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  February 2012: Volume 3, Issue 5

Psoriasis: Phototherapy in the Era of Biologic Agents

In this Issue...


With the arrival of biologic therapies, treatment algorithms for patients with psoriasis have evolved and dermatologists must now incorporate the biologics among traditional systemic treatments, including phototherapy. Early publications on the safety of biologic therapy focused on clinical, short-term adverse effects. As the longer-term knowledge base on these agents broadens, however, safety issues are being identified with respect to skin cancer and the possible role played by biologics in carcinogenesis. Both efficacy and cost-effectiveness must be considered by dermatologists as they make therapeutic decisions while, at the same time, keeping their patients' and society's best interests in mind.

In this issue, we review recent safety, efficacy, and financial issues regarding the use of systemic psoriasis treatments, specifically the biologics and phototherapy.
   LEARNING OBJECTIVES
  After participating in this activity, the participant will demonstrate the ability to:

  Describe the evolving trends in treatment combinations with light therapy plus biologics, using narrowband ultraviolet B (NB-UVB) phototherapy and etanercept as a model
  Discuss emerging safety and financial issues regarding the use of phototherapy and/or biologics for the treatment of psoriasis
  Articulate the real-world efficacy of psoralen plus ultraviolet A (PUVA) therapy vs biologic agents for the treatment of psoriasis
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This program launched on October 11, 2011 and is published bi-monthly; activities expire 2 years from the date of publication.

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As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of financial relationships with industry from any individual in a position to control the content of a CME activity sponsored by OCME. Members of the Planning Committee are required to disclose all relationships regardless of their relevance to the content of the activity. The Program Directors reported the following:
Susan Matra Rabizadeh, MD, MBA discloses that she serves on the advisory board and is receiving an honorarium from Allergan.
Mark Lebwohl, MD discloses that he has received grants for clinical research from Can-Fite Biopharma and Clinuvel. He also disclosed that he has worked as a consultant for and receiving honorarium from Abgenomics, Allos, Amgen, Astellas, DermaGenoma, DermiPsor, Ethicon, Genentech, GlaxoSmithKline-Stiefel, Glenmark Pharmaceuticals, HelixBioMedix, Janssen Ortho Biotech, LEO Pharmaceuticals, Novartis, Nycomed, Onset Therapeutics, Pfizer, Valeant Pharmaceuticals.
No other planners have indicated that they have any financial interests or relationships with a commercial entity.
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This activity has been developed for dermatologists, nurses, dermasurgeons, dermatopathologists, pediatric dermatologists, Immunodermatologists, wound care specialists and allied healthcare providers.
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   IN THIS ISSUE
  COMMENTARY from our Guest Authors
  Phototherapy Plus Biologics: How Safe Is the Combination?
  Etanercept Plus NB-UVB: An Evolving Model of Combination Therapy
  Cost-Effectiveness of Therapies for Moderate to Severe Psoriasis
  Biologics vs PUVA: A Comparison of Real-World Efficacy
 Program Directors

Bernard A. Cohen, MD
Professor of Pediatrics and Dermatology and Director of Pediatric Dermatology,
Johns Hopkins Children’s Center
Baltimore, MD

Susan Matra Rabizadeh, MD, MBA
Department of Dermatology
Cedars-Sinai Medical Group
Beverly Hills, CA

Mark Lebwohl, MD
Professor and Chairman
Department of Dermatology
The Mount Sinai School of Medicine
New York, NY

Elizabeth Sloand, PhD, CRNP
Assistant Professor of Pediatric Nursing
The Johns Hopkins University
School of Nursing
Baltimore, MD
   GUEST AUTHORS OF THE MONTH
 Commentary & Reviews:
Warwick L. Morison, MD
Professor of Dermatology
The Johns Hopkins University School of Medicine
Baltimore, Maryland

Elisabeth G. Richard, MD
Assistant Professor of Dermatology
The Johns Hopkins University School of Medicine
Baltimore, Maryland

 Guest Faculty Disclosures

Elisabeth G. Richard, MD discloses that she has no financial relationship with commercial supporters.

Warwick L. Morison, MD discloses that he is a consultant for Photomedex.


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The authors have indicated there will be no references to unlabeled or unapproved uses of drugs or products in this presentation.

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Length of Activity
1 hour
1 contact hour Nurses

Release Date

February 14, 2012

Expiration Date

February 13, 2014



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   COMMENTARY

Psoriasis is a chronic, inflammatory skin condition, affecting approximately 2% of the world's population.1 Among individuals with psoriasis, 25% can be classified as having a moderate (3% to 10% body surface area [BSA]) to severe (>10% BSA) level of disease. Psoriasis is the most common autoimmune disease in the United States.2 Systemic therapy, which is the core of moderate to severe psoriasis treatments, includes phototherapy (UVB and PUVA), methotrexate, oral retinoids, cyclosporine, and the newer biologic agents. Current biologics include tumor necrosis factor alpha (TNF-α) inhibitors (adalimumab, etanercept, infliximab); interleukin (IL)12/23 inhibitors (ustekinumab); and T-cell blockers (alefacept).

With the advent of the biologics, the therapeutic algorithm has evolved and dermatologists must embrace new combinations of treatments that use biologics plus traditional systemic therapy, including phototherapy. The concerns over adverse reactions associated with traditional therapies, including hepatotoxicity, nephrotoxicity, and skin cancer, have become even more complex. With the biologic agents, clinicians must also now consider infections, autoimmune disorders, demyelinating diseases, and the risk for malignancy.3,4 Since the overall treatment costs and financial burden to both the patient and society cannot be ignored, economics also becomes a factor in clinical decision making and cannot be overlooked.

Etanercept was the first biologic approved for use in the psoriatic spectrum of disease, receiving US Food and Drug Administration (FDA) approval in 2002 for the treatment of psoriatic arthritis. The agent was initially approved for the treatment of rheumatoid arthritis (RA) in 1998. Likewise, infliximab was approved for the treatment of Crohn's disease in 1998.

Combination therapy has long been used for psoriasis, with the advent of etanercept and other biologic agents ushering in a new era of disease treatment. Concerns about safety, both short-term and long-term, naturally ensued.5 In the years since the approval of biologic therapies, more data have emerged, generating information about long-term effects, including safety. Key studies include Wolfe and Michaud's 2007 report in the rheumatology literature.6 Their analysis of a US database of patients with RA revealed that across all biologic therapies, treatment was associated with an increased risk for skin cancer, but not for solid tumors or lymphoproliferative malignancies. Although the mechanism of action has yet to clarified, such recent studies as that by Gambichler and colleagues, reviewed in this issue, 7 are beginning to shed light on this evolving story. Likewise, Faurschou and associates examined infliximab and inhibition of DNA repair in UVB-irradiated premalignant keratinocytes, concluding that infliximab may contribute to the accumulation of mutagenic changes in DNA and thus enhance skin carcinogenesis.8

In the 3 years between the reports by Kircik and coworkers9 and Gambichler and collaborators,10 safety concerns over combinations of biologics and NB-UVB phototherapy are being raised. In 2008, safety issues surrounding the use of etanercept plus NB-UVB were addressed in a more global fashion in a study by Kircik and colleagues.9 By 2011, Gambichler and associates included in their discussion more guarded recommendations on this combination, encouraging the therapy as a "bridge" and using NB-UVB as an adjuvant to enhance the efficacy of etanercept. The authors acknowledged the data on TNF-α inhibitors and risk for skin cancer, as well as the need for more long-term safety data.10

Another reality to be considered with the use of biologic agents is the economic factor. As health care costs spiral upwards, efforts to address cost-effectiveness are critical. Staidle and coworkers conducted a pharmacoeconomic analysis that addressed this issue, concluding that phototherapy and methotrexate are the most cost-effective systemic therapies for persons with psoriasis.11 A recent study from the United Kingdom confirmed that total health care costs associated with the use of biologic agents for the treatment of severe psoriasis are significantly higher than those with the use of traditional therapy.12 Studies such as these verify the inherently obvious: Biologics are more expensive and are driving the rising costs of psoriasis therapy.13 Additional factors to consider include the financial implications of treatment, as well as the duration of remission associated with an individual treatment. A 2010 comparison of psoriasis treatment costs estimated the cost of PUVA to be between $3347 and $4235 per year, whereas the annual cost of infliximab ranged between $20,717 and $23,639.13 Infliximab costs 5 to 7 times more than a course of PUVA and is equally effective. Another consideration to bear in mind is that among the systemic therapies for psoriasis, only 2 have been shown to induce a durable remission of >6 months—PUVA and alefacept.15,16

Human nature often leads us to believe that "new" is better than "old." In their study reviewed below, Inzinger and collaborators undertook a direct comparison of the "new"—biologic therapy—with the "old"—PUVA therapy—for the treatment of moderate to severe psoriasis.14 Using Psoriasis Area and Severity Index (PASI) scores, the authors found that a course of PUVA was more effective than 3 of the biologics evaluated, similarly effective to 2 of the biologics, and equally as effective as infliximab.

There are other issues to consider as well. PUVA therapy is associated with skin cancer and photoaging of the skin, particularly in persons with Fitzpatrick skin types I and II. In individuals with Fitzpatrick skin type III, the risk is probably small, and in those with higher Fitzpatrick skin types (IV to VI), the risk is probably nonexistent. NB-UVB phototherapy has not been associated with either photoaging or skin cancer, but that may be attributable to the paucity of good long-term studies. Patient convenience is another consideration when evaluating psoriasis treatments. Since phototherapy is time-consuming and is not always geographically available, infrequent injections of a biologic agent can be an attractive alternative.

Phototherapy will not be replaced by the biologics. A valid role remains for the treatment of psoriasis, let alone the myriad of other dermatologic conditions that are treated with the use of UV light. From atopic dermatitis to sclerosing skin diseases, from vitiligo to cutaneous T-cell lymphoma, phototherapy remains a mainstay of treatment for many dermatologic disorders.17 Additionally, not every patient is a candidate for biologic therapy. The treatment of psoriasis in pregnant women and in children can be a therapeutic challenge, and phototherapy remains a valid modality.

From safety to cost to efficacy, clinicians must consider multiple factors when selecting a psoriasis therapy in the age of biologics. It is an evolving picture, with each new study yielding more details to bear in mind. Phototherapy will most certainly remain a key player in the treatment algorithm for patients with moderate to severe psoriasis. If one looks at methotrexate as an example, although it is an "older," traditional therapy, the agent continues to be a valid and widely used option today. Phototherapy is still considered a useful therapeutic option in current dermatologic practice and care of patients with psoriasis, even in the age of biologics.

Commentary References

1. Schön MP, Boehncke W-H. Psoriasis. N Engl J Med. 2005;352(18):1899-1912.
2. National Psoriasis Foundation. About psoriasis. http://psoriasis.org/about-psoriasis. Accessed January 6, 2012.
3. Heffernan M. Combining traditional systemic and biologic therapies for psoriasis. Semin Cutan Med Surg. 2010;29(1):67-69.
4. Cather JC, Menter A. Combining traditional agents and biologics for the treatment of psoriasis. Semin Cutan Med Surg. 2005;24(1):37-45.
5. Lebwohl M. Combining the new biologic agents with our current psoriasis armamentarium. J Am Acad Dermatol. 2003;49(2 suppl):S118-S124.
6. Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum. 2007;56(9):2886-2895.
7. Gambichler T, Tigges C, Dith A, et al. Impact of etanercept treatment on ultraviolet B-induced inflammation, cell cycle regulation and DNA damage. Br J Dermatol. 2011;164(1):110-115.
8. Faurschou A, Gniadecki R, Wulf HC. Infliximab inhibits DNA repair in ultraviolet B-irradiated premalignant keratinocytes. Exp Dermatol. 2008; 17(11):933-938.
9. Kircik L, Bagel J, Korman N, et al; Unite Study Group. Utilization of narrow-band ultraviolet light B therapy and etanercept for the treatment of psoriasis (UNITE): efficacy, safety, and patient-reported outcomes. J Drugs Dermatol. 2008;7(3):245-253.
10. Gambichler T, Tigges C, Scola N, et al. Etanercept plus narrowband ultraviolet B phototherapy of psoriasis is more effective than etanercept monotherapy at 6 weeks. Br J Dermatol. 2011;164(6):1383-1386.
11. Staidle JP, Dabade TS, Feldman SR. A pharmacoeconomic analysis of severe psoriasis therapy: a review of treatment choices and cost efficiency. Expert Opin Pharmacother. 2011;12(13):2041-2054.
12. Fonia A, Jackson K, Lereun C, Grant DM, Barker JN, Smith CH. A retrospective cohort study of the impact of biologic therapy initiation on medical resource use and costs in patients with moderate to severe psoriasis. Br J Dermatol. 2010;163(4):807-816.
13. Beyer V, Wolverton SE. Recent trends in systemic psoriasis treatment costs. Arch Dermatol. 2010;146(1):46-54.
14. Inzinger M, Heschl B, Weger W, et al. Efficacy of psoralen plus ultraviolet A therapy vs. biologics in moderate to severe chronic plaque psoriasis: retrospective data analysis of a patient registry. Br J Dermatol. 2011;165(3): 640-645.
15. Gordon PM, Diffey BL, Matthews JNS, Farr PM. A randomized comparison of narrow-band TL-01 phototherapy and PUVA photochemotherapy for psoriasis. J Am Acad Dermatol. 1999;41(5 pt 1):728-732.
16. Langley RG, Gordon KB. Duration of remission of biologic agents for chronic plaque psoriasis. J Drugs Dermatol. 2007;6(12):1205-1212.
17. Walker D, Jacobe H. Phototherapy in the age of biologics. Semin Cutan Med Surg. 2011;30(4):190-198.
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   Phototherapy Plus Biologics: How Safe Is the Combination?
Gambichler T, Tigges C, Dith A, et al. Impact of etanercept treatment on ultraviolet B-induced inflammation, cell cycle regulation and DNA damage. Br J Dermatol. 2011; 164(1):110-115.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
 View journal abstract   View full article
Etanercept is a soluble TNF receptor and acts as a competitive inhibitor of TNF-α. Etanercept prevents the interaction between TNF-α ands it cell surface receptor. Other inflammatory cytokines are also modulated by etanercept. UVB phototherapy induces the release of TNF-α by keratinocytes. Both UVB and etanercept are used for the treatment of patients with moderate to severe psoriasis. Several studies have examined the combination of UVB plus etanercept, with results suggesting that UVB phototherapy seems to improve patients' response to etanercept. The combination was shown to be associated with a greater reduction in PASI scores compared with etanercept monotherapy. In this study, the authors evaluate another component of this combination therapy: What is the effect on photocarcinogenicity?

In a large cohort of patients with RA, the TNF-α antagonists have been associated with an increased risk for nonmelanoma skin cancer.1 In the current study, Gambichler and colleagues studied this association by examining the effect of etanercept on UVB-induced erythema formation and the production of UVB-induced markers of DNA damage.

The investigators conducted a prospective, controlled study in which 11 subjects with moderate to severe psoriasis were treated with UVB at 2 minimal erythema doses (MEDs; 280 to 320 nm) on healthy skin on the upper back. Then, a UVB dose of twice the MED (2 MEDs) was administered at an adjacent site, and punch biopsies were obtained from the 2-MED site 1 hour, 24 hours, and 72 hours later. Patients were then given etanercept 50 mg via subcutaneous injection, and 48 hours later (peak etanercept serum level), they were given another 2 MEDs on adjacent, healthy, untreated skin. Punch biopsies were then repeated at the second, 2-MED site 1 hour, 24 hours, and 72 hours later. As a comparison, punch biopsies were taken from untreated healthy skin in control subjects. Treated skin was assessed with the use of colorimetry, and immunohistochemical studies for caspase 3, cyclin D1, IL-12, Ki-67, p16, p53, survivin, thymine dimers (TDs), and TNF-α were performed on biopsy specimens.

UVB-induced erythema formation as assessed via colorimetry did not differ significantly between UVB-treated and UVB-plus-etanercept–treated skin. Likewise, DNA damage, as measured by TD formation, did not differ significantly between the 2 groups. Significant differences in immunoreactivity, however, were reported for cyclin D1, p53, and survivin. Both cyclin D1 and p53 were decreased in UVB-plus- etanercept–treated sites, whereas survivin was increased in UVB-plus-etanercept –treated sites.

Wild-type p53 protein, a tumor suppressor gene, protects cells from DNA-damaging agents. Normally, DNA damage triggers an increase in p53 production and the p53 protein shuts down cell replication, allowing time for DNA repair and/or apoptosis (ie, programmed cell death). The enhanced apoptosis seen in association with increased p53 is thought to eliminate cells with irreparable DNA damage. cyclin D1 is a proto-oncogene involved in regulating cell cycle progression—namely, the G1-to-S-phase transition. Production of cyclin D1 following DNA damage is essential for p53-mediated apoptosis. Since survivin is considered an inhibitor of apoptosis, overexpression of survivin protects keratinocytes from UV-induced apoptosis in the skin.

The authors' findings suggest that etanercept may affect the UV-induced mediators of apoptosis in a manner that potentially increases the risk for photocarcinogenesis when UVB is used with in combination with etanercept—specifically, decreased p53, decreased cyclin D1, and increased survivin. Although the sample size in this exploratory trial was small, these data, when considered in conjunction with other studies on TNF-α blockers and UVB, must raise doubts about the true safety of these combinations in terms of photocarcinogenesis. Patient selection and counseling is critical when considering these combinations, and more long-term studies are warranted to clarify the associated risks.

References

1. Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum. 2007;56(9):2886-2895.
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   Etanercept Plus NB-UVB: An Evolving Model of Combination Therapy
Kircik L, Bagel J, Korman N, et al; Unite Study Group. Utilization of narrow-band ultraviolet light B therapy and etanercept for the treatment of psoriasis (UNITE): efficacy, safety, and patient-reported outcomes. J Drugs Dermatol. 2008;7(3):245-253.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
 View journal abstract   View full article
When treating a patient with moderate to severe plaque psoriasis, traditional therapies have included small molecules (methotrexate and cyclosporine), as well as UV light therapy (UVB and PUVA). The development of targeted biologic agents broadens the therapeutic armamentarium for moderate to severe psoriasis. Etanercept, which was the first of these agents to gain US FDA approval, is a fully human soluble TNF receptor.

In clinical practice, however, many patients have recalcitrant psoriasis, and combination therapy may be required to optimize treatment response. Traditionally, topical steroids and UV phototherapy have been used in combination with older systemic therapy. With the advent of etanercept and the other biologic agents, however, new combinations must be studied using phototherapy—namely, NB-UVB as an adjunct to biologic therapy. In this 12-week, single-arm, open-label, prospective study, the investigators evaluated the efficacy, safety, and patient-reported outcomes with combination NB-UVB plus etanercept therapy.

A total of 86 patients with stable, active moderate to severe plaque psoriasis from 16 sites were enrolled in this study. All patients received subcutaneous etanercept 50 mg twice weekly and NB-UVB phototherapy 3 times per week for 12 weeks. The primary outcome measure was the proportion of patients achieving a ≥75% improvement in PASI scores from baseline (PASI-75) at week 12. Secondary outcomes included time to PASI-75, proportion of patients obtaining PASI-90 and PASI-100, the Physician Global Assessment (PGA), the Dermatology Life Quality Index (DLQI), and the Patient Global Assessment (PtGA). Safety endpoints (ie, adverse events) were also recorded.

At 12 weeks, 26% of patients had achieved PASI-100, 58% had achieved PASI-90, and 85% had achieved PASI-75. The majority of patients (70%) achieved PASI-75 by week 8. Secondary endpoints also showed improvement, with the DLQI improving by 84% and the PtGA improving by 78% by week 12.

At least 1 adverse reaction was reported in 82% of the patients, with UVB-induced erythema (63%) and injection-site reactions (16%) being the most common. Two serious adverse reactions were recorded, including a case of angina pectoris and a case of cellulitis.

The results of this study showed that the combination of NB-UVB plus etanercept was efficacious and well tolerated, producing clinically meaningful results, including PASI score improvements and patient-reported outcomes. In terms of safety, the safety profile of the combination therapy was consistent with the short-term safety profile of each individual treatment alone.

Although separate treatment arms were not included in this study, the authors make several assumptions based on known 12-week PASI-75 rates with both NB-UVB (62%) and etanercept 50 mg twice weekly (50%). They extrapolate that assuming the effects of the 2 therapies are additive and independent, the expected 12-week PASI-75 rate with combination therapy would be 81%. The PASI-75 rate observed in this study was 85%. The investigators believe their observed rate is validated by the expected, extrapolated rate.

The authors acknowledge the limitations of this study, including lack of a comparative arm and the short duration of treatment. They recognize the fact that longer-term studies are needed to optimize the combination and maximize the sustainment of improved PASI scores. Regardless, data from this study demonstrate that the efficacy of etanercept may be enhanced with the addition of NB-UVB phototherapy.

Gambichler T, Tigges C, Scola N, et al. Etanercept plus narrowband ultraviolet B phototherapy of psoriasis is more effective than etanercept monotherapy at 6 weeks. Br J Dermatol. 2011;164(6):1383-1386.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
 View journal abstract   View full article
With the paucity of available data on combination treatments with anti-TNF-α agents and phototherapy for psoriasis, Gambichler and associates compared etanercept plus NB-UVB phototherapy with etanercept monotherapy over 6 weeks.

In this prospective study, the authors followed 14 patients with moderate to severe psoriasis who were treated with medium-dose, subcutaneous etanercept 25 mg twice weekly, for the 6-week study period. All patients received NB-UVB 3 times per week during the same time period. A marker lesion was selected on the right and left side of the trunk of each patient, and a modified PASI (M-PASI) score was determined from this plaque. It was randomly determined which plaque (right vs left) would be shielded from NB-UVB in each patient. Biopsies were obtained from each site (etanercept monotherapy vs combination therapy with etanercept plus NB-UVB) at the end of the 6 weeks and were graded histologically, with grade 0 representing normal skin and grade 4 exhibiting the histology of well-developed psoriasis. Immunohistochemical markers were also obtained from the biopsy specimens, assessing CD1a, CD4, CD8, involucrin, and Ki-67.

At the end of 6 weeks, a significantly greater reduction in M-PASI was observed in the etanercept-plus-NB-UVB side vs the etanercept-only side (P<.011). Likewise, the histologic grading of psoriasis was significantly lower (ie, closer to normal skin) in the side treated with the combination of NB-UVB plus etanercept (P=.045). In skin treated with combination therapy, there was significantly less epidermal immunoreactivity for CD1a, CD4, and CD8, but no difference in the markers of proliferation and differentiation—that is, Ki-67 and involucrin. Over the course of the study, aside from some mild UV-induced erythema, no adverse reactions were reported.

The authors demonstrated that in this 6-week study, combination therapy with etanercept plus NB-UVB phototherapy significantly lowers the M-PASI and histologic score compared with etanercept monotherapy. Limitations of this study include a small sample size, no NB-UVB–only arm, and no assessment of quality of life (QOL) measures. Nonetheless, the investigators were able to validate the findings of other studies that have demonstrated the efficacy of combination therapy.1 Furthermore, they further elucidated the role of NB-UVB as an additive "bridge" to patients' relatively slow initial response to etanercept, with the combination being more effective as early as 6 weeks.

In contrast to the 2008 findings by Kircik and associates1 (Review #2, above), the authors of this study have the advantage of several more years of safety data as they draw their conclusions, hence their suggestion to use combination therapy as a bridge, rather than endorsing it as long-term therapy. Studies such as that by Gambichler and associates2 (Review #1, above) add to the literature, perhaps foreshadowing the possible long-term carcinogenic risks associated with TNF-α inhibitors, particularly in terms of nonmelanoma skin cancer.

The authors recommend restricting TNF-α inhibitors use in combination with NB-UVB to short time periods, in order to obtain a quicker therapeutic response. They recommend against long-term treatment with these combinations, particularly in patients with a baseline increased risk for skin cancer. Long-term safety of biologics and phototherapy is certainly a story in progress.

References

1. Kircik L, Bagel J, Korman N, et al; Unite Study Group. Utilization of narrow-band ultraviolet light B therapy and etanercept for the treatment of psoriasis (UNITE): efficacy, safety, and patient-reported outcomes. J Drugs Dermatol. 2008;7(3):245-253.
2. Gambichler T, Tigges C, Dith A, et al. Impact of etanercept treatment on ultraviolet B-induced inflammation, cell cycle regulation and DNA damage. Br J Dermatol. 2011; 164(1):110-115.

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   Cost-Effectiveness of Therapies for Moderate to Severe Psoriasis
Staidle JP, Dabade TS, Feldman SR. A pharmacoeconomic analysis of severe psoriasis therapy: a review of treatment choices and cost efficiency. Expert Opin Pharmacother. 2011;12(13):2041-2054.

(For non-subscribers to this journal, an additional fee may apply to obtain full-text articles.)
 View journal abstract   View full article
Estimated annual health care costs associated with the treatment of psoriasis are $11.3 billion and continue to rise at a rate greater than that of inflation. This figure reflects both direct medical costs and indirect costs (ie, work loss). Efforts to curb health care spending necessitate that when selecting a therapy, consideration must be given to the overall cost. In patients with moderate to severe psoriasis, systemic agents are utilized and cost-effectiveness studies for these treatments have been published; however, the majority of studies use only PASI scores as their measure.

In the current study, the authors reviewed the literature to create a cost-effectiveness analysis using both QOL data and PASI-75 scores. The DLQI was used to assess patients' QOL. This index, which is determined by answers to a series of questions, has a range of 0 to 30. A 5-point change in DLQI total score represents the minimally important difference (MID) for patients with moderate to severe psoriasis.

Many individuals with psoriasis have a significant decrease in both their health-related QOL and their emotional QOL. Patients with psoriasis report a decline in mental and physical functioning that is comparable to that in patients with cancer, hypertension, diabetes, and depression. Changes in DLQI correlate well with changes in patients' clinical outcomes, as well as decreases in patients' PASI-75 scores.

The cost-effectiveness model was based on a previous case analysis applied to a continuous treatment regimen for 1 year. Cost-effectiveness ratios were determined using DLQI and PASI-75 scores. Analysis included cost of medication, office visits, laboratory monitoring, and other required tests. Fees were based on the Medicare fee schedule and monitoring tests, as per published guidelines. Treatment schedules were based on standard, widely accepted protocols.

Annual costs for psoriasis treatment ranged from $1330 for methotrexate 15 mg per week to $48,731 for high-dose etanercept (50 mg twice weekly). On average, annual costs for maintenance regimens were $5713 for phototherapy (all modalities), $11,029 for oral systemics, and $26,708 for biologics. The cost of the biologic agents is approximately 2 to 5 times that of older treatments.

The average DLQI improvements (where reported) ranged from 4.9 with alefacept to 9.7 with infliximab. Mean improvements in DLQI with NB-UVB were 8.5. Improvements in PASI-75 scores ranged from 21% of alefacept-treated patients to >80% of infliximab- or PUVA-treated patients. To obtain an MID in the DLQI, annual costs ranged from $3032 with NB-UVB to $59,564 with alefacept. In terms of PASI-75 scores, methotrexate was the most cost-effective ($657 to $1094) and alefacept was the least cost-effective ($124,800).

The investigators' analysis demonstrates that phototherapy, including home UVB, outpatient NB-UVB, and PUVA, as well as methotrexate, have the best cost-to-efficacy ratios. Overall, phototherapy was the most cost-effective treatment when considering both PASI-75 and DLQI MID. Adverse events associated with the use of phototherapy (increased risk for skin cancer and sunburn) are relatively minor compared with the risks associated with other systemic treatment choices. Among the biologic agents, infliximab was the most cost-effective, with ustekinumab close behind.

Study limitations include challenges with standardizing study and patient characteristics across many different studies, as well as extrapolation of PASI and DLQI scores. Overall, this study offers a good cost-effectiveness analysis of current therapies for moderate to severe psoriasis and demonstrates that phototherapy remains among the most cost-effective treatment modalities.
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   Biologics vs PUVA: A Comparison of Real-World Efficacy
Inzinger M, Heschl B, Weger W, et al. Efficacy of psoralen plus ultraviolet A therapy vs. biologics in moderate to severe chronic plaque psoriasis: retrospective data analysis of a patient registry. Br J Dermatol. 2011;165(3):640-645.

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Improved understanding of the immunologic basis of psoriasis has led to the development of biologic agents, adding new treatment options for patients with psoriasis. These agents target key steps in the pathogenesis of psoriatic disease. PUVA photochemotherapy is a well-established, well-documented effective treatment for psoriasis. The benefits of PUVA are numerous, including reduction in levels of such chemokines and cytokines as IL-22, IL-17, IL-23, IL-8, TNF-α, vascular endothelial growth factor (VEGF), and intercellular adhesion molecule 1 (ICAM-1). PUVA also can reduce the activation and number of T cells, having in essence a "biologic-like" effect. The authors of this study set out to directly compare the clinical efficacy of PUVA vs the biologics for the treatment of patients with moderate to severe psoriasis. .

Inzinger and coworkers conducted an observational, retrospective analysis of patient clinical data from the Psoriasis Registry, Department of Dermatology, Medical University of Graz, in Graz, Austria. Patients were treated between 2003 and 2010 under daily life conditions, outside of clinical trials. A total of 172 patients with chronic plaque psoriasis were analyzed. Patients had been treated with oral PUVA and/or at least 1 of the biologic agents for a total of 248 treatment courses analyzed. Overall, 64 patients had received oral PUVA, 96 had received a biologic agent, and 12 had received both oral PUVA and, at a later time, a biologic agent. Endpoints of the study were complete clearance (CR), PASI-90 scores, and PASI-75 scores at the end of PUVA treatment or at the end of 12 weeks of biologic therapy. Median time for PUVA treatment was 10.3 weeks with 8-methoxypsoralen (8-MOP) and 9.2 weeks with 5-methoxypsoralen (5-MOP). Treatment efficacy was based on a reduction in PASI scores.

With PUVA , the intention-to-treat observed rates were CR of 22%, PASI-90 of 69%, and PASI-75 of 86%. These rates were statistically superior to those with alefacept (P=.0002), efalizumab (P=.0053), adalimumab (P=.0034), etanercept (P=.0086), and ustekinumab (P=.028). When a worst-case-scenario analysis was used, the rates with PUVA were CR of 15%, PASI-90 of 58%, and PASI-75 of 69%. In these analyses, PUVA was statistically superior only to alefacept (P=.0013), efalizumab (P=.015), and etanercept (P=.0037). The efficacy rates with both PUVA and biologic agents in these patients compared favorably with those previously reported in controlled studies. This is important, because the data analyzed in this study were from patients treated under daily, real-life conditions, not in controlled studies.

Limitations of this analysis include the fact that PUVA and biologics have not been compared head to head in a blinded, placebo-controlled trial. This type of trial would be difficult to conduct, as PUVA induces erythema and pigmentation. Another limitation of this study is the small number of patients in the database who were treated with certain biologic agents. Lastly, some biologics do not achieve maximum efficacy at 12 weeks—the chronologic endpoint in this study—thus, PASI reduction may have been underestimated by using the 12-week endpoint.

Conclusions drawn from this study are that under real-life conditions, PUVA is a more effective antipsoriatic therapy than several of the biologics, including etanercept, alefacept, and efalizumab. PUVA was possibly (but not statistically significantly) more effective than adalimumab and ustekinumab, and equally as effective as infliximab, in reducing PASI scores in this group of patients with chronic, moderate to severe plaque psoriasis.

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