following: (1) total expected annual cost of health-care resources consumed during clinical management with and without excimer laser, (2) expected annual costs associated with individual second-line therapies, (3) expected annual remission days and treatment-free days associated with individual second-line therapies, and (4) the cost effectiveness of second-line therapies.
Using published information and clinical experience, a disease-intervention model was developed to reflect AAD-recommended care for patients with psoriasis and to reveal the clinical and economic consequences of second-line treatment selections. Modeling was facilitated with the aid of DATA™ (TreeAge Software), a decision-analysis software program.
In the model(Figure 1) as in recommended clinical practice, disease management starts with a topical steroid plus calcipotriene as first-line therapy. This regimen is commonly modified until the most effective combination is identified and then maintained as long as it is safe and effective. For patients who do not respond sufficiently to this topical regimen or who cannot tolerate it for any reason or who become refractory to it, some form of second-line therapy is provided at the discretion of the caregiver. Depending on severity and distribution of disease, potential second-line therapies include tazarotene plus steroid, UVA phototherapy plus psoralen (PUVA), UVB phototherapy, anthralin plus steroid, and intralesional corticosteroid injections (ICI). The excimer laser is considered in this secondary mix of care and related simulations.
In the absence of data that depict the precise proportion of patients who receive a particular second-line therapy following first-line treatment failure and with the knowledge that most patients will receive a rotational mix of treatments to perpetuate clinical responses over time [14, 15], we assumed that an equal proportion of patients would receive each potential second-line alternative and that patients failing first-choice second-line treatment would be retreated with a different second-line selection—indeed, the rotation of treatments that is commonly observed in actual clinical practice. For completeness, we included anthralin plus steroid as well as ICI, two relatively low-cost options, even though their utilization is limited.
The model was populated and clinical outcomes were computed using published data on probabilities for superior response or clearing (i.e., 75 % or greater improvement in the physical signs and symptoms of disease) and probabilities for relapse as well as the duration of remission associated with both first-line and second-line therapies (see Table 2). Days on and off therapy and remission days associated with each treatment alternative were subsequently revealed.
Economic outcomes associated with first-line and second-line treatment regimens were computed from resource costs found in Redbook (drug costs) and Physician Fee Schedule (Medicare reimbursement based on procedural codes) [16, 17]. Probability and cost variables were assigned to each branch of the model, and expected economic outcomes were calculated by multiplying resource costs by probabilities for anticipated clinical events throughout the tree. Costs were rolled back to initiation of first-line therapy to include all anticipated treatment expenses (i.e., all costs for all resources consumed during primary and secondary treatment) and to reveal the total expected per-patient cost for 1 year of care. Thereafter, the excimer laser second-line treatment branch was removed from the model, and the total expected per-patient annual cost of care was again computed to reveal the economic impact of the laser. Additionally, total expected per-patient annual costs for individual second-line therapies were calculated by rolling back costs to the initiation of second-line treatments, thus excluding the expected cost of first-line care. Expected second-line costs, however, are somewhat muted by the rotational mix of second-line care that comes into play following failure of any original second-line choice. Therefore, we also computed the expected cost of success branches only for each potential second-line choice. Clinical outcomes for treatment-free days and remission days also were computed for each of these different scenarios. Clinical and economic inputs as well as their sources are listed in Tables 3 - 7.
All clinical and economic outputs are reported in Tables 8 - 11.
The management of psoriasis can be challenging on several levels. For patients and providers, resolution of disease is the primary therapeutic objective. Complete and prolonged clearance is the preferred outcome, but one that is elusive in almost all cases. For payers, cost control is vital, so treatment regimens that are less costly or more cost-effective are favored.
For patients with 10 percent or less body-surface involvement, topical corticosteroids, with relatively low acquisition costs, are the mainstay of first-line care but can be problematic when used alone . Their onset of action is fast, but exacerbation of disease can also be rapid upon treatment discontinuation. Side effects, such as telangiectasia, striae, epidermal thinning, scar extension, acne, glaucoma, and suppression of hypothalamus-pituitary-adrenal activity are concerns . Moreover, over time effectiveness is lost. For these reasons, the more expensive calcipotriene  or possibly tazarotene is commonly combined with a topical corticosteroid for initial disease management . The combination is beneficial for the majority of patients but must be used almost continuously, uninterrupted, or pulsed, to achieve and then maintain a response after successful disease control. Continuous daily or twice-daily applications of one or more creams or ointments can be time consuming, cosmetically inelegant, and objectionable for many patients, especially during work days. Because treatment is continuous, disease control can be prolonged, but treatment-free days are rare. For this reason, cost effectiveness varies according to the outcome that is measured. For example, if one considers only remission but fails to appreciate the importance of patient convenience, satisfaction, and quality of life, the combination of topical corticosteroid and calcipotriene can be viewed as cost effective. On the other hand, if time off of therapy is valued, the combination is cost-ineffective because treatment-free days are minimal and patients must contend with the daily inconvenience and annoyance that accompanies topical combination therapy. Regardless, for those patients who do not succeed on a primary combination regimen due to initial failure or reduced effectiveness over time or intolerance for any reason, secondary treatments are subsequently utilized. Individually, second-line treatments all offer benefits but also have limitations. In the evaluation of second-line therapies, the same principles of cost effectiveness apply.
Corticosteroids plus anthralin or tazarotene as secondary treatments have many of the same benefits and limitations as the previously mentioned topical combination regimen, with a few notable differences. Regimens with anthralin are complicated and so untidy that they are hardly used at all in the United States, having been replaced by topical calcipotriene and tazarotene. Anthralin is initially applied in low concentrations for brief periods, then used in higher concentrations for up to 30 minutes per treatment . Applications by cotton-tip swabs or gloved hand are directed only to well-defined plaques because anthralin is irritating to unprotected skin and surrounding tissue. Moreover, the product tends to stain contact surfaces (e.g., skin, clothing, linens, furniture, and bathtub or sink) so keen attention during application and throughout the therapeutic interval is advised. (Note—the cost of items damaged from staining was not included in our analyses.)
Topical tazarotene, the first receptor-selective retinoid approved for psoriasis, is effective as a second-line agent when used twice-daily with fluocinonide (0.05 %), a corticosteroid that increases the speed of response and reduces the perilesional irritation that tends to occur with tazarotene monotherapy [23, 24]. As with combination regimens of calcipotriene or anthralin with corticosteroids, treatment with tazarotene and corticosteroid is prolonged to maintain or improve the response once an initial therapeutic success is achieved. As with calciprotriene plus steroid combination therapy, the expression of cost effectiveness is confounded by limited treatment-free days in the presence of a reasonably durable response.
Lesions that fail to respond to initial topical therapy also may be controlled with triamcinolone injected directly into the dermis underlying small resistant plaques. Drug concentrations for the intralesional corticosteroid injections (ICI) range from 3 mg per mL to 10 mg per mL, depending on size, thickness, and location of lesions. Under these circumstances, the steroid is gradually released over a 3-4-week period. Repeated injections may be required every 4-6 weeks to improve or maintain the response. Side effects associated with this relatively inexpensive intervention are pain, potential local atrophy, and systemic absorption.
Although ICI is among the least expensive interventions and is cost effective, its utilization is limited to tightly localized small lesions and to relatively few patients who will tolerate repeat injections. Indeed, ICI is probably underused despite its cost effectiveness. Potential steroid resistance and the likelihood of epidermal thinning also limit the utility of this secondary treatment modality.
Retinoids by themselves, with no additional therapy, are generally ineffective for most forms of psoriasis [25, 26]. Required doses cause significant side effects, such as hair loss, nail thinning, dried and chapped mucous membranes and skin, and hyperlipidemia . The most serious problem associated with retinoid utilization are birth defects in the offspring of women who use these drugs before or during pregnancy. Retinoids can be effective, however, when used judiciously in very low doses in combination with ultraviolet light.
Phototherapies, including UVB, UVA plus psoralen (PUVA), and the 308-nm excimer laser, are the final options for second-line treatments that are considered in this health economic assessment. Unlike UVB and PUVA modalities, the excimer laser delivers narrow-band light that can be directed with greater intensity at isolated psoriatic lesions instead of the entire body. According to the American Academy of Dermatology guidelines, these interventions are useful for patients with lesions that are limited but refractory to topical agents, lesions that are widespread, or when disruption of daily activities or employment compromise patient well-being . Logically, UVB and PUVA have more utility when disease is widespread; whereas, the excimer laser is more suitable when disease is more contained. For these reasons, phototherapies are selectively used on different patient populations rather than generally used for all patients who fail first-line care. Some overlapping of subgroups is expected, however. In our model, 16 percent of all patients who fail first-line therapy were subsequently assigned to each potential second-line option.
Generally, for the phototherapies included in the model, side effects are similar in nature (erythema and possible blistering common to sunburns) during routine supervised exposures, although burns are more severe with PUVA than with UVB. The notable exceptions of dermatologic neoplasia (including melanoma) are more frequently related to PUVA treatments than UVB or narrow-band UVB [29, 30, 31]. Regardless, the incidence of neoplasia is too low to have a significant economic effect in our analyses and therefore is not considered. Likewise, the costs to manage other minor but more frequent adverse reactions are insignificant and are not included.
On the basis of other aspects of clinical management with phototherapies, such as the number of treatment sessions required to achieve clinical success, the time between treatments, and the cost of all resources consumed during each course of care, the excimer laser has the most favorable expected economic outcomes of the three phototherapies evaluated. The excimer laser also has the most favorable expected clinical outcomes overall, but results in this category are sensitive to minor changes in clinical inputs (response and relapse probabilities as well as duration of remission), raising doubt about the statistical significance of such a conclusion. Therefore, assuming clinical outcomes are equivalent, the excimer laser is still be more cost effective on the basis of lower expected costs arising from fewer health care visits. Moreover, when compared to any of the potential selections for second-line care, phototherapy or topical therapies, the 308-nm excimer laser has superior cost effectiveness when one considers the cost to achieve a treatment-free day.
In conclusion, the addition of the excimer laser to the rotational mix of second-line therapies for patients with mild-to-moderate plaque psoriasis results in additional and substantial clinical benefits without incremental cost to payers. This finding can provide guidance for all those interested in disease management because it suggests that providers and patients can gain an advantage when the intervention is appropriately utilized. Additionally, because the intervention is associated with fewer treatment sessions and treatment days compared to other standard therapy and is less troublesome to use, there is an opportunity to increase patient satisfaction, which contributes to plan satisfaction. Finally, because total expected annual per-patient costs are equivalent with or without the excimer laser included as part of comprehensive care, payers bear no incremental financial risk for laser utilization. On the other hand, patients may bear incremental indirect costs (loss of work or productivity from time spent in treatment) when phototherapies are used, but even in this instance, incremental indirect costs associated with the laser should be less than those associated with other forms of phototherapy because fewer treatment sessions are expected but must be verified. All these considerations support decisions to utilize and reimburse 308-nm excimer laser procedures as a part of the second-line mix of therapy for plaque psoriasis resistant to first-line topical therapy.
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