Use of Biologic Agents in Combination with Other Therapies for the Treatment of Psoriasis

Jennifer C. Cather 0 1 2 Jeffrey J. Crowley 0 1 2 0 J. J. Crowley Bakersfield Dermatology , 5101 Commerce Drive, Suite 101, Bakersfield, CA 93309 , USA 1 J. C. Cather (&) Modern Dermatology, A Baylor Health Texas Affiliate , 9101 North Central Expressway, Suite 150, Dallas, TX 75231 , USA 2 J. C. Cather Modern Research Associates , Dallas, TX , USA Psoriasis is a chronic inflammatory skin disorder, which is associated with a significant negative impact on a patient's quality of life. Traditional therapies for psoriasis are often not able to meet desired treatment goals, and high-dose and/or long-term use is associated with toxicities that can result in end-organ damage. An improved understanding of the involvement of cytokines in the etiology of psoriasis has led to the development of biologic agents targeting tumor necrosis factor (TNF)-a and interleukins (ILs)-12/23. While biologic agents have improved treatment outcomes, they are not effective in all individuals with psoriasis. The combination of biologic agents with traditional therapies may provide improved therapeutic options for patients who inadequately respond to a single drug or when efficacy may be increased with supplementation of another treatment. In addition, combination therapy may reduce safety concerns and cumulative toxicity, as lower doses of individual agents may be efficacious when used together. This article reviews the current evidence available on the efficacy and safety of combining biologic agents with systemic therapies (methotrexate, cyclosporine, or retinoids) or with phototherapy, and the combination of biologic agents themselves. Guidance is provided to help physicians identify situations and the characteristics of patients who would benefit from combination therapy with a biologic agent. Finally, the potential clinical impact of biologic therapies in development (e.g., those targeting IL17A, IL-17RA, or IL-23 alone) is analyzed. 1 Introduction Psoriasis is a chronic inflammatory skin disease, which affects approximately 3 % of the general population in the USA [1]. The most common form of the disease, plaque psoriasis, is characterized by the development of chronic erythematous plaques covered with silvery white scales, which most commonly appear on the elbows, knees, scalp, umbilicus, and lumbar regions [2]. Psoriasis has been associated with a significant negative impact on the patients quality of life, due to the disfiguring effect of the skin lesions and, for some, the functional impairment resulting from joint pain [3]. Additionally, individuals with psoriasis are more susceptible to specific debilitating comorbidities, including cardiometabolic dysfunction, fatigue, and depression [46]. The treatment strategy for psoriasis depends on a variety of factors (e.g., the medical history, tolerability of therapies and potential for side effects, and disease severity). Regarding disease severity, there is no commonly accepted definition of mild versus moderate-to-severe psoriasis [7]. Moreover, a patient may have mild disease on the basis of body surface area (BSA) involvement, but localization of lesions in vulnerable areas (e.g., the face, feet, hands, and/ or genitals) may warrant systemic therapy. Some guidelines provide specific criteria to help evaluate the severity of a patients psoriasis, but all recognize the importance of assessing both the physical and psychosocial burden when considering the best treatment approach [710]. The US National Psoriasis Foundation recommends that patients with BSA involvement \5 % should be considered candidates for topical therapy, whereas those with BSA C5 % should be considered candidates for systemic therapy alone or in combination with phototherapy [9]. A rule of tens has also been proposed, whereby BSA [10 %, Psoriasis Area Severity Index (PASI) [10, or Dermatology Life-Quality Index (DLQI) [10 identify patients with severe disease [10]. More recently, a European consensus meeting defined mild psoriasis as BSA B10 %, PASI B10, and DLQI B10; and moderateto-severe psoriasis warranting systemic therapy as BSA or PASI [10 and DLQI [10 [7]. The American Academy of Dermatology (AAD) guidelines present a treatment decision tree based on the presence or absence of psoriatic arthritis and categorization of psoriasis as limited or extensive disease, but specific definitions of these terms are not provided [8]. The ultimate goal of systemic therapy is to eliminate the systemic inflammatory burden of psoriasis and to completely clear the skin [7]. Historically, conventional systemic treatment options for psoriasis have included methotrexate, cyclosporine, and oral retinoids such as acitretin [11]. However, the use of these systemic agents has been limited by insufficient clinical efficacy, safety concerns, or both [7, 12, 13]. Cyclosporine is generally considered the most effective of these agents, providing a rapid response [14]. However, nephrotoxicity, hypertension, and numerous drug interactions may limit its use. Moreover, the duration of cyclosporine use is limited when it is prescribed for psoriasis (1 year in the USA, 2 years in the UK). The hepatotoxic effects of methotrexate necessitate particular caution when it is used in patients with liver problems or in those consuming large amounts of alcohol. Both methotrexate and retinoids are teratogenic [14]. None of these agents fully meets the needs of patients, and many are contraindicated because of the presence of comorbidities. Patient dissatisfaction with conventional systemic therapies has been well documented. Patients have voiced displeasure over inconvenient administration of traditional psoriasis therapies and their related side effects (e.g., hirsutism with cyclosporine, gastrointestinal intolerance with methotrexate, and hair loss and cheilitis with acitretin) [13]. Approximately 40 % of patients on systemic therapy alone have expressed dissatisfaction with their treatment outcomes [15], and overall patient satisfaction has been found to be lower with systemic therapy (cyclosporine, methotrexate, or acitretin) than with biologic agents, biologic/methotrexate combinations, or phototherapy [16]. Dissatisfaction with therapy is a major contributor to diminished adherence among patients with dermatologic disorders; inadequate treatment can therefore add to the already substantial burden of poor health-related quality of life associated with psoriasis [17, 18]. Over the past two decades, our understanding of the etiology of psoriasis has evolved; it is now recognized that both the innate and adaptive immune pathways are involved in its pathogenesis [19, 20]. Consequently, drugs that target specific components of the immune responses involved in the pathogenesis of psoriasis have been developed in an attempt to improve treatment efficacy, safety, and tolerability [21]. These agents include biologics that target cytokines such as tumor necrosis factor (TNF)-a and interleukins (ILs) 12 (...truncated)