Published in UAB Insight, Summer 2008
Treatment Options for Moderate to Severe Plaque Psoriasis
ABSTRACT: New treatments are available to clear psoriasis and control the disease.
CME OBJECTIVE: The reader will be familiar with the recent guidelines for management of psoriasis and the pros and cons of different options.
Boni E. Elewski, MD, grant and research support Abbot Labs, Amgen, Barrier Therapeutics Inc, Centocor, Mediquest Therapeutics Inc, Novartis, Schering Plough, Stiefel Laboratories Inc; honoraria Amgen, Astellas Pharma Inc, Intendis Inc, NanoBio Corp, Schering Plough; stockholder Amgen; Craig A. Elmets, MD, grant and research support Abbot Labs, Genentech, Astellas Pharma Inc; consultant Amgen, Astellas Pharma Inc; honorarium Amgen; other financial support Amgen, Centocor
Flakes. Scales. Itchiness. Redness. Swelling. Depression. Constant companions for the approximately 7 million Americans with psoriasis, a chronic, systemic, inflammatory disorder characterized by scaly erythematous patches, papules, and plaques. "No one needs to suffer from psoriasis," says UAB dermatologist Boni E. Elewski, MD. "Everyone can be treated without the draconian measures used in the past."
The most common form of this disease is plaque psoriasis, which affects up to 90% of patients. Well-demarcated erythematous plaques of various sizes can arise on all parts of the body, most often on the elbows, knees, scalp, trunk, and buttocks. Other forms - inverse, erythrodermic, pustular, guttate - affect fewer patients. Nail involvement can occur in all subtypes.
About 80% of individuals have mild to moderate disease, and 20% have moderate to severe psoriasis, defined as affecting more than 5% of the body surface. The Psoriasis Area and Severity Index (PASI), often used in clinical trials to assess improvement, measures disease severity and coverage. The usual threshold for a therapy to be considered effective is 75% improvement from baseline (PASI 75).
Psoriasis patients have high rates of sexual dysfunction and anxiety, feel stigmatized, and may self-isolate. The writer John Updike, who suffered from psoriasis, wrote "Puddles of flakes form wherever I rest my flesh. ... The name of the disease, spiritually speaking, is Humiliation." Up to 60% have depression, 10% wish to die, and 5% have suicidal ideation (Int J Dermatol. 1993;32:188-190). Assessments of disease severity are based on a composite of psychosocial and physical factors.
Recent research links psoriasis with a growing number of comorbidities that include increased risk of myocardial infarction and atherosclerosis; metabolic syndrome; lymphoma; squamous cell carcinoma of the skin, particularly in patients who have undergone long-term phototherapy; and psoriatic arthritis and other immune-mediated inflammatory diseases.
Therapies
The American Academy of Dermatology recently published new guidelines of care for management of psoriasis and psoriatic arthritis (J Am Acad Dermatol. 2008;58:851-864). UAB dermatologist Craig A. Elmets, MD, coauthored the recommendations. "Advances in our understanding of the pathogenesis of psoriasis and particularly the role that a hyperactive immune system plays in the disease have resulted in expanded treatment options that substantially improve the lives of psoriasis patients," he says.
Moderate and severe disease usually necessitate systemic treatment, but Elewski uses phototherapy for specific indications. "PUVA [psoralen plus ultraviolet A light] is an option for patients, but the increased risk of skin cancer rules it out for many," she says. For localized psoriasis, the excimer laser (308 nm) provides precision delivery of high-intensity narrowband UVB light. "The laser achieves clearance or significant improvement in about 10 treatments," she says.
Methotrexate and cyclosporine are appropriate for short-term interventions, but they carry limiting toxicities and side effects. Long-term cyclosporine therapy impairs renal function and may cause hypertension and contribute to risk of certain cancers. Dermatologists often combine oral retinoids with phototherapy, but adverse side effects also restrict their use.
Biologics
Compared with other systemic therapies, biologics provide greater improvement for longer periods with fewer side effects. They can clear skin in as few as 3 months. Treatment decisions about biologics must involve several factors and patients must be carefully selected, Elewski says. "We screen and regularly monitor patients for infection or a compromised immune system, impaired liver function, hepatitis, tuberculosis, demyelinating diseases, and other conditions." Several drugs require at-home injections, while others require multiple clinic visits, and some patients are noncompliant. Biologics each have inherent toxicities and safety issues, cost up to $25,000 a year, and are not uniformly covered by insurance. Some insurers restrict use to those who have not responded to phototherapy or systemic drugs, but "the striking efficacy and greater safety often warrant the use of these newer therapeutic agents," Elmets says.
The Food and Drug Administration has approved five biologics for psoriasis: Alefacept (Amevive), efalizumab (Raptiva), infliximab (Remicade), adalimumab (Humira), and etanercept (Enbrel).
Alefacept and efalizumab target pathogenic T cells. Alefacept inhibits the action of memory-effector lymphocytes and reduces their number. Injections are given weekly for 12 weeks. In phase 3 trials, 21% of patients achieved at least PASI 75 (J Am Acad Dermatol. 2003;49[suppl 2]:S87-S97). "I find 1 in 9 patients respond well to alefacept," Elewski says. "It works slowly but off-treatment response is prolonged, and subsequent courses tend to extend the remission period." Alefacept induces CD4 lymphocyte reduction and is not appropriate for immunosuppressed patients with low CD4 counts.
Efalizumab blocks T-cell adhesion and trafficking into the dermis and epidermis. In phase 3 studies, 44% of patients achieved PASI 75 at 24 weeks but relapsed or flared when treatment discontinued (N Engl J Med. 2003;349:2004-2013). Side effects include headache, chills, fever, nausea, myalgia, and a flare-up of symptoms if the drug is withdrawn.
TNF Inhibitors
Adalimumab, etanercept, and infliximab are tumor necrosis factor (TNF) inhibitors. Adalimumab is a human monoclonal antibody that binds to circulating and cell-bound TNF-Ą and blocks interaction at cell surfaces. Patients self-administer injections every other week. In phase 3 studies, 71% of patients achieved PASI 75 at week 16, with similar response rates at 60 weeks (J Am Acad Dermatol. 2007;58:106-115).
Etanercept is a human receptor fusion protein. In phase 3 studies at week 24, 44% of patients taking 25 mg twice weekly achieved PASI 75, and 59% of those taking 50 mg twice weekly achieved PASI 75 (N Engl J Med. 2003;349:2014-2022). Response declines when dose is decreased, and when patients discontinue the drug pretreatment levels of disease return within 3 months.
Infliximab is a chimeric monoclonal antibody that binds to TNF-Ą and neutralizes its effects. Continuous therapy is more effective than intermittent therapy. The drug elicits a rapid response but may lose efficacy with time. In trials, at week 10 80% of patients achieved PASI 75; 61% maintained that score at week 50 (Lancet. 2005;366:1367-1374).
Interleukin 12/23 Monoclonal Antibodies
Recent research indicates inhibition of interleukin (IL)-12 and IL-23 with a monoclonal antibody targeting the p40 subunit protein may be efficacious. IL-12 and IL-23 mediate adaptive immune function and contribute to T-cell development in psoriasis. Overexpression of IL-12 or IL-23 is associated with a greater risk for psoriasis (Clin Biochem. 2006;39[2]:119-125).
In a recent randomized study, a fully human IL-12/23 antibody (ABT-874) demonstrated statistically significant efficacy. At week 12 the drug achieved PASI 75 or greater in 90% of patients receiving one of several dosing regimens. In the single-dose group, 63% of patients reached PASI 75 or better by week 12, and nearly 100% of patients reached at least PASI 50. Adverse events were limited to injection site reactions (Arch Dematol. 2008;144[2]:200-207). Elewski, Elmets, and other UAB researchers are involved in the pivotal phase 3 trials testing the safety and efficacy of ABT-874 in two dosing regimens.
Another IL-12/23 monoclonal antibody, ustekinumab, has demonstrated durable (76 weeks) efficacy and safety in the PHOENIX trials, two large randomized trials that assessed almost 2000 patients, some enrolled at UAB. Overall, treatment with two 45 mg or 90 mg injections at week 0 and week 4 followed by dosing every 12 weeks achieved PASI 75 in >75% of patients. More than 90% experienced clinically meaningful improvements. Treatment withdrawal resulted in gradual disease recurrence, indicating the potential need for maintenance therapy. Adverse event rates were low, with few serious infections, malignancies, or cardiovascular events (Lancet. 2008;371:1665-1674; 1675-1684). A group of partial responders achieved PASI 75 when researchers increased dosing to 8-week intervals. "These are some of the highest response rates we have seen for any psoriasis drugs and the low incidence of side effects is particularly encouraging," Elewski says.
FOR MORE INFORMATION:
Dr. Boni Elewski
Dr. Craig Elmets
1.800.UAB.MIST
mist@uabmc.edu