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

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)-α 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 IL-17A, IL-17RA, or IL-23 alone) is analyzed.

Related papers:

title: Psoriasis prevalence among adults in the United States.
abstract: Psoriasis is a chronic inflammatory disorder associated with significant morbidity and mortality. Up-to-date prevalence data on psoriasis provide the foundation for informing population research, education, and health policy.



We sought to determine the prevalence of psoriasis among US adults.



We performed a cross-sectional study using National Health and Nutrition Examination Survey 2009 through 2010 data to determine psoriasis prevalence rates.



From 6218 participants older than 20 years of age, 6216 respondents provided complete information regarding a psoriasis diagnosis. The prevalence of psoriasis among US adults ages 20 years and older is 3.2% (95% confidence interval [CI] 2.6%-3.7%). A total of 7.2 million US adults had psoriasis in 2010; an estimated 7.4 million US adults were affected in 2013. When stratifying the sample by race among those between ages 20 and 59 years, the psoriasis prevalence was highest in Caucasians at 3.6% (95% CI 2.7%-4.4%), followed by African Americans (1.9%; 95% CI 1.0%-2.8%), Hispanics (1.6%; 95% CI 0.5%-2.8%), and others (1.4%; 95% CI 0.3%-2.6%). The prevalence of psoriasis among US adults has not changed significantly since 2003 to 2004 (P > .05).



Dermatologist evaluation and skin photographs were unavailable for the 2009 through 2010 surveys.



In the United States, psoriasis remains a common, immune-mediated disease, affecting 7.4 million adults. Its prevalence has remained stable since the mid-2000s.

title: The Psychosocial Burden of Psoriasis
abstract: Skin diseases such as psoriasis can profoundly influence a patient’s self-image, self-esteem, and sense of well-being. Psoriasis is a multifactorial inflammatory condition with a disease burden that extends beyond the physical symptoms experienced by patients. Psoriasis affects all aspects of quality of life, including physical, psychologic, social, sexual, and occupational elements.
 Objective: The goal of this article was to review the published literature on the impact of psoriasis on quality of life.
 Methods: Relevant studies were identified through a comprehensive search of MEDLINE, EMBASE, and the Derwent Drug File databases of English-language articles published between 1993 and 2005 using the terms psoriasis in combination with quality of life, cost, cost-benefit analysis, economic, employment, days lost, healthcare, hospitalization, managed care, outcomes research, occupation, payers, and psychosocial. The reference lists of identified articles were checked for additional studies that might have been missed in the original searches.
  Data suggest that social stigmatization, high stress levels, physical limitations, depression, employment problems and other psychosocial co-morbidities experienced by patients with psoriasis are not always proportional to, or predicted by, other measurements of disease severity such as body surface area involvement or plaque severity.
  It is essential to include measures of psychosocial morbidity when assessing psoriasis severity and treatment efficacy because of the substantial role that psychosocial burden plays in patient perception of disease severity, quality of life, and disease course.

title: Common burden of chronic skin diseases? Contributors to psychological distress in adults with psoriasis and atopic dermatitis
abstract: Chronic skin diseases, such as atopic dermatitis and psoriasis, are known to affect quality of life by heightening psychological distress. Knowledge about factors contributing to psychological distress is essential for supporting physicians in diagnostic and multidisciplinary treatment options for patients psychologically at risk.

title: Psoriasis and its comorbidities.
abstract: Psoriasis is a multi-systemic chronic inflammatory skin disease targeting 2% to 3% of the general population. It is a prototype of immune dysregulation mediated by TH1 proinflammatory cytokines such as TNF-?, IFN-Y, IL-6, and IL-12, to name a few. Psoriasis, traditionally viewed as an inflammatory skin disorder of unknown origin, is increasingly recognized as an inflammatory skin disease with far reaching systemic effects. There is growing and emerging evidence that psoriasis patients have a higher prevalence of associated comorbid disease with cardiometabolic dysfunction and psoriatic arthritis being at the forefront. It appears that psoriatic skin disease severity portends a serious risk for development of these comorbidities. As such, patients with moderate to severe psoriatic skin disease are found to have a higher association with these extracutaneous disease manifestations.

title: Definition of treatment goals for moderate to severe psoriasis: a European consensus
abstract: Patients with moderate to severe psoriasis are undertreated. To solve this persistent problem, the consensus programme was performed to define goals for treatment of plaque psoriasis with systemic therapy and to improve patient care. An expert consensus meeting and a collaborative Delphi procedure were carried out. Nineteen dermatologists from different European countries met for a face-to-face discussion and defined items through a four-round Delphi process. Severity of plaque psoriasis was graded into mild and moderate to severe disease. Mild disease was defined as body surface area (BSA) ≤10 and psoriasis area and severity index (PASI) ≤10 and dermatology life quality index (DLQI) ≤10 and moderate to severe psoriasis as (BSA > 10 or PASI > 10) and DLQI > 10. Special clinical situations may change mild psoriasis to moderate to severe including involvement of visible areas or severe nail involvement. For systemic therapy of plaque psoriasis two treatment phases were defined: (1) induction phase as the treatment period until week 16; however, depending on the type of drug and dose regimen used, this phase may be extended until week 24 and (2) maintenance phase for all drugs was defined as the treatment period after the induction phase. For the definition of treatment goals in plaque psoriasis, the change of PASI from baseline until the time of evaluation (ΔPASI) and the absolute DLQI were used. After induction and during maintenance therapy, treatment can be continued if reduction in PASI is ≥75%. The treatment regimen should be modified if improvement of PASI is <50%. In a situation where the therapeutic response improved ≥50% but <75%, as assessed by PASI, therapy should be modified if the DLQI is >5 but can be continued if the DLQI is ≤5. This programme defines the severity of plaque psoriasis for the first time using a formal consensus of 19 European experts. In addition, treatment goals for moderate to severe disease were established. Implementation of treatment goals in the daily management of psoriasis will improve patient care and mitigate the problem of undertreatment. It is planned to evaluate the implementation of these treatment goals in a subsequent programme involving patients and physicians.

title: Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics.
abstract: Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this first of 5 sections of the guidelines of care for psoriasis, we discuss the classification of psoriasis; associated comorbidities including autoimmune diseases, cardiovascular risk, psychiatric/psychologic issues, and cancer risk; along with assessment tools for skin disease and quality-of-life issues. Finally, we will discuss the safety and efficacy of the biologic treatments used to treat patients with psoriasis.

title: National Psoriasis Foundation clinical consensus on disease severity.
abstract: A task force of the National Psoriasis Foundation Medical Board was convened to evaluate the current severity criteria of mild, moderate, and severe psoriasis and to make recommendations concerning a 2-tiered categorization of severity based on current clinical practice and related to intent to treat.



This volunteer task force, led by David M. Pariser, MD, included Jerry Bagel, MD, Joel M. Gelfand, MD, MSCE, Neil J. Korman, MD, PhD, Christopher T. Ritchlin, MD, Bruce E. Strober, MD, PhD, Abby S. Van Voorhees, MD, and Melodie Young, MSN, RN, ANP. Meetings were held by teleconference and were coordinated and funded by the National Psoriasis Foundation.



This task force reviewed psoriasis severity criteria and other published psoriasis consensus statements. Current standards of care and expert opinion were used to inform the process.


CONSENSUS PROCESS
Based on meetings of the task force and under the guidance of David M. Pariser, MD, a statement was drafted by Elizabeth J. Horn, PhD, presented to the task force, and reviewed and approved by the task force. This statement was then reviewed and approved by Robert E. Kalb, MD, Gerald G. Krueger, MD, and Alan Menter, MD. The National Psoriasis Foundation Medical Board reviewed and endorsed this statement by a majority vote on March 2, 2006, at the medical board meeting.



This clinical consensus statement proposes a 2-tiered system for plaque psoriasis therapy that reflects more accurately than the current system how patients are treated in clinical practice. This statement, focused on plaque psoriasis, is intended to assist medical professionals and insurance payers in understanding these 2 categories of patients with psoriasis and choosing appropriate therapies for these patients.

title: Current severe psoriasis and the Rule of Tens
abstract: This review addresses the problems of defining severity of psoriasis. Concepts of severity depend on the timescale perspective from which judgement is made. Measurement needs to include assessment of signs, impact on the patient's life and the history of the disease. The concept of severity in relationship to quality of life measurement scores has been defined, so it is now possible to postulate a standard, easily remembered concept to help define ‘severe psoriasis’ in the clinic. The proposed Rule of Tens for current severe psoriasis from the clinician's viewpoint is: ‘Current Severe Psoriasis = Body Surface Area involved > 10% or Psoriasis Area and Severity Index score > 10 or Dermatology Life Quality Index score > 10’.

title: Consensus guidelines for the management of plaque psoriasis.
abstract: The Canadian Guidelines for the Management of Plaque Psoriasis were reviewed by the entire National Psoriasis Foundation Medical Board and updated to include newly approved agents such as ustekinumab and to reflect practice patterns in the United States, where the excimer laser is approved for psoriasis treatment. Management of psoriasis in special populations is discussed. In the updated guidelines, we include sections on children, pregnant patients or pregnant partners of patients, nursing mothers, the elderly, patients with hepatitis B or C virus infections, human immunodeficiency virus-infected patients, and patients with malignant neoplasms, as well as sections on tumor necrosis factor blockers, elective surgery, and vaccinations.

title: The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-membership survey.
abstract: Psoriasis can have a profound impact on a patient's quality of life.



To assess patients' perspectives on the impact of psoriasis on their lifestyle and emotional well-being and the social ramifications of living with the disease; to determine the range of therapies available; and to ascertain patients' satisfaction with the management of their disease.



A 4-page, self-administered questionnaire was mailed on July 13 and 14, 1998, to the entire membership of the National Psoriasis Foundation (N = 40 350), and followed by a telephone survey of responders with severe psoriasis.



Patients' perspectives on the psychosocial impact of psoriasis and the effectiveness of the management of their disease.



Of the 40 350 questionnaires mailed out, a response rate of 43% was realized. The most frequent symptoms experienced by the mail-survey respondents were scaling (94%), itching (79%), and skin redness (71%); 39% reported that psoriasis covered 10% or more of their bodies. A total of 6194 patients with severe psoriasis were entered into the database for the telephone survey. Of these, 79% reported that psoriasis had a negative impact on their lives, 40% felt frustrated with the ineffectiveness of their current therapies, and 32% reported that treatment was not aggressive enough.



The unprecedented response to the survey provides compelling evidence that individuals with psoriasis believe that the disease has a profound emotional and social as well as physical impact on their quality of life. Many patients with psoriasis, particularly those with severe disease, are frustrated with the management of their disease and by the perceived ineffectiveness of their therapies. Physicians may need to improve communication with their patients and should reevaluate their management of psoriasis.

title: Traditional systemic treatments have not fully met the needs of psoriasis patients: results from a national survey.
abstract: Many psoriasis patients are dissatisfied with current therapies. However, patient-centered levels of satisfaction with individual treatments have not been well described.



To assess patients' satisfaction with 4 systemic treatment options available before 2002.



We used data from a recent national survey. Psoriasis patients were randomly recruited from the general US population, members of the Psoriasis Foundation, and persons who contacted the Psoriasis Foundation but did not join. The interview included questions about use and satisfaction with specific Psoriasis therapy.



Of 1197 psoriasis patients interviewed, 311 (26%) indicated current or past use of methotrexate, psoralen plus ultaviolet A (PUVA), cyclosporin, and/or acitretin (users). Compared with those who had never used any of these systemic therapies, users reported more extensive disease (adjusted odds ratio [OR] = 2.90, 95% confidence interval [CI] = 1.87-4.49) and higher Psoriasis Disability Index scores (category V: adjusted OR = 2.31, 95% CI = 1.22-4.36). After adjusting for these variables, more than one third of patients were dissatisfied with each therapy, except for PUVA (14%). Patients were most satisfied with methotrexate and PUVA. However, less than 40% of the users indicated they were very satisfied with any of the 4 therapies assessed. Only 10% of persons who ever used cyclosporin were currently using it. In a paired analysis, cyclosporin users were significantly less satisfied with cyclosporin than with other therapies ( P = .01).



For most patients, none of the 4 systemic therapies widely utilized in 2002 for psoriasis were highly satisfactory. If we are to learn whether new treatments satisfy patients' needs, long term, prospective, comparative studies of heterogeneous patient populations that include patients' assessments are needed.

title: Association of dissatisfaction with care and psychiatric morbidity with poor treatment compliance.
abstract: To examine factors associated with compliance with dermatologic treatment.



Longitudinal study. Quality of life and psychological well-being were measured before the dermatologic visit with a self-completed questionnaire. Telephone interviews were performed 3 days and 4 weeks after the visit to evaluate patient satisfaction and medication adherence, respectively.



Outpatient clinics of a large dermatologic hospital in Rome, Italy.



A total of 1389 outpatients were contacted and 722 (52%) agreed to participate. Among them, 424 responded to the inclusion criteria and were enrolled in the study. Of these, 396 (93%) completed the telephone interviews.



Self-reported compliance with dermatologic treatment.



The dermatologists' prescriptions were not exactly followed by 44% of patients. In multiple logistic regression analysis, treatment adherence was strongly associated with complete satisfaction. Poor quality of life on the emotions scale (indicating mainly high levels of shame and embarrassment) was also associated with medication adherence. On the contrary, a strong negative association was observed between psychiatric morbidity and compliance.



This is the first longitudinal study on dermatologic patients showing that dissatisfaction with care and psychiatric morbidity are significantly and independently associated with poor medication adherence. To improve medication adherence, particular attention should be dedicated to the physician's interpersonal skills, which emerged as a major component of patient satisfaction. Moreover, our results highlight the need for a timely identification and appropriate management of psychiatric disorders in everyday dermatologic practice.

title: Psoriasis: symptoms, treatments and its impact on quality of life.
abstract: Psoriasis affects between 1% and 3% of the population and there is no cure for this chronic skin disease. This article gives an overview of the condition and available treatments. It focuses on managing symptoms, the range of medications available and the impact this chronic condition can have on a sufferer's quality of life. The article looks at medication non adherence remaining the biggest obstacle to management of the condition and the debilitating effect psoriasis can have on an individual's self-esteem and general well-being. It concludes by considering the role of patient support services such as the touch programme.

title: Psoriasis: rationale for targeting interleukin‐17
abstract: The exact pathogenesis of plaque psoriasis remains to be fully determined, but it is thought to depend on environmental and genetic factors that stimulate dysregulated innate and adaptive immune responses in the skin. The cytokine interleukin (IL)‐17A plays a key role in host defence against extracellular bacteria and fungi. An increasing body of evidence suggests that IL‐17A is also important in psoriasis pathogenesis. While IL‐17A is a key product of Th17 cells, it is also produced by neutrophils, mast cells and Tc17 cells. Each of these cell types is found in psoriatic lesions. IL‐17A acts on keratinocytes to increase expression of chemokines (e.g. CCL20, CXCL1, CXCL3, CXCL5, CXCL6 and CXCL8) involved in recruiting myeloid dendritic cells, Th17 cells and neutrophils to the lesion site. IL‐17A induces production of antimicrobial peptides and proinflammatory cytokines that, in turn, may help sustain immune responses in the skin. Blocking IL‐17A improved psoriasis‐like pathology in experimental models, and reductions in IL‐17 signalling have been associated with response to tumour necrosis factor‐α blockers in patients with psoriasis. Agents that inhibit IL‐17 are in development and preliminary clinical results for IL‐17 inhibitors indicate the importance of IL‐17A in psoriasis pathophysiology. In a proof‐of‐concept and two phase II trials, three agents markedly reduced disease severity in patients with moderate‐to‐severe plaque psoriasis. One agent downregulated cytokines, chemokines and proteins associated with inflammatory responses in lesional skin. In summary, IL‐17A is an attractive therapeutic target, which may allow selective intervention to address the dysregulated immune system in plaque psoriasis.

title: IL-17 targeted therapies for psoriasis
abstract: Psoriasis is a chronic, disabling, inflammatory skin disease whose pathogenesis still remains to be fully elucidated. Genetic and environmental factors induce an immune response mediated by several cytokines and chemokines, including IL-17A. Areas covered: Emerging evidence now suggests that IL-17A is central in the pathogenesis of psoriasis. Three agents neutralizing IL-17 (i.e., secukinumab and ixekizumab) or antagonizing its receptor (i.e., brodalumab) are in development and are being studied in Phase III clinical trials to evaluate their overall efficacy and safety. However, Phase II results of IL-17 blockade with each of these agents has shown a marked improvement of disease severity, thus confirming the pathogenic relevance of IL-17 in mediating crucial inflammatory circuits in psoriasis.  Anti-IL-17 agents are likely to become important future therapeutics in this disease and the may potentially impact on cardiovascular diseases, arthritis and other comorbidities associated with psoriasis.

title: Biologic Therapies in the Treatment of Psoriasis: A Comprehensive Evidence-Based Basic Science and Clinical Review and a Practical Guide to Tuberculosis Monitoring
abstract: The treatment of psoriasis has undergone a revolution with the advent of biologic therapies including infliximab, etanercept, adalimumab, efalizumab, golimumab, certolizumab, alefacept, secukinumab, abatacept, and ustekinumab. These medications are designed to target specific components of the immune system and are a major technological advancement over traditional immunosuppressive medications. Herein, we present a comprehensive, unbiased comparison of these medications focusing on their differences. For example, TNF antagonists can differ in the way they are dissolved and administered, the effector molecules they can bind, serum peak and trough levels, the types of intracellular signals they can induce, the in vivo complexes that they can form, their protein structure, and their incidence and timing of rare adverse events, among other things. A critical review of the clinical studies that have tested the efficacy of these molecules is also presented including head-to-head comparison trials. The safety of biologics in terms of their long-term adverse events is discussed, as is their use in different types of psoriasis and in different patient populations. Finally, all anti-TNF agents have been associated with a variety of serious and “routine” opportunistic infections, particularly tuberculosis. For this reason, anti-tuberculosis testing both prior to the initiation of a biologic therapy and annually during treatment is pertinent. The uses and limitations of both the tuberculin skin test (TST) and QuantiFeron®-TB Gold (QFT) are discussed, as is the care of patients who present with latent tuberculosis infection prior to the initiation of biologic therapy. Recommendations for tuberculosis monitoring are provided.

title: Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial
abstract: Tumour necrosis factor alpha (TNFalpha) is thought to play a part in the pathogenesis of psoriasis. We assessed the efficacy and safety of continuous treatment with infliximab, a monoclonal antibody that binds to and neutralises the activity of TNFalpha, in patients with psoriasis.



In this phase III, multicentre, double-blind trial, 378 patients with moderate-to-severe plaque psoriasis were allocated in a 4:1 ratio to receive infusions of either infliximab 5 mg/kg or placebo at weeks 0, 2, and 6, then every 8 weeks to week 46. At week 24, placebo-treated patients crossed over to infliximab treatment. Skin and nail signs of psoriasis were assessed using the psoriasis area and severity index (PASI) and nail psoriasis severity index (NAPSI), respectively. The primary endpoint, analysed on an intention-to-treat-basis, was the proportion of patients achieving at least a 75% improvement in PASI from baseline to week 10.



At week 10, 80% (242/301) of patients treated with infliximab achieved at least a 75% improvement from their baseline PASI (PASI 75) and 57% (172/301) achieved at least a 90% improvement (PASI 90), compared with 3% and 1% in the placebo group, respectively (p<0.0001). At week 24, PASI 75 (82% for infliximab vs 4% for placebo) and PASI 90 (58%vs 1%) were maintained (p<0.0001). At week 50, 61% achieved PASI 75 and 45% achieved PASI 90 in the infliximab group. Infliximab was generally well tolerated in most patients.



Infliximab is effective in both an induction and maintenance regimen for the treatment of moderate-to-severe psoriasis, with a high percentage of patients achieving sustained PASI 75 and PASI 90 improvement through 1 year.

title: A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis.
abstract: Previous studies of infliximab in psoriasis have demonstrated rapid improvement with induction therapy and sustained response with regularly administered maintenance therapy.



The efficacy and safety of continuous (every-8-week) and intermittent (as-needed) maintenance regimens were compared.



Patients with moderate-to-severe psoriasis (n = 835) were randomized to induction therapy (weeks 0, 2, and 6) with infliximab 3 mg/kg or 5 mg/kg or placebo. Infliximab-treated patients were randomized again at week 14 to continuous or intermittent maintenance regimens at their induction dose.



At week 10, 75.5% and 70.3% of patients in the infliximab 5 mg/kg and 3 mg/kg groups, respectively, achieved PASI 75; 45.2% and 37.1% achieved PASI 90 (vs 1.9% [PASI 75] and 0.5% [PASI 90] for placebo; P < .001). Through week 50, PASI responses were better maintained with continuous compared with intermittent therapy within each dose, and with 5 mg/kg compared with 3 mg/kg continuous therapy.



Longer term (>1 year) maintenance therapy and further study of infliximab serum concentrations over this period, in both PASI 75 responders and non-responders, would be preferable.



Through week 50, response was best maintained with continuous infliximab therapy. Infliximab was generally well-tolerated in most patients.

title: Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial.
abstract: Tumor necrosis factor-alpha is a key mediator in the pathogenesis of psoriasis. Infliximab is a monoclonal antibody that specifically binds to tumor necrosis factor-alpha, blocking its biologic activity.



The purpose of this study was to access the efficacy and safety of infliximab induction therapy for patients with severe plaque psoriasis.



In this multicenter, double-blind, placebo-controlled trial, 249 patients with severe plaque psoriasis were randomly assigned to receive intravenous infusions of either 3 or 5 mg/kg of infliximab or placebo given at weeks 0, 2, and 6. The primary end point was the proportion of patients who achieved at least 75% improvement in Psoriasis Area and Severity Index score from baseline at week 10. At week 26, patients whose Physician Global Assessment indicated moderate or severe disease were eligible for a single intravenous infusion of their assigned treatment to assess the safety of retreatment after a 20-week, treatment-free interval.



At week 10, 72% of patients treated with infliximab (3 mg/kg) and 88% of patients treated with infliximab (5 mg/kg) achieved a 75% or greater improvement from baseline in Psoriasis Area and Severity Index score compared with 6% of patients treated with placebo (P <.001). Improvement was observed in both infliximab groups as early as 2 weeks. Overall, 63%, 78%, and 79% of patients in the placebo, 3-, and 5-mg/kg groups, respectively, reported one or more adverse events.



Infliximab treatment resulted in a rapid and significant improvement in the signs and symptoms of psoriasis. Infliximab was generally well tolerated.

title: Etanercept as monotherapy in patients with psoriasis.
abstract: Inflammatory cytokines such as tumor necrosis factor (TNF) have been implicated in the pathogenesis of psoriasis. We evaluated the safety and efficacy of etanercept, a TNF antagonist, for the treatment of plaque psoriasis.



In this 24-week, double-blind study, 672 patients underwent randomization and 652 either received placebo or received etanercept subcutaneously at a low dose (25 mg once weekly), a medium dose (25 mg twice weekly), or a high dose (50 mg twice weekly). After 12 weeks, patients in the placebo group began twice-weekly treatment with 25 mg of etanercept. The primary measure of clinical response was the psoriasis area-and-severity index.



At week 12, there was an improvement from base line of 75 percent or more in the psoriasis area-and-severity index in 4 percent of the patients in the placebo group, as compared with 14 percent of those in the low-dose--etanercept group, 34 percent in the medium-dose--etanercept group, and 49 percent in the high-dose-etanercept group (P<0.001 for all three comparisons with the placebo group). The clinical responses continued to improve with longer treatment. At week 24, there was at least a 75 percent improvement in the psoriasis area-and-severity index in 25 percent of the patients in the low-dose group, 44 percent of those in the medium-dose group, and 59 percent in the high-dose group. The responses as measured by improvements in the psoriasis area-and-severity index were paralleled by improvements in global assessments by physicians and the patients and in quality-of-life measures. Etanercept was generally well tolerated.



The treatment of psoriasis with etanercept led to a significant reduction in the severity of disease over a period of 24 weeks.

title: A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction
abstract: In previous studies, etanercept significantly improved plaque psoriasis and was well tolerated.

title: Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1)
abstract: Interleukins 12 and 23 have important roles in the pathophysiology of psoriasis. We assessed ustekinumab, a human monoclonal antibody directed against these cytokines, for the treatment of psoriasis.



In this phase III, parallel, double-blind, placebo-controlled study, 766 patients with moderate-to-severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then every 12 weeks; or placebo (n=255) at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. Patients who were initially randomised to receive ustekinumab at week 0 who achieved long-term response (at least 75% improvement in psoriasis area and severity index [PASI 75] at weeks 28 and 40) were re-randomised at week 40 to maintenance ustekinumab or withdrawal from treatment until loss of response. Both randomisations were done with a minimisation method via a centralised interactive voice response system. The primary endpoint was the proportion of patients achieving PASI 75 at week 12. Analyses were by intention to treat. 
All randomised patients were included in the efficacy analysis. 171 (67.1%) patients receiving ustekinumab 45 mg, 170 (66.4%) receiving ustekinumab 90 mg, and eight (3.1%) receiving placebo achieved PASI 75 at week 12 (difference in response rate vs placebo 63.9%, 95% CI 57.8-70.1, p<0.0001 for 45 mg and 63.3%, 57.1-69.4, p<0.0001 for 90 mg). At week 40, long-term response had been achieved by 150 patients in the 45 mg group and 172 patients in the 90 mg group. Of these, 162 patients were randomly assigned to maintenance ustekinumab and 160 to withdrawal. PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p<0.0001 by log-rank test). During the placebo-controlled phase, adverse events occurred in 278 (54.5%) of the 510 patients receiving ustekinumab and 123 (48.2%) of the 255 receiving placebo. Serious adverse events occurred in six (1.2%) of 510 patients receiving ustekinumab and in two (0.8%) of 255 receiving placebo in this phase. The pattern of adverse events was much the same in the placebo crossover and randomised withdrawal phases as it was in the placebo-controlled phase.



Ustekinumab seems to be efficacious for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least a year in most patients.

title: Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2)
abstract: Ustekinumab, a human monoclonal antibody against interleukins 12 and 23, has shown therapeutic potential for psoriasis. This study assessed the efficacy and safety of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders.



In this multicentre, phase III, double-blind, placebo-controlled study, 1230 patients with moderate-to-severe psoriasis (defined by a psoriasis area and severity index [PASI] score > or =12, and at least 10% total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n=409) or 90 mg (n=411) at weeks 0 and 4, then every 12 weeks, or placebo (n=410). Partial responders (ie, patients achieving > or =50% but <75% improvement from baseline in PASI) were re-randomised at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks. Both randomisations were done with a minimisation method via a centralised interactive voice response. The primary endpoint was the proportion of patients achieving at least 75% improvement in PASI (PASI 75) at week 12. Analyses were by intention to treat. 
All randomised patients were included in the efficacy analysis. 273 (66.7%) patients receiving ustekinumab 45 mg, 311 (75.7%) receiving ustekinumab 90 mg, and 15 (3.7%) receiving placebo achieved the primary endpoint (difference in response rate 63.1%, 95% CI 58.2-68.0, p<0.0001 for the 45 mg group vs placebo and 72.0%, 67.5-76.5, p<0.0001 for the 90 mg group vs placebo). More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks (22 [68.8%] vs 11 [33.3%]; difference in response rate 35.4%, 95% CI 12.7-58.1, p=0.004). There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45 mg. During the placebo-controlled phase, 217 (53.1%) patients in the 45 mg group, 197 (47.9%) in the 90 mg group, and 204 (49.8%) in the placebo group experienced adverse events; serious adverse events were seen in eight (2.0%) patients in the 45 mg group, five (1.2%) in the 90 mg group, and eight (2.0%) in the placebo group.



Although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen.

title: Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial.
abstract: Adalimumab is a fully human monoclonal antibody that binds tumor necrosis factor, a key proinflammatory cytokine involved in the pathogenesis of psoriasis.



We sought to evaluate clinical efficacy and safety of adalimumab for moderate to severe psoriasis and investigate continuous versus interrupted therapy.



We conducted a 52-week, multicenter study of 1212 patients randomized to receive adalimumab (40 mg) or placebo every other week for the first 15 weeks. At least 75% improvement in the Psoriasis Area and Severity Index (PASI) score was the criterion for advancement through this multiphase study.



At week 16, 71% (578 of 814) of adalimumab- and 7% (26 of 398) of placebo-treated patients achieved greater than or equal to 75% improvement in the PASI score. During weeks 33 to 52, the percentage of patients rerandomized to placebo who lost adequate response (defined as <50% improvement in the PASI response relative to baseline and at least a 6-point increase in PASI score from week 33) was 28% compared with 5% of patients treated continuously with adalimumab.



Lack of an active comparator and evaluation of maintenance of response beyond week 52 are limitations.



Adalimumab is efficacious and well-tolerated in the treatment of chronic plaque psoriasis.

title: Systemic combination treatment for psoriasis: a review.
abstract: Psoriasis is a chronic inflammatory skin disease, which affects approximately 2.6% of the population in Northern Europe and Scandinavia. In order to achieve disease control, combinations of systemic treatments are sometimes needed for variable time periods. However, no evidence-based guidelines exist for the use of systemic combination therapy. Therefore, our aim was to review the current literature on systemic anti-psoriatic combination regimens. We searched PubMed and identified 98 papers describing 116 studies (23 randomized) reporting on the effect of various systemic combination treatments. The most thoroughly investigated combination was retinoid and phototherapy. Further controlled research is needed to define the safest and most effective combination regimens.

title: Long‐term control of recalcitrant psoriasis with combination infliximab and methotrexate
abstract: Recently, the National Institute for Health and Clinical Excellence (NICE) approved infliximab for very severe psoriasis refractory to standard systemic treatments. This appraisal considered several large multicentre studies that had shown the short-term efficacy and safety of infliximab. However, as psoriasis is usually a life-long condition, the ultimate goal has to be an effective and safe long-term treatment; for infliximab and other biological treatments, these criteria remain unfulfilled. In 2001, we reported one of the first patients with psoriasis to be treated successfully with infliximab. A 40year-old man who had first developed psoriasis at the age of 8 years, was referred to the Psoriasis Clinic in Manchester. Previously, the patient had been treated with psoralen ultraviolet A, ciclosporin, methotrexate, hydroxycarbamide, azathioprine, etretinate and acitretin. Some of these treatments had proved ineffective, and others had caused unacceptable toxicity. In particular, ciclosporin had caused chronic kidney disease (creatinine 135 lmol ⁄ L; normal range 50–120). In August 2000, he was on weekly methotrexate 20 mg and folic acid 5 mg, his Psoriasis Area and Severity Index (PASI) was 27.2 and his psoriasis-related psychosocial disability, as assessed by a validated visual analogue scale, was scored at the maximum of 10; at this point, he was given infliximab (5 mg ⁄ kg). Within 3 weeks of the first infusion, there was a significant improvement in both his PASI (4.1) and his psychosocial disability score (1). He was then maintained on the methotrexate and folic acid and required 6-monthly infliximab (5 mg ⁄ kg) infusions to cover flares of his psoriasis. After 18 months, on account of raised hepatic enzymes and serum type III procollagen levels, the patient s methotrexate was discontinued. Within 4 weeks, he required a further infusion of infliximab, which again achieved clearance of his psoriasis, but this again relapsed after just 9 weeks while he was still off methotrexate. As the liver biochemistry had reverted to normal, the patient was restarted on methotrexate, but at a reduced dose of 10 mg ⁄ week in conjunction with folic acid 5 mg ⁄ week. This combination treatment has maintained excellent control of his psoriasis and he has continued to receive infliximab infusions (5 mg ⁄ kg) every 6 months when his psoriasis flares. One month after his most recent infliximab infusion, his PASI was 3.3 and his Dermatology Life Quality Index was 2 ⁄ 30 (Fig 1a,b). Over the past 5 years he has experienced no adverse events and his liver biochemistry, type III procollagen, full blood count, urea, creatinine and electrolytes have all remained stable. This patient started infliximab before studies that showed its effectiveness as monotreatment for psoriasis were published, and before the now accepted loading and maintenance schedules were set. Therefore, the treatment regimen used in this case is of considerable interest. Concomitant methotrexate appears to have had an infliximab-sparing effect and may have contributed to the long-term control of the psoriasis by inhibiting the development of antibodies to the murine portion of infliximab, thus the serum concentration of infliximab remains high. The pharmacokinetics of infliximab and the relationship between serum concentrations and efficacy is unclear. Studies suggest that trough serum concentrations < 0.1 mg ⁄ mL and > 10 mg ⁄ mL are associated with non-response and response, respectively. However, interpatient variability exists, so that some

title: Combination systemic therapies in psoriatic arthritis
abstract: Psoriatic arthritis (PsA) is a chronic, progressive, and debilitating disorder. When monotherapy fails, combination therapy is necessary for the long-term management of these patients. There is currently no review on this subject, and the purpose of this study was to investigate and describe the current literature on combination therapy in PsA. A PubMed MeSH search was performed for psoriatic arthritis and combination therapy, which yielded at total of 83 articles. After excluding reviews and commentaries, and pursuing relevant citations, a total of 21 articles on the subject were found: one study of NSAIDs and methotrexate, three studies of cyclosporine and methotrexate, three studies of non-TNF biologic inhibitors (alefacept, ustekinumab) and methotrexate, and 14 studies of anti-TNF-inhibitors (etanercept, adalimumab, infliximab, golimumab) and methotrexate. The combination of cyclosporine and methotrexate reduces the dosages and also the side effects of each agent, allowing better disease control with less toxicity. Methotrexate in combination with biologic agents, either non-TNF inhibitors or anti-TNF inhibitors, may have a role in decreasing side effects, but it does not appear to improve clinical symptoms beyond those attained by biologic monotherapy.

title: Alefacept in combination with methotrexate for the treatment of psoriatic arthritis: results of a randomized, double-blind, placebo-controlled study.
abstract: To evaluate the efficacy and safety of alefacept in combination with methotrexate (MTX) for the treatment of psoriatic arthritis (PsA).



Patients were eligible for this randomized, double-blind, placebo-controlled trial if they were ages 18-70 years and had active PsA (> or = 3 swollen joints and > or = 3 tender joints) despite treatment with MTX for > or = 3 months (a stable dosage for > or = 4 weeks prior to enrollment). Patients were stratified according to psoriasis body surface area (BSA) involvement (> or = 3% or < 3%). Alefacept (15 mg) or placebo was administered intramuscularly once weekly for 12 weeks in combination with MTX, followed by 12 weeks of observation during which only MTX treatment was continued. The primary efficacy end point was the proportion of patients achieving a 20% improvement in disease activity according to the American College of Rheumatology criteria (an ACR20 response) at week 24.



One hundred eighty-five patients were randomly assigned to receive alefacept plus MTX (n = 123) or placebo plus MTX (n = 62). At week 24, 54% of patients in the alefacept plus MTX group achieved an ACR20 response, compared with 23% of patients in the placebo plus MTX group (P < 0.001). Mean reductions in tender and swollen joint counts in patients receiving alefacept plus MTX were -8.0 and -6.3, respectively. In patients with psoriasis involving > or = 3% BSA (n = 87), a 50% reduction from the baseline Psoriasis Area Severity Index at week 14 was achieved by 53% of patients receiving alefacept plus MTX compared with 17% of those receiving placebo plus MTX (P < 0.001). Most adverse events were mild to moderate in severity. In the alefacept plus MTX group, the incidence of serious adverse events was low (1.6%), and no opportunistic infections or malignancies were reported.



Alefacept in combination with MTX may be an effective and safe treatment for PsA.

title: Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial
abstract: Many patients with psoriasis develop psoriatic arthritis, a chronic inflammatory disease that afflicts peripheral synovial, axial, and entheseal structures. The fully human monoclonal antibody ustekinumab is an efficacious treatment for moderate-to-severe plaque psoriasis. We did a randomised, placebo-controlled, phase 3 trial to assess the safety and efficacy of ustekinumab in patients with active psoriatic arthritis.



In this phase 3, multicentre, double-blind, placebo-controlled trial at 104 sites in Europe, North America, and Asia-Pacific, adults with active psoriatic arthritis (≥5 tender and ≥5 swollen joints, C-reactive protein ≥3·0 mg/L) were randomly assigned (1:1:1, by dynamic central randomisation based on an algorithm implemented by an interactive voice-web response system) to 45 mg ustekinumab, 90 mg ustekinumab, or placebo at week 0, week 4, and every 12 weeks thereafter. At week 16, patients with less than 5% improvement in both tender and swollen joint counts entered masked early-escape and were given 45 mg ustekinumab (if in the placebo group) or 90 mg ustekinumab (if in the 45 mg group). At week 24, all remaining patients in the placebo group received ustekinumab 45 mg, which they continued at week 28 and every 12 weeks thereafter. Our primary endpoint was 20% or greater improvement in American College of Rheumatology (ACR20) criteria at week 24. .



Between Nov 30, 2009, and March 30, 2011, 615 patients were randomly assigned-206 to placebo, 205 to 45 mg ustekinumab, and 204 to 90 mg ustekinumab. More ustekinumab-treated (87 of 205 [42·4%] in the 45 mg group and 101 of 204 [49·5%] in the 90 mg group) than placebo-treated (47 of 206 [22·8%]) patients achieved ACR20 at week 24 (p<0·0001 for both comparisons); responses were maintained at week 52. At week 16, proportions of patients with adverse events were similar in the ustekinumab and placebo groups (171 of 409 [41·8%] vs 86 of 205 [42·0%]).



Ustekinumab significantly improved active psoriatic arthritis compared with placebo, and might offer an alternative therapeutic mechanism of action to approved biological treatments.



Janssen Research & Development.

title: Alefacept with methotrexate for treatment of psoriatic arthritis: open-label extension of a randomized, double-blind, placebo-controlled study.
abstract: A single course of alefacept intramuscularly in combination with methotrexate (MTX) was effective in treating both psoriasis and psoriatic arthritis (PsA).



We sought to determine the efficacy and safety of an additional course of alefacept intramuscularly in combination with MTX in patients with PsA.



In this open-label extension study, patients with PsA on stable doses of MTX were treated with an additional 12 weekly intramuscular injections of alefacept followed by 12 weeks of observation. Efficacy of PsA treatment was measured as 20% reduction in American College of Rheumatology criteria (ACR20).



At the end of the open-label extension phase, 86 of 160 (54%) patients achieved ACR20, of which 28 of 55 had received placebo plus MTX and 58 of 105 received alefacept plus MTX in the prior double-blind phase. Although there was no increase in the proportion of patients achieving ACR20 after a second course of alefacept plus MTX, those achieving ACR50 and ACR70 increased from 17% and 7%, respectively, in the double-blind phase to 32% and 12%, respectively, in the open-label extension phase.



In this open-label extension phase of the study there was no control group and the effect on psoriasis in these patients was not measured.



Patients with psoriasis and PsA on stable doses of MTX derive benefit for both conditions from one or more courses of alefacept, with further benefit in PsA apparent after a second course of treatment. No additional toxicity was observed.

title: European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies
abstract: Psoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD).  The recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement.  Ten recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extra-articular manifestations of PsA. Five overarching principles and a research agenda were defined.  These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.

title: Combining the new biologic agents with our current psoriasis armamentarium.
abstract: Combination therapy, rotational therapy, and sequential therapy have been used for psoriasis in attempts to achieve greater efficacy and greater safety. The purpose of this manuscript is to review potential advantages and disadvantages of new biologic agents as we look forward to their use in combination regimens with other systemic, topical, and light therapies. Data on the efficacy and toxicity of existing systemic therapies and new biologic agents is reviewed with an emphasis on potential additive or synergistic benefits or toxicities. The mechanism of action of biologic agents differs from systemic agents currently in use, suggesting that there may be additive effects in treating psoriasis. The absence of hepatotoxicity and nephrotoxicity are important advantages when considering combination therapy with biologic agents. The advantages of the use of biologic therapies in combination or rotation with other systemic agents will have to be demonstrated in clinical trials. Mechanisms of action of the biologic therapies suggest that there is potential for additive benefit when used in combination regimens.

title: From the Medical Board of the National Psoriasis Foundation: The risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies.
abstract: Many studies have identified cardiovascular risk factors in patients with psoriasis. Some psoriasis therapies may increase cardiovascular disease (CVD) and others may decrease CVD.



We reviewed the literature to define the impact of common psoriasis therapies on cardiovascular measures and outcomes.



Phototherapy has no major cardiovascular impact and may reduce levels of proinflammatory cytokines. Acitretin increases serum lipids and triglycerides, but has not been shown to increase cardiovascular risk. Cyclosporine A increases blood pressure, serum triglycerides, and total cholesterol. Methotrexate is associated with a decreased risk of CVD morbidity and mortality. Among the biologics, data for tumor necrosis factor inhibitors suggest an overall reduction in cardiovascular events. Most data on short-term ustekinumab use suggest no effect on major adverse cardiovascular events, however some authorities remain concerned. Nevertheless, ustekinumab use over a 4-year period shows a decrease in major adverse cardiovascular events when compared both with the general US population and with psoriatics in Great Britain.



Most studies lack the power and randomization of large clinical trials and long-term follow-up periods. In addition, the increased risk of CVD associated with psoriasis itself is a confounding factor.



Some therapies for moderate to severe psoriasis, including methotrexate and tumor necrosis factor inhibitors, may reduce cardiovascular events in psoriatic patients. Ustekinumab appears to be neutral but there may be a long-term benefit. Appropriate patient counseling and selection and clinical follow-up are necessary to maximize safety with these agents. Further long-term study is necessary to quantify the benefits and risks associated with biologic therapies.

title: Combination use of ustekinumab with other systemic therapies: a retrospective study in a tertiary referral center.
abstract: Patients with moderate to severe psoriasis may not respond adequately to single systemic agent and may require combination systemic therapy.



To evaluate the prevalence, indications, and response to combination systemic therapy with ustekinumab for psoriasis in a tertiary referral center.



This retrospective study comprised 102 psoriasis patients treated with ustekinumab at a single tertiary care center. Data was collected pertaining to history of psoriasis, past and current therapies including use of concomitant psoriasis agents, response to therapy, and side effects while on ustekinumab.



Twenty-two of 102 (22%) patients were identified as receiving combination systemic treatment involving ustekinumab and at least one additional agent. The most common indication for combination therapy was psoriatic arthritis (35%), followed by bridging therapy (26%), inadequate psoriasis control (13%), prevention of non-melanoma skin cancers (17%), and control of palmoplantar disease (9%). Methotrexate was the additional agent in 12 patients, cyclosporine in 7 patients, acitretin in 5 patients, and 1 patient received a second biologic agent, first etanercept and then adalimumab. Overall, the reduction in body surface area (BSA) was 80% for patients on combination therapy. For those patients on combination therapy for psoriatic arthritis, 75% had resolution or stabilization of their symptoms. Only one patient, receiving cyclosporine, discontinued combination therapy due to adverse side effects.



Combination systemic therapy with ustekinumab can be effective and well tolerated for patients who cannot be adequately treated with ustekinumab alone.

title: Clinical practice guideline for an integrated approach to comorbidity in patients with psoriasis
abstract: The relationship between psoriasis and associated diseases has drawn particular interest in recent years. To provide appropriate management of psoriasis from an early stage, it is necessary to include prompt diagnosis of concomitant disease and to prevent and treat any comorbidity found. Such an integrated approach also serves to ensure that the drugs used to treat associated diseases do not interfere with the management of psoriasis, and vice versa.

title: Biologics in combination with nonbiologics: efficacy and safety
abstract: The mechanisms of action of biologic therapies differ from the currently used systemic therapies by attacking specific steps in the pathogenesis pathway of psoriasis. Preliminary data show that combination therapy using biologics may allow for improved therapeutic efficacy with fewer side effects, including decreased risk of hepatotoxicity and nephrotoxicity commonly associated with the most widely used systemic agents, methotrexate, and cyclosporine. However, some concerns have been raised regarding the increased immunosuppression, increased risk of infection, potential for development of certain types of malignancy, as well as the significant increased cost of therapy. Both potential benefits and toxicities of combination therapy will be reviewed here. Long‐term clinical studies are warranted to more accurately quantify the risks and benefits associated with combination therapy. The role of combination therapy will continue to be refined over the next few years to maximize its potential in the treatment of resistant psoriasis.

title: Combining etanercept with traditional agents in the treatment of psoriasis: a review of the clinical evidence
abstract: Psoriasis is a chronic, systemic inflammatory disorder manifesting primarily in skin and potentially in joints, frequently necessitating treatment with conventional systemic therapies, phototherapy or biological agents. Patients with moderate to severe disease suffer a diminished quality of life, experience significant comorbidities and have a higher mortality. Although traditional treatments are effective in the short‐term, their use is often limited by concerns over long‐term toxicity, including end‐organ damage and risk of malignancy. Combination therapy is a commonly used approach and is often more effective than any single agent. Lower doses of two treatments in combination can also minimize potential side effects from a single agent at higher doses. Etanercept is a recombinant human tumour necrosis factor (TNF)α receptor (p75) protein fused with the Fc portion of IgG1 that binds to TNFα. This article reviews the evidence on the efficacy and safety of etanercept in combination with methotrexate, acitretin, narrowband UVB and cyclosporin. The largest body of evidence assesses the combination with methotrexate, although evidence is available for the other combinations. Data suggest that although highly effective as monotherapy, etanercept in combination with a conventional systemic agent can enhance efficacy and allow drug sparing. Potentially, the combination may also result in faster treatment responses and permit safe transitioning from one systemic agent to another. Evidence to date suggests that these benefits can be achieved without significant additional toxicity, although long‐term data on the efficacy and safety of the combination in psoriatic populations is limited and further evaluation is warranted.

title: Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents.
abstract: Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this fourth of 6 sections of the guidelines of care for psoriasis, we discuss the use of traditional systemic medications for the treatment of patients with psoriasis. Treatment should be tailored to meet individual patients' needs. We will discuss in detail the efficacy and safety, and offer recommendations for the use of the 3 most commonly used, and approved, traditional systemic agents: methotrexate, cyclosporine, and acitretin. We will also briefly discuss the available data for the use of azathioprine, fumaric acid esters, hydroxyurea, leflunomide, mycophenolate mofetil, sulfasalazine, tacrolimus, and 6-thioguanine in psoriasis.

title: A consensus report on appropriate treatment optimization and transitioning in the management of moderate‐to‐severe plaque psoriasis
abstract: There is limited information on systemic and biological treatment optimization and transitioning in routine clinical practice.

title: Chemoprevention of Nonmelanoma Skin Cancer with Systemic Retinoids: Practical Dosing and Management of Adverse Effects
abstract: In patients with nonmelanoma skin cancer that is high risk or characterized by numerous tumors, chemoprevention with systemic retinoids may effectively decrease the number of new tumors whereas the chemosuppressive effects may reduce the risk of recurrence or disease progression. A patient's intolerance of the mucocutaneous effects of retinoid therapy or abnormal laboratory findings may hamper continuous therapy.  To present a method for optimizing tolerance of systemic retinoids for chemoprevention and for monitoring and managing adverse events.  After reviewing the data on the use of systemic retinoids for chemoprevention, we developed a simplified approach for administering oral retinoids for chemoprevention of nonmelanoma skin cancer as well as basic guidelines for the prevention and management of adverse effects and appropriate laboratory monitoring.  Chemoprevention with systemic retinoids in patients with a history of numerous tumors or high-risk skin cancer can be optimized with graduated dose escalation and preventive strategies for the most common adverse effects. Routine laboratory monitoring may assist in detecting adverse effects, which can be managed in most cases.  In our experience, the effective use of systemic retinoids for chemoprevention of nonmelanoma skin cancer in high-risk patients can be optimized through a standardized, proactive approach.

title: Treatment with anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibody dramatically decreases the clinical activity of psoriasis lesions.
abstract: We treated a 57-year-old woman for refractory inflammatory bowel disease with a humanized anti-tumor necrosis factor alpha monoclonal antibody (Infliximab). The patient also had a 15-year history of Crohn's disease and a 20-year history of moderate to severe psoriasis. She received a single infusion of Infliximab (5 mg/kg). Two weeks after the infusion her psoriasis had dramatically improved in appearance. To our knowledge, our case is the first reported instance of successful anti-tumor necrosis factor alpha therapy in psoriasis.

title: Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24‐week, randomized, controlled, investigator‐blinded pilot trial
abstract: Combination treatments may increase efficacy while reducing dosages and side‐effects of individual agents. No randomized controlled trials have been published combining biologics with conventional agents for psoriasis.

title: Combination therapy with tumor necrosis factor inhibitors in psoriasis treatment.
abstract: Psoriasis is a systemic disease that affects approximately 2% of the US population. Traditional treatment modalities include phototherapy, topical therapy, methotrexate, cyclosporine, and retinoids. Three tumor necrosis factor (TNF) inhibitors have been approved by the US Food and Drug Administration for the treatment of plaque psoriasis: etanercept, infliximab, and adalimumab. The combination of TNF inhibitors with phototherapy and topical and systemic agents may be effective in treating patients who are recalcitrant to monotherapy. We examine clinical trials that evaluated the efficacy and safety of combination treatments with TNF inhibitors. This review elucidates that combination therapy is both effective and well tolerated among patients with refractory psoriasis. Furthermore, combination therapy may allow for reduction of required treatment doses, thereby decreasing the potential for toxicity. It is important to note, however, that the studies reviewed here are limited in the long-term follow-up of patients. We conclude that dermatologists can safely and effectively incorporate combination therapy with TNF inhibitors in the treatment of patients with recalcitrant psoriasis.

title: Combination treatments for psoriasis: a systematic review and meta-analysis.
abstract: To summarize the current state of evidence for combination topical and systemic therapies for mild to severe psoriasis.



We performed a systematic search for all entries in PubMed, CINAHL, Cochrane Review, and EMBASE related to combination treatments for psoriasis through July 2010.



We included randomized controlled trials that reported proportion of disease clearance or mean change in clinical severity score (or provided these data through communication with study authors) for efficacy of a combination treatment for psoriasis compared with 1 or more corresponding monotherapies.



Study data were extracted by 3 independent investigators, with disagreement resolved by consensus. The proportion of patients who achieved clearance, definition of clearance, means and standard deviations for baseline disease symptom score and final disease symptom score, and major design characteristics were extracted for each study.



Combination treatments consisting of vitamin D derivative and corticosteroid, vitamin D derivative and UV-B, vitamin A derivative and psoralen-UV-A, vitamin A derivative and corticosteroid, vitamin A derivative and UV-B, corticosteroid and hydrocolloid occlusion dressings, UV-B and alefacept, and vitamins A and D derivatives were more effective than 1 or more monotherapies using the likelihood of clearance as the outcome. Blinding status and potency of the corticosteroid treatment used were significant sources of heterogeneity between studies.



The results demonstrate the need for additional long-term trials with standardized outcome measures to evaluate the efficacy and adverse effects of combination therapies for psoriasis and highlight the possible effects of trial design characteristics on results.

title: Infliximab plus methotrexate is superior to methotrexate alone in the treatment of psoriatic arthritis in methotrexate-naive patients: the RESPOND study
abstract: To compare the efficacy and safety of treatment with infliximab plus methotrexate with methotrexate alone in methotrexate-naive patients with active psoriatic arthritis (PsA).  In this open-label study, patients 18 years and older with active PsA who were naive to methotrexate and not receiving disease-modifying therapy (N=115) were randomly assigned (1:1) to receive either infliximab (5 mg/kg) at weeks 0, 2, 6 and 14 plus methotrexate (15 mg/week); or methotrexate (15 mg/week) alone. The primary assessment was American College of Rheumatology (ACR) 20 response at week 16. Secondary outcome measures included psoriasis area and severity index (PASI), disease activity score in 28 joints (DAS28) and dactylitis and enthesitis assessments.  At week 16, 86.3% of patients receiving infliximab plus methotrexate and 66.7% of those receiving methotrexate alone achieved an ACR20 response (p<0.02). Of patients whose baseline PASI was 2.5 or greater, 97.1% receiving infliximab plus methotrexate compared with 54.3% receiving methotrexate alone experienced a 75% or greater improvement in PASI (p<0.0001). Improvements in C-reactive protein levels, DAS28 response and remission rates, dactylitis, fatigue and morning stiffness duration were also significantly greater in the group receiving infliximab. In the infliximab plus methotrexate group, 46% (26/57) had treatment-related adverse events (AE) and two patients had serious AE, compared with 24% with AE (13/54) and no serious AE in the methotrexate-alone group.  Treatment with infliximab plus methotrexate in methotrexate-naive patients with active PsA demonstrated significantly greater ACR20 response rates and PASI75 improvement compared with methotrexate alone and was generally well tolerated.

title: Adalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA Study: an investigator-initiated, randomised, double-blind, parallel-group, placebo-controlled trial
abstract: An investigator-initiated, double-blinded, placebo-controlled, treat-to-target protocol ( studied whether adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment in early rheumatoid arthritis (ERA) increased the frequency of low disease activity (DAS28CRP<3.2) at 12 months.  In 14 Danish hospital-based clinics, 180 disease-modifying anti-rheumatic drugs (DMARD)-naïve ERA patients (<6 months duration) received methotrexate 7.5 mg/week (increased to 20 mg/week within 2 months) plus adalimumab 40 mg every other week (adalimumab-group, n=89) or methotrexate+placebo-adalimumab (placebo-group, n=91). At all visits, triamcinolone was injected into swollen joints (max. four joints/visit). If low disease activity was not achieved, sulfasalazine 2 g/day and hydroxychloroquine 200 mg/day were added after 3 months, and open-label biologics after 6–9 months. Efficacy was assessed primarily on the proportion of patients who reached treatment target (DAS28CRP<3.2). Secondary endpoints included DAS28CRP, remission, Health Assessment Questionnaire (HAQ), EQ-5D and SF-12. Analysis was by intention-to-treat with last observation carried forward.  Baseline characteristics were similar between groups. In the adalimumab group/placebo group the 12-month cumulative triamcinolone doses were 5.4/7.0 ml (p=0.08). Triple therapy was applied in 18/27 patients (p=0.17). At 12 months, DAS28CRP<3.2 was reached in 80%/76% (p=0.65) and DAS28CRP was 2.0 (1.7–5.2) (medians (5th/95th percentile ranges)), versus 2.6 (1.7–4.7) (p=0.009). Remission rates were: DAS28CRP<2.6: 74%/49%, Clinical Disease Activity Index≤2.8: 61%/41%, Simplified Disease Activity Index<3.3: 57%/37%, European League Against Rheumatism/American College of Rheumatology Boolean: 48%/30% (0.0008<p<0.014, number-needed-to-treat: 4.0–5.4). Twelve months HAQ, SF12PCS and EQ-5D improvements were most pronounced in the adalimumab group. Treatments were well tolerated.  Adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment did not increase the proportion of patients who reached the DAS28CRP<3.2 treatment target, but improved DAS28CRP, remission rates, function and quality of life in DMARD-naïve ERA.

title: Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomised CONCERTO trial
abstract: CONCERTO was a randomised, double-blind, parallel-armed study of methotrexate (MTX) in combination with adalimumab to assess whether an increasing trend of efficacy and decreased safety exists when increasing MTX dose in patients with early rheumatoid arthritis (RA).  Early, biologic and MTX-naive RA patients (N=395) were evenly randomised to open-label adalimumab (40 mg every other week) plus weekly blinded 2.5, 5, 10 or 20 mg MTX for 26 weeks. Clinical, radiographic and functional outcomes were analysed using two-sided linear trend tests or one-way analysis of covariance.  Statistically significant increasing trends were observed in the proportion of patients achieving the primary endpoint, 28-joint count disease activity score with C reactive protein (DAS28(CRP)) <3.2 (42.9%, 44.0%, 56.6% and 60.2% for 2.5, 5, 10 or 20 mg/week MTX, respectively), DAS28(CRP) <2.6 and American College of Rheumatology 50/70/90 responses with increasing doses of MTX in combination with adalimumab. No statistical differences in minimal clinically important differences in physical function were detected. Statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose by validated clinical indices; differences comparing 10 and 20 mg MTX were minimal. Adalimumab serum concentrations increased with ascending dose up to 10 mg MTX. More patients experienced infectious adverse events with increasing MTX dose.  Increasing doses of MTX in combination with adalimumab demonstrated a statistically significant trend in improved clinical outcomes that mimicked the adalimumab pharmacokinetic profile. In early RA patients initiating adalimumab combination therapy, efficacy of 10 and 20 mg/week MTX appeared equivalent.

title: Etanercept therapy allows the tapering of methotrexate and sustained clinical responses in patients with moderate to severe psoriasis
abstract: Methotrexate, the most common systemic small molecule used in the treatment of moderate to severe psoriasis, is associated with significant toxicities and adverse events. Long‐term continuous usage is not recommended due to potential liver toxicity, myelosuppression, and other side effects. Abrupt cessation of methotrexate without tapering can lead to flare‐up and rebound of psoriasis. Here we describe sustained clinical responses in 6 patients with psoriasis following gradual cessation of methotrexate through the addition of etanercept therapy.

title: Etanercept for the treatment of psoriasis: combination therapy with other modalities.
abstract: Etanercept is a self-administered medication that has FDA approval for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Etanercept is a human fusion protein of the tumor necrosis factor receptor (TNFR) and the Fc region of IgG1 that binds to and presumably inhibits the pro-inflammatory and pro-proliferative activity of the tumor necrosis factor (TNF). A recent multisite, randomized, double-blind, placebo-controlled study conclusively demonstrates that etanercept as monotherapy effectively treats patients with moderate-to-severe plaque psoriasis. This effect is dose-responsive, with the etanercept 50 mg twice-weekly dose significantly more effective than the 25 mg twice-weekly dose in reducing the Psoriasis Area and Severity Index (PASI) score over both 12 and 24 weeks of continuous therapy. Nevertheless, clinical trials do not instruct the dermatologist on how to practically integrate etanercept into a patient's pre-existing treatment regimen. Many psoriasis patients are already on other systemic therapies or have a medical history that necessitates a tailored approach to their therapy. Further, in some patients, etanercept at 25 mg twice weekly is ineffective in maximally clearing a patient of psoriasis. Below are cases that demonstrate how etanercept can be combined with other medications in order to both maximize clinical efficacy and minimize potential risk.

title: Etanercept for severe psoriasis and psoriatic arthritis: observations on combination therapy
abstract: The antitumour necrosis factor (TNF) activity of etanercept has been utilized to generate an important and novel treatment for rheumatoid arthritis. TNF has also been implicated in the pathogenesis of psoriasis. 
 
 
 
Objectives To determine whether blockade of TNF activity by etanercept may provide an additional treatment option for patients with psoriasis. 
 
 
 
Methods In an uncontrolled trial, etanercept was added to the treatment regimen in six patients with severe recalcitrant psoriasis (three also with psoriatic arthritis) partially resistant to other ongoing systemic agents. 
 
 
 
Results In each case, the disease activity showed marked improvement on addition of etanercept therapy. No added toxicity was found with etanercept. 
 
 
 
Etanercept appears to be a promising immunomodulatory agent that can be used in combination therapy for the treatment of psoriasis, and a prospective controlled trial may be warranted.

title: The added therapeutic efficacy and safety of alefacept in combination with other (systemic) anti‐psoriatics in refractory psoriasis
abstract: Alefacept is a biologic treatment for psoriasis, with a selective effect on memory effector T cells. Few data are available on the combination of alefacept with either topical or systemic anti‐psoriatics. We studied the effect of alefacept combination treatment on clinical disease severity scores and on circulating T‐cell subsets.  Twelve patients with moderate‐to‐severe psoriasis were included and treated with alefacept for a period of 12 weeks. Patients were allowed to continue the anti‐psoriatic therapies they used prior to the study. Severity of disease and expression of T‐cell markers CD4, CD8, CD45RA, CD45RO, CD94, CD161, CD25, and CLA were assessed at baseline and after treatment.  Seven of 12 included patients used a concomitant systemic therapy: either methotrexate (n = 4), acitretin (n = 2) or cyclosporine (n = 1). PASI reductions in this group after 12 and 24 weeks were 40% and 55%, respectively. Several lymphocyte subsets showed a reduction in circulating numbers. These decreases were independent of the use of an additional systemic psoriasis therapy.  The concomitant use of systemic anti‐psoriatic medication in combination with alefacept has a noteworthy impact on efficacy results. No differences in circulating psoriasis‐relevant T‐cell populations between patients with or without an additional systemic treatment were seen.

title: A multicenter, open‐label study of repeat courses of intramuscular alefacept in combination with other psoriasis therapies in patients with chronic plaque psoriasis
abstract: To evaluate the safety and efficacy of multiple courses of alefacept in combination with traditional psoriasis therapy for the treatment of chronic plaque psoriasis (CPP).  Patients with CPP requiring systemic therapy were eligible for this study. Patients received up to three courses of intramuscular alefacept 15 mg once weekly for 12 weeks. One concomitant psoriasis therapy (topical agents, methotrexate, cyclosporine, systemic retinoids, or ultraviolet B [UVB]) per course was allowed. The extent of disease was determined using the 7‐point Physician Global Assessment (PGA; scale ranging from 0 = clear to 6 = severe).  More than 73% of patients improved by ⩾ one PGA category and ⩾44% of patients improved by ⩾ two PGA categories across all concomitant treatments. Clinical responses tended to be greatest in patients who received alefacept plus UVB. The incidences of serious infections (⩽1%) and malignancies (⩽2%) were low across all courses and all combinations.  Multiple courses of alefacept appear to be well tolerated and demonstrate efficacy in patients with CPP when administered with other psoriasis therapies.

title: Successful treatment of severe recalcitrant psoriasis with combination infliximab and methotrexate
abstract: Plaques of psoriasis contain increased levels of cytokines, including tumour necrosis factor‐alpha (TNF‐α), which are thought to be essential to the maintenance of the psoriatic process. We report the successful treatment of severe, recalcitrant psoriasis when infliximab (a monoclonal antibody to TNF‐α) was used in combination with methotrexate.

title: Infliximab, as sole or combined therapy, induces rapid clearing of erythrodermic psoriasis
abstract: but only HPV 72 was present in biopsies of the flat leucoplakic dysplastic lesions. This finding might indicate a particular preference of HPV 72 for the induction of oral mucosa dysplasias. Long-term follow-up of HIV-infected patients could provide more insights in the natural behaviour and clinical course of oral HPV infection. In general practice, screening programmes for HPV-related diseases in HIV-positive individuals should include both the anogenital area (using highresolution anoscopy) and the oral cavity (inspection with the naked eye).

title: Biologic therapies for psoriasis: practical experience in a U.K. tertiary referral centre
abstract: Large‐scale clinical trials provide clear evidence of the efficacy and short‐term toxicity of biologic therapies for psoriasis. However, to date, there are few reports of the practical use of these therapies outside of the trial setting and, to our knowledge, none from a U.K. cohort of patients with psoriasis.

title: Infliximab for the treatment of psoriasis in the U.K.: 9 years’ experience of infusion reactions at a single centre
abstract: Infliximab is an antitumour necrosis factor‐α chimeric monoclonal antibody that is an established treatment for severe chronic plaque psoriasis. The recommended administration of a 2‐h infusion followed by 2 h of monitoring is practised due to the potential occurrence of infusion reactions. However, accelerated infusions and shortened monitoring periods are used in patients with rheumatological disorders and inflammatory bowel disease without an increase in adverse events.

title: Infliximab treatment for psoriasis in 120 patients on therapy for a minimum of one year: a review.
abstract: Infliximab is a chimeric monoclonal antibody, which acts by binding to both the soluble and membrane-bound tumor necrosis factor-?. In clinical practice, it is used as either monotherapy or in combination with other systemic therapies, particularly methotrexate. This study reviews clinical response and adverse events in 120 psoriasis patients with moderate-to-severe psoriasis who have received infliximab for a minimum of one year. The medical records of 120 infliximab-treated psoriasis patients at our referral psoriasis clinic in Dallas between 2002-2008 were reviewed for response rates, side effects and concomitant therapies. Of 120 charts reviewed, 112 (93%) patients had plaque type psoriasis, six (5%) had recalcitrant palmoplantar disease and two (1.6%) had severe acropustulosis of Hallopeau. Eighty-four (70%) patients had symptomatic psoriatic arthritis. The mean follow-up time was 2.2±1.1 years. One hundred and nine (91%) of the 120 patients had clearance of their psoriasis (response of more than 90% of initial BSA) at a median time of 12 weeks. Concomitant systemic treatments, primarily methotrexate, were given to 62 (52%) patients. Nineteen patients (16%) discontinued infliximab in the post-one-year treatment period for a variety of reasons, primarily failure to maintain adequate response. One hundred and four (87%) of patients required more than the standard dose of 5 mg/kg every eight weeks to maintain clearance. Infliximab either as monotherapy or in combination with traditional antipsoriatic agents is an effective and well-tolerated treatment option for patients with moderate to severe psoriasis and psoriatic arthritis on therapy for over one year and continuing for the long term.

title: Effectiveness of adalimumab dose escalation, combination therapy of adalimumab with methotrexate, or both in patients with psoriasis in daily practice
abstract: To increase effectiveness of standard adalimumab treatment 40 mg every other week (EOW) for patients with psoriasis, dose escalation to 40 mg every week or addition of methotrexate (MTX) are possible strategies.  Daily practice data about adalimumab treatment were extracted from a prospective observational cohort. We analyzed all patients with insufficient efficacy of adalimumab EOW who received 1) adalimumab dose escalation, 2) addition of MTX to adalimumab EOW, or 3) both. Effectiveness was analyzed after 12 and 24 weeks using PASI50, PASI75, and mean differences in PASI.  Forty-seven treatment episodes (TE) of adalimumab dose escalations, 11 of MTX addition and six combinations were analyzed. After a first episode of adalimumab dose escalation, 25% and 35% achieved PASI50 after 12 and 24 weeks, respectively. After MTX introduction to adalimumab EOW, 9% and 18% achieved PASI50 after 12 and 24 weeks, respectively. No related serious adverse events were reported. Twenty-five percent of first TE with adalimumab dose escalation induced a PASI50 response after 12 weeks and 35% after 24 weeks. Addition of MTX to adalimumab EOW resulted in PASI50 in 9% after 12 weeks and 18% after 24 weeks. Defining patient-groups that will benefit from these interventions is important.

title: Adalimumab or Cyclosporine as Monotherapy and in Combination in Severe Psoriatic Arthritis: Results from a Prospective 12-month Nonrandomized Unblinded Clinical Trial
abstract: To assess the efficacy and safety of adalimumab or cyclosporine (CYC) as monotherapy or combination therapy for patients with active psoriatic arthritis (PsA), despite methotrexate (MTX) therapy.  A prospective 12-month, nonrandomized, unblinded clinical trial of 57, 58, and 55 patients who received CYC (2.5–3.75 mg/kg/day), adalimumab (40 mg every other week), or combination, respectively. Lowering of concomitant nonsteroidal antiinflammatory drugs (NSAID) and corticosteroids and reductions of adalimumab and/or CYC doses in responding patients were not restricted.  Mean numbers of tender/swollen joints at baseline were 9.7/6.7 in CYC-treated, 13.0/7.8 in adalimumab-treated, and 14.5/9.4 in combination-treated patients, indicating lesser disease severity of patients assigned to the first group. The Psoriatic Arthritis Response Criteria at 12 months were met by 65% of CYC-treated (p = 0.0003 in favor of combination treatment), 85% of adalimumab-treated (p = 0.15 vs combination treatment), and 95% of combination-treated patients, while the American College of Rheumatology-50 response rates were 36%, 69%, and 87%, respectively (p < 0.0001 and p = 0.03 in favor of combination treatment). A significantly greater mean improvement in Health Assessment Questionnaire Disability Index was achieved by combination treatment (−1.11) vs CYC (−0.41) or adalimumab alone (−0.85). Combination therapy significantly improved Psoriasis Area and Severity Index-50 response rates beyond adalimumab, but not beyond the effect of CYC monotherapy. Doses of NSAID and corticosteroids were reduced in combination-treated patients; CYC doses and frequency of adalimumab injections were also reduced in 51% and 10% of them, respectively. No new safety signals were observed.  The combination of adalimumab and CYC is safe and seemed to produce major improvement in both clinical and serological variables in patients with severely active PsA and inadequate response to MTX.

title: A clinical trial of combination therapy with etanercept and low dose cyclosporine for the treatment of refractory psoriasis.
abstract: Over the past decade, combination therapies have become a mainstay of dermatologic care in psoriasis. Combination therapies are often more effective and safer than large dose single-agent therapies. With the emergence of new biologic therapies, dermatologists now have a wider array of tools to treat psoriasis. Although much data exists regarding cyclosporine or biologic agents alone for psoriasis, little is known about the efficacy, safety and tolerability of combination regimens.



We designed a study to evaluate the efficacy and safety of etanercept and cyclosporin combination therapy in patients with refractory psoriasis.



We administered oral cyclosporine (200 mg daily) and subcutaneous etanercept 50 mg weekly injections until symptoms improved, then maintained treatment at a reduced dose. Seven patients with refractory psoriasis were evaluated 4 weekly.



All 7 patients showed rapid responses to combination therapy. Mean Psoriasis Area and Severity Index reductions following conditioning therapy (mean: 6.85 weeks) and maintenance therapy (mean: 56.5 weeks) were 94.9% and 93.2%, respectively.



Etanercept and low-dose cyclosporine combination therapy appears to be a safe and efficacious alternative treatment strategy for patients with refractory psoriasis. The combination induced rapid improvement in patients with refractory psoriasis and dramatically improved their quality of life. Clinical studies including larger patient cohort are required to validate the safety and efficacy of this combination therapy.

title: Efficacy of Short-Term Cyclosporine Treatment to Control Psoriasis-Related Events during Efalizumab Therapy
abstract: Efalizumab is a recombinant humanized anti-CD11a monoclonal antibody that blocks the activation, adhesion and trafficking of T cells and has been approved for the treatment of moderate-to-severe plaque psoriasis. To document management of the fluctuations in symptom control that patients with psoriasis sometimes experience during treatment, we performed a retrospective analysis of our experience using cyclosporine as an intercurrent treatment to control psoriasis-related adverse events (AEs) in 10 patients who had received continuous efalizumab therapy for 20–200 weeks prior to recurrence of symptoms. Combination therapy with cyclosporine and efalizumab was generally well tolerated and controlled the relapse effectively. There were no reports of severe AEs during combination treatment, and no clinically significant changes were noted in clinical and laboratory values. Although mild, localized psoriasis recurred in most of these patients after cyclosporine termination, no patient experienced rebound or psoriasis flare and all continued with long-term efalizumab treatment.

title: Risk of cancer in psoriasis: a systematic review and meta‐analysis of epidemiological studies
abstract: The relationship between psoriasis and increased cancer risk is debated.

title: The increased risk of skin cancer is persistent after discontinuation of psoralen+ultraviolet A: a cohort study.
abstract: A-treated psoriasis patients are at increased risk for nonmelanoma skin cancer. To assess the persistence of cancer risk among patients who have discontinued psoralen+ultraviolet A and the risk of a first tumor with the passage of time, we prospectively studied the incidence in a cohort of 1,380 psoriasis patients treated with psoralen+ultraviolet A. We observed a total of 27,840 person-years of which 59.4% were considered years without psoralen+ultraviolet. No significant decrease in risk was noted during the first 15 years after psoralen+ultraviolet A was discontinued. Subsequently, the risk of squamous cell carcinoma was reduced (incidence rate ratio=0.79; 95%CI=0.62, 1.01 on treatment vs >15 years off). After 25 years, about 7% of patients with < or =200 psoralen+ultraviolet A treatments and more than half of the patients with > or =400 treatments develop at least one squamous cell carcinoma. After 25 years, almost one third of the patients exposed to > or =200 treatments developed at least one basal cell carcinoma. In conclusion, substantial exposure to psoralen+ultraviolet A dramatically increases the risk of nonmelanoma skin cancer and prior exposure to psoralen+ultraviolet A remains an important issue in the management of patients because the cancer risk associated with psoralen+ultraviolet A is persistent.

title: Novel combination regimens: Biologics and acitretin for the treatment of psoriasis – a case series
abstract: Combination therapy has long been a mainstay of psoriasis treatment, particularly for those that suffer from moderate-to-severe disease. The biologics represent a new and exciting approach to psoriasis treatment though their use in combination regimens has not been adequately examined. This brief series reports on the combination of biologics with acitretin in the treatment of psoriasis.

title: When there is no single best biological agent: psoriasis and psoriatic arthritis in the same patient responding to two different biological agents
abstract: Guidelines and treatment strategies for the new biological agents have been developed, but dermatologists continue to face difficulties in adopting these guidelines into their daily practices. We report a patient with psoriasis and psoriatic arthritis whose skin lesions responded only to efalizumab, and the arthritis to etanercept. This case shows that different biological agents may achieve different success rates even in the same patient. Each biological agent offers different advantages and disadvantages, which sometimes make it difficult to choose the single best agent for a patient. Psoriasis often becomes one of the most difficult diseases to treat and does not respond to any single antipsoriatic agent. Perhaps in the future, rotational or combination treatment with different biological treatments will be used.

title: Combining systemic retinoids with biologic agents for moderate to severe psoriasis
abstract: Moderate to severe psoriasis, which is defined as psoriasis affecting more than 20% of the body surface area, often requires a combination of therapies to achieve remission. Although numerous data exist regarding the use of acitretin and biologic agent therapy alone for psoriasis, little is known about the efficacy, safety, and tolerability of acitretin combined with biologic agents.

title: Combination of efalizumab and acitretin in chronic plaque psoriasis
abstract: 1 Formigon M, Alsina MM, Mascaro JM, Rivera F. Becker’s nevus and ipsilateral breast hypoplasia – androgen-receptor study in two patients.  Genet 1997; 68: 357–361. 6 Agrawal S, Garg VK, Sah SP, Agarwalla A. Acne in Becker’s nevus.

title: Combination treatment with a tumour necrosis factor antagonist and an oral retinoid: efficacy in severe acral psoriasis?
abstract: A . FU J IMOTO , 5 Y . SH IMOMURA Laboratory of Genetic Skin Diseases, and Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan Departments of Dermatology, and Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut, Lebanon Jordan University of Science and Technology, Irbid, Jordan Correspondence: Yutaka Shimomura.  yshimo@med.niigata-u.ac.jp

title: Refractory generalized pustular psoriasis responsive to a combination of adalimumab and acitretin
abstract: combination of adalimumab and acitretin Editor, Generalized pustular psoriasis is a distinctive rare variant of psoriasis which may become complicated by systemic alterations. Its management causes some difficulties, despite the availability of new modes of treatment with biologic therapy. The combination of biologics with acitretin has already been described for the treatment of moderate-to-severe plaque psoriasis but not for pustular psoriasis. We report a patient with generalized pustular psoriasis resistant to systemic conventional and biologic therapy, treated successfully with adalimumab in combination with acitretin. A 21-year-old woman presented with a 14-year history of pustular eruptions arising on an erythematous skin associated with scaly erythematous plaques; this was diagnosed clinically and histologically as pustular psoriasis. The patient had suffered an icthyosiform dermatitis during early childhood but was otherwise healthy. She had initially been treated with topical agents and intermittent courses of oral acitretin (0.5–1.0 mg/kg/d) since October 1994. In January 2004, the patient developed an acute severe thrombocytopenia that led to acitretin interruption, although the causal relationship with the drug was unclear. The patient then experienced a flare in psoriasis accompanied by fever and general malaise. Over the following four years, she was treated with different drugs as monotherapy or in combination. Firstly, treatment with oral intermittent cycles of cyclosporin (3 mg/kg/d) was ineffective. Then, acitretin monotherapy was restarted (50 mg/d), but achieved only a partial improvement with no side effects. Psoralen combined with ultraviolet A (PUVA) therapy was administered with acitretin for 12 weeks for a total dose of 37.5 J/cm and achieved a partial response. During a second cycle of PUVA therapy, after two doses of 2.0 J/cm and 2.5 J/cm, the patient developed a severe generalized pustular flare of psoriasis and required hospitalization . Oral methotrexate (20 mg/week) was started, but new episodes of malaise and disseminated cutaneous lesions proved this to be unsuccessful. Intravenous infusions of infliximab (6 mg/kg) were added to methotrexate. The patient presented an increase in transaminase levels, and methotrexate was substituted by acitretin. This combination facilitated a remarkable improvement in the patient’s psoriasis, achieving almost complete clearance of the lesions, but the effectiveness of the therapy decreased progressively and relapses occurred. Infliximab was then substituted by subcutaneous adalimumab (80 mg at baseline, 40 mg at week 1, and then 40 mg every two weeks), which, in combination with acitretin (50 mg/d), achieved a dramatic improvement in the skin lesions . After 11 months of continuous treatment, the patient’s psoriasis remains well controlled despite the progressive reduction of the acitretin dose (to 30 mg/d). The combination of acitretin with a biologic agent represents, in some cases, a unique approach in the Figure 1 Severe pustular generalized flare requiring hospitalization

title: A randomized study comparing the combination of nbUVB and etanercept to etanercept monotherapy in patients with psoriasis who do not exhibit an excellent response after 12 weeks of etanercept
abstract: There is a lack of data on the combination of phototherapy with etanercept in patients who have not shown an excellent response to etanercept monotherapy.  To study the combination of narrow-band ultraviolet B (nbUVB) phototherapy with etanercept in patients not demonstrating an improvement of 90% in their Psoriasis Area Severity Index (PASI-90) after 12 weeks of etanercept.  Psoriatic patients not reaching PASI-90 after 12 weeks of etanercept therapy were randomized (1:1) to receive either etanercept (50 mg once a week) monotherapy or in combination with nbUVB three times weekly for periods of 4 weeks.  Seventy-five patients were randomized. Only 21.6% of patients achieved adherence of 80% or more for nbUVB treatments. At week 24, PASI-90 was reached by 16.2% of patients in the etanercept plus nbUVB group when compared with 15.8% of patients in the etanercept monotherapy group (p = 1.000). In patients with high adherence to nbUVB, the PASI-90 at week 16 was 42.9% for etanercept with nbUVB when compared with 3.4% for etanercept monotherapy (p = 0.018). Both treatments were well tolerated.  Addition of nbUVB after 12 weeks of etanercept did not significantly improve the clinical response except for a subset of patients with high adherence to nbUVB.Clinical Trials Registration number: NCT00640393.

title: Utilization of narrow-band ultraviolet light B therapy and etanercept for the treatment of psoriasis (UNITE): efficacy, safety, and patient-reported outcomes.
abstract: Moderate to severe psoriasis is a significant inflammatory disease that frequently requires systemic therapies to effectively treat the underlying disorder. Etanercept and narrow-band ultraviolet light B (NB-UVB) are widely used to treat this disease.



To evaluate the effectiveness, tolerability, and patient-reported outcomes of combination etanercept plus NB-UVB phototherapy in moderate to severe plaque psoriasis.



This 12-week, single-arm, open-label study evaluated the combination of etanercept 50 mg twice weekly and NB-UVB thrice weekly in 86 patients. The primary outcome measure was > or =75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75). Other measures included PASI 90, PASI 100, and the Dermatology Life Quality Index (DLQI).



At week 12, 26.0% achieved PASI 100, 58.1% achieved PASI 90, and 84.9% of patients achieved PASI 75. Mean improvement from baseline in DLQI was 84.4%. No unexpected, untoward adverse events were noted.



A 12-week course of etanercept plus NB-UVB phototherapy was well tolerated and produced clinically meaningful improvements in signs and symptoms of moderate to severe plaque psoriasis and in patient-reported outcomes. Further investigation of the safety and efficacy of the use of such combination for this indication in controlled clinical trials would be of interest.

title: Adalimumab plus narrowband ultraviolet B light phototherapy for the treatment of moderate to severe psoriasis.
abstract: Combining systemic agents with phototherapy is becoming a standard of care for patients with moderate to severe psoriasis. The combination of adalimumab and phototherapy has not been previously explored.



In this 24-week single-arm open-label study, adults with moderate to severe psoriasis received adalimumab 40 mg every other week and narrowband (NB)-UVB phototherapy three times a week for 12 weeks and then were followed for 12 weeks without treatment. Response to therapy was determined using the Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA) affected and Physician's Global Assessment (PGA) of psoriasis.



Twenty patients were enrolled with mean baseline scores of 17.0 for PASI, 21.2 for BSA and 3.5 for PGA. Half (10/20) of the patients achieved PASI 75 response by week 4. At the end of treatment at week 12, 19 (95%) patients achieved PASI-75, 15 (75%) patients achieved PASI-90 and 11 (55%) patients achieved PASI-100. Seventeen (85%) patients were clear or almost clear (PGA score =1). Mean baseline PASI, BSA and PGA scores improved by 95 percent, 93 percent and 80 percent, respectively. Disease improvement was observed through the end of follow up period at week 24. No serious adverse events were noted.



Concurrent use of adalimumab and NB-UVB phototherapy was clinically effective and well tolerated in patients with moderate to severe psoriasis. This combination regimen represents a new treatment option for clinical practice and warrants further investigation in controlled clinical trials.

title: Combined treatment with etanercept 50 mg once weekly and narrow-band ultraviolet B phototherapy in chronic plaque psoriasis.
abstract: The combination of etanercept, a tumour necrosis factor α inhibitor, with narrow-band ultraviolet B (NB-UVB) phototherapy has recently been reported to be effective in moderate-to-severe plaque psoriasis, yielding better results than either monotherapy. To assess the efficacy and safety of this combined treatment using the lower approved etanercept dosage. In this single-arm open-label study patients received etanercept 50 mg once weekly combined with NB-UVB phototherapy three times weekly for 8 weeks, followed by etanercept alone until week 12. We evaluated the proportion of patients achieving 75%, 90% and 100% improvement of their initial PASI score (PASI75, PASI90, and PASI100, respectively). Patients were 19 men and 14 women, mean age 48.3 years ± 12.1 standard deviation (SD) and mean baseline Psoriasis Area and Severity Index (PASI) score 22.5 ± 7.5. On treatment weeks 4, 8, and 12, 24.2%, 66.7%, and 81.8% of patients achieved PASI75; 8.0%, 15.1%, and 57.6% reached PASI90, and 0%, 6.0%, and 24.2% attained PASI100, respectively. There were no severe side effects. Low-dosage etanercept combined with NB-UVB phototherapy is an effective, safe and economical approach to treat moderate-to-severe plaque psoriasis. Further studies are clearly required to assess its long-term efficacy and safety.

title: Etanercept plus narrowband ultraviolet B phototherapy of psoriasis is more effective than etanercept monotherapy at 6 weeks
abstract: A substantial portion of patients with psoriasis does not achieve a satisfactory response under antitumour necrosis factor (TNF)‐α biological therapies.

title: Treatment with 311‐nm ultraviolet B accelerates and improves the clearance of psoriatic lesions in patients treated with etanercept
abstract: Some patients with plaque‐type psoriasis respond slowly to treatment with etanercept. In such cases combining etanercept with conventional treatments might be helpful.

title: 311 nm ultraviolet B‐accelerated response of psoriatic lesions in adalimumab‐treated patients
abstract: Treatment with the tumor necrosis factor‐alpha antibody adalimumab for 12–16 weeks produces a satisfactory response [i.e., 75% reduction in psoriasis area and severity index (PASI)] in a majority (70–80%) of patients with psoriasis. We asked whether 311 nm ultraviolet B (UVB) can improve therapeutic response of psoriatic lesions to adalimumab.

title: Treatment with 311‐nm ultraviolet B enhanced response of psoriatic lesions in ustekinumab‐treated patients: a randomized intraindividual trial
abstract: Treatment with the interleukin‐12/23 antibody ustekinumab produces a satisfactory response [i.e. 75% reduction in Psoriasis Area and Severity Index (PASI) compared with baseline (PASI 75)] in the majority of patients with moderate to severe chronic plaque‐type psoriasis.

title: Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2013 MauiDerm Meeting.
abstract: Psoriasis. There are 41 genetic susceptibility loci identified with considerable overlap to other autoimmune disorders. The pathogenesis of psoriasis involves the interplay between innate immune response and acquired immunity related to the interleukin (IL)-23 and Th17 pathway. New agents in Phase 3 trials include IL-17 and IL-17 receptor blockers (secukinumab, ixekizumab, brodalumab). 
 
So-called “third-generation” drugs for psoriasis include those that block proteins in the IL-23/Th17 pathway, including ustekinumab and those under development (tildrakizumab, guselkumab, secukinumab, ixekizumab, and brodalumab). Recent long-term safety data on ustekinumab report rates of adverse events lower or similar to those of other biologic agents. Phosphodiesterase-4 (PDE-4) inhibitors, such as apremilast, are in late-stage clinical trials. Additional new small-molecule therapy includes tofacitinib, a drug that blocks the Janus kinase (JAK) pathway, implicated in inflammation. Pharmacological therapy effective in treating psoriatic arthritis can be used to treat skin psoriasis, but with varying levels of effectiveness and tolerability. Indeed, dermatologists may be able to leverage the use of a variety of drugs used for other rheumatologic conditions to treat psoriasis (and vice versa). 
 
In 1997, the World Health Organization (WHO) declared that obesity was a global epidemic and, this year, in 2013, the American Medical Association has classified obesity as a disease. Obesity affects about 500 million adults globally; in the United States, about 30 to 35 percent of the population is obese. Obesity is comorbid with many heath conditions, including, but not limited to, osteoarthritis, obstructive sleep apnea, diabetes, cardiovascular disease, and other diseases associated with chronic inflammation. This chronic inflammation may play a role in psoriasis and may explain why obese individuals have lower response rates to certain psoriasis therapies, such as occurred in the PSUMMIT1 trial. Given the prevalence of obesity, the connection between obesity and psoriasis will be an important clinical focus in the future. 
 
Recent investigations and meta-analyses confirm the association between psoriasis and diabetes mellitus type 2 along with other cardiovascular risk factors, such as hypertension, hyperlipidemia, and coronary artery disease. These diseases may share certain genetic susceptibility. However, it cannot be overlooked that the psoriasis population has a higher rate of independent risk factors for heart disease, such as smoking, alcohol misuse, and obesity. The so-called “psoriatic march” suggests that psoriasis drives heart disease. However, an older retrospective Veterans Affairs (VA) study suggests that reducing chronic inflammation via methotrexate may reduce cardiovascular risk as well as treat psoriasis. More recently, studies have shown that biologic use is also associated with fewer cardiovascular events over time. 
 
Cutaneous oncology. Mohs micrographic surgery remains an important mainstay in dermatology although not every patient with basal cell carcinoma should be considered a candidate. The risks associated with Mohs surgery can be highly individual, depending on the location of the cancer, the nature of the tumor, and whether or not the patient is immunosuppressed. 
 
Prevalent and challenging to treat, squamous cell carcinoma requires careful evaluation and a detailed personalized care plan for optimal outcomes. The location of the tumor, the depth of the invasion, and whether or not perineural invasion has occurred may significantly impact surgical success. Immunosuppressed patients are at greater risk of metastases. When the tumor and location are high risk, adjunct radiation therapy may be indicated.