Volume 2, Number 1 (Summer 2008)
Oregon Health & Science University, Portland, Oregon
Psoriasis, a common chronic skin disorder, is sometimes associated with another immune-mediated disorder, psoriatic arthritis. During the 4th annual Advances in Cosmetic and Medical Dermatology meeting, experts in the field discussed the relationship between psoriasis and psoriatic arthritis, examined current knowledge of how biologic agents may target particular pathways implicated in the pathogenesis of these diseases, and reviewed the results of studies testing these drugs in affected patients. In addition, they explained research into agents that inhibit tumor necrosis factor-a and various recommendations for patient monitoring when these drugs are used. The speakers also described methods for diagnosing psoriatic arthritis at the earliest possible time and the results of studies investigating small-molecule compounds against inflammatory diseases.
|Dr. Isenhath is Chief Resident in the Department of Dermatology, Oregon Health & Science University, Portland, Oregon.|
Psoriasis is a chronic, immune-mediated disorder that affects 2%3% of the population.1,2 Collectively, approximately 30% of patients with psoriasis also have chronic, inflammatory psoriatic arthritis.3 This patient population exhibits a broad range of symptoms, yet 80%90% have plaque-type psoriasis. The prevalence of psoriatic arthritis generally increases with greater skin involvement, but the severity of skin disease does not necessarily correspond with that of the joints.
Psoriasis has a profound impact on an individual’s quality of life.4 Most dermatologists agree that first-line therapy for patients with moderate-to-severe psoriasis or psoriatic arthritis should include systemic agents. Experts participating in the recent 4th annual Advances in Cosmetic and Medical Dermatology meeting, held in Wailea, Maui, Hawaii, from February 25 to March 1, 2008, reviewed recent advances in the systemic treatment of psoriasis and associated arthritis as well as novel therapeutic agents that may be available in the future.
Speakers at this session included Bruce Strober, MD, Assistant Professor, Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York; Craig Leonardi, MD, Associate Clinical Professor of Dermatology, St. Louis University Medical School, Missouri; Andrew Blauvelt, MD, Professor, Department of Dermatology, Oregon Health & Science University, Portland; and Arthur Kavanaugh, MD, Director, Center for Innovative Therapy, Division of Rheumatology, Allergy, and Immunology, University of California at San Diego. These speakers discussed the biologic basis of psoriasis and psoriatic arthritis; biologic therapies for patients with moderate-to-severe disease; the dosing, efficacy, and side-effect profiles of these agents; and ways to choose the best possible drug for specific patient situations.
Ustekinumab and ABT-874 are two new biologic agents that target key cytokines in the inflammatory process of psoriasis. Recent insights into the pathogenesis of the disease have led to increased attention on these agents over the past several years.
Both of these monoclonal antibodies target the p40 subunit of interleukin (IL)-12 and IL-23 and, therefore, are referred to as antiIL-12/23 molecules. IL-12 stimulates T-helper (Th) 1 cells, whereas IL-23 stimulates Th17 cells, a relatively new group of T cells that are distinct from classic Th1 and Th2 cells. IL-12/23 p40 is overexpressed in psoriasis plaques5 and has been implicated in the pathogenesis of psoriasis.6 These promising new agents may provide relief for patients with moderate-to-severe psoriasis and psoriatic arthritis. Properties of these biologics that target cytokines, as well as currently used biologics that target T cells, in the treatment of psoriasis and psoriatic arthritis, are presented in Table 1.7,8
In a 28-week, placebo-controlled, crossover, phase III clinical study, 1,996 psoriasis patients were randomized to receive either 45 or 90 mg of ustekinumab or placebo at weeks 0 and 4 and then every 12 weeks thereafter.9 Patients given placebo were crossed over to receive treatment beginning at 12 weeks.
The 75% reduction in the Psoriasis Area and Severity Index (PASI) score (PASI-75) at week 12 was 76 for patients taking 90 mg of the drug, 67 for those taking 45 mg, and 4 for those using placebo. Furthermore, 73%, 68%, and 5% of patients, respectively, were clinically cured or had minimal disease as a result of therapy.
Through week 20, 50% of patients given active treatment and 49% of those given placebo had at least one adverse event, which included headache, upper respiratory tract infection, arthritis, fatigue, and diarrhea; 22% of those given active treatment and 20% of the placebo group had infections. There was no observable association between the use of a higher dose and an increased rate of adverse events or infections. Serious infection was observed in 1 of 820 (0.1%) patients treated and 2 of 410 (0.5%) patients in the placebo group.
These results generated excitement in the dermatologic community for several reasons. First, this biologic had a PASI-75 similar to that of infliximab or adalimumab, the two well-established biologics targeting tumor necrosis factor-alpha (TNF-a) that are used to treat psoriasis and psoriatic arthritis. Second, only two injections of the drug were given over 3 months; this regimen, which involved significantly fewer injections than needed with currently established injectable biologics, may be well received by patients needing chronic treatment to control their disease. Third, the adverse-event rate with this drug was similar to that seen with placebo, and the events were relatively minor, indicating that this drug may be safer than the TNF-a inhibitors.
In a phase II, 48-week, placebo-controlled clinical trial, 180 patients with moderate-to-severe plaque psoriasis were randomized to receive placebo, 100 mg of ABT-874 every other week, or 200 mg of the drug given as a single dose, one dose every week, one dose every other week, or one dose every week for just 4 weeks.8 Except for patients who received just one 200-mg dose over the study period, all treated patients had a PASI-75 of 90% or greater (Figure 1), compared with those in the placebo group, who had a PASI-75 of 3% (P < 0.001). Phase III clinical trials are currently under way; as with testing of ustekinumab, the early results for ABT-874 are encouraging.
Ustekinumab and ABT-874 are promising new biologics for treating psoriasis. The phase II/III results demonstrated the efficacy and adverse-event profile of IL-12/23 monoclonal antibodies in treating the disease and established a central role for this therapeutic class in the pathophysiology of psoriasis. Both medications are likely to gain approval for treating moderate-to-severe psoriasis within the next few years.
TNF-a inhibitors continue to be an important class of drugs for treating patients with moderate-to-severe psoriasis.10
Adalimumab is a human immunoglobulin (Ig)-G1 monoclonal antibody that blocks interaction between TNF-a and the p55 and p75 cell-surface receptors.11,12 The US Food and Drug Administration (FDA) recently approved the use of this drug for psoriasis; it also is approved to treat psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and Crohn’s disease. Patients inject themselves with 40 mg of the drug subcutaneously (SC) on a biweekly basis.
The efficacy and safety of adalimumab and the other biologic agents used for psoriasis have been well documented in placebo-controlled studies. However, until recently, no such studies directly compared a biologic agent with traditional systemic agents, such as methotrexate.
Adalimumab vs methotrexate. A phase III, randomized, double-blind, placebo-controlled trial was the first to compare the efficacy and safety of a biologic (adalimumab) and methotrexate to treat psoriasis.13 Patients with moderate-to-severe plaque psoriasis were randomized to receive 80 mg of adalimumab SC at week 0 and then either 40 mg of the drug every other week; 7.5 mg of oral methotrexate, which was increased, as needed and tolerated, to 25 mg weekly; or placebo for 16 weeks. The primary efficacy endpoint was the proportion of patients achieving at least a PASI-75 after 16 weeks.
In all, a PASI-75 was achieved by 80% of adalimumab-treated patients, 36% of the methotrexate group (P < 0.001), and 19% of the placebo group (P < 0.001). From a safety perspective, adverse events were similar among the treatment groups; however, adverse reactions leading to study discontinuation (4 of 110 patients) actually were greatest among the methotrexate group and mainly were related to hepatic adverse events.
This study had a few notable limitations, including the relatively low PASI-75 in the methotrexate group and the relatively high PASI-75 response rate in the placebo group. The PASI-75 in the methotrexate group (36%) was much lower than that indicated by a recent study (60%).11,14 This may have resulted from the relatively conservative methotrexate dosing parameters in this study (ie, a slow increase of the methotrexate dose) and/or the longer time for methotrexate to obtain clinical efficacy (ie, the PASI-75 for methotrexate may be greater if assessed at 16 or 20 weeks rather than at 12 weeks). Hopefully, this groundbreaking study will lead to further clinical trials comparing biologic agents with traditional systemic agents in treating psoriasis.
Adalimumab safety profile in inflammatory diseases. In studying the safety of adalimumab in various patient populations, including those affected by ankylosing spondylitis, Crohn’s disease, psoriasis, psoriatic arthritis, and rheumatoid arthritis, Burmester et al10 found that most adverse effects were seen in the “most ill” patients, such as those with long-standing rheumatoid arthritis and Crohn’s disease (Table 2). Younger, healthier patients generally did better with respect to adverse effects. Specifically, patients with psoriasis and psoriatic arthritis had an excellent benefit-to-risk profile; thus, the TNF-a inhibitors were considered to be safe, effective medications in this patient population.
These results were encouraging for the many dermatologists who are using TNF- inhibitors, primarily for patients with psoriasis and psoriatic arthritis. Certainly, clinicians must follow specific safety guidelines and perform appropriate laboratory testing and clinical examination when treating any patient with a TNF-a inhibitor.
Etanercept is a soluble, fully human, receptor-fusion protein consisting of the human TNF-a p75 receptor and the fragment, crystallizable portion of human IgG1. This fusion protein binds to TNF-a, thus blocking its proinflammatory effects.15 The 4-day half-life of etanercept is relatively short.
Etanercept currently is FDA approved for treating psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and ankylosing spondylitis. The self-administered adult dose is 50 mg/wk SC, which may be given as 25 mg SC twice weekly or 50 mg SC once weekly.16
Use in children and adolescents. Etanercept has been effective in treating adults with psoriasis and is indicated for juvenile rheumatoid arthritis patients as young as 4 years of age.16
The first study assessing etanercept’s efficacy and safety in children and adolescents with psoriasis was reported recently.17 In this phase III, randomized, placebo-controlled study, 211 patients (417 years of age) were assigned to receive once-weekly etanercept or placebo and followed for 48 weeks. The randomization included two crossover periods. First, patients were randomized to receive etanercept or placebo for 12 weeks. Next, all patients received etanercept for 24 weeks. Finally, patients were randomized to receive either treatment or placebo for an additional 12 weeks.
At week 12, the percentages of patients given etanercept who achieved a 90%, 75%, and 50% reduction in PASI were 27%, 57%, and 75%, respectively, whereas the respective percentages for those given placebo were 7%, 11%, and 23% (P < 0.001). At week 36, after 24 weeks of open-label etanercept, the PASI-75 was 68% and 65% for patients initially assigned to etanercept or placebo, respectively, indicating that etanercept has a rapid, sustained clinical benefit. At the conclusion of the trial, the PASI-75 response was lost by 26 of 69 patients (42%) assigned to placebo at the second randomization. Four serious adverse events occurred in the etanercept group, including three infections; all resolved without sequelae or cessation of etanercept therapy.
These results showed etanercept to have a rapid, effective clinical benefit in many children and adolescents with moderate-to-severe psoriasis. A low rate of infection was noted. However, children have a relatively high incidence of infections (ie, upper respiratory infection), so clinicians must be ready and able to deal with minor infections that may or may not resolve without sequelae when concomitant antiTNF-a therapy is used. Although these results were encouraging, they must be considered with cautious optimism until larger studies demonstrating etanercept’s clinical efficacy and long-term safety are completed.
All patients given TNF-a inhibitors must be selected and monitored appropriately (Table 3).18 Screening for a personal or family history of neurologic disease is important. It is important to avoid treating patients with demyelinating neurologic disorders, optic neuritis, congestive heart failure, or active bacterial infections, and to use caution when treating those infected in the past with hepatitis-B virus (HBV). Before initiating therapy, the following tests are recommended: a purified protein derivative (PPD) test, a complete blood count (CBC) with platelet count, and renal and hepatic function testing; further, screen patients for the presence of HBV, hepatitis C virus, and human immunodeficiency virus. Annual laboratory tests are limited to a CBC with platelet count, comprehensive metabolic panel including liver function tests, and PPD; it is recommended that patients given infliximab undergo a comprehensive metabolic panel every 3 months.
Lastly, immunization recommendations include pneumococcal vaccination at baseline and influenza vaccinations at baseline and annually.
Approximately 30% of patients with psoriasis experience chronic inflammatory arthritis.3 As previously noted, the prevalence of psoriatic arthritis increases with psoriatic skin involvement, but the severity of skin disease does not correspond with arthritic severity. Skin disease precedes joint involvement in 80% of cases; however, joints are the presenting manifestation in 5%10% of patients who develop psoriasis.3
The joint disease in psoriasis is clearly distinct from that of rheumatoid arthritis, and patients with psoriasis tend to develop arthritis at a younger age than do those with rheumatoid disease. Specifically, those with psoriasis tend to have less symmetric disease and more proliferation on roentgenographic examination. About equal numbers of men and women present with psoriatic joint manifestations.
Enthesial tissue represents the transition point where tendon inserts onto bone. Enthesitis is the earliest evidence of psoriatic arthritis. It often presents at the posterior heel with swelling and, sometimes, tenderness of the tendon insertion site.
Most of the time, however, patients with enthesitis are asymptomatic. Thus, because many patients will have subclinical disease activity, and clinical examination of this area may be difficult, clinicians have used imaging studies to better predict early disease activity. Importantly, treating subclinical enthesitis may prevent the development of inflammatory arthritis.
Gisondi et al19 used ultrasonography to determine the presence of subclinical enthesial inflammation in patients with chronic plaque psoriasis who had no signs or symptoms of psoriatic arthritis. Specifically, investigators studied the Achilles tendon, the quadriceps tendon, the patellar enthesis, and the plantar aponeurosis. The investigators found increased enthesial abnormalities more often in asymptomatic psoriasis patients than in controls.
In similar studies, others have looked at fat-suppressed magnetic resonance imaging (MRI) to determine subclinical enthesitis in patients with psoriatic arthritis.20 Use of MRI allowed investigators to find increased joint inflammation that was not appreciated during clinical examination.
These preliminary studies provide insight about predicting the earliest manifestations of psoriatic arthritis; certainly, further studies assessing subclinical inflammation and its role in the pathogenesis of symptomatic psoriatic arthritis are necessary. Whether diagnosis of subclinical inflammation leads to prevention of symptomatic disease must be addressed before imaging modalities such as ultrasonography or MRI are used routinely in this setting. These noninvasive measures of inflammation may allow for earlier intervention, treatment, and, perhaps, even prevention of psoriatic arthritis.
The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), an international multidisciplinary organization that seeks to advance the field of psoriasis and psoriatic arthritis, formed in 2003. Currently, over 200 rheumatologists, dermatologists, radiologists, geneticists, methodologists, epidemiologists, representatives from patient service leagues, and biopharmaceutical industry representative members contribute to further research into the diagnosis and treatment of these diseases.
Recently, the group reviewed data on currently established systemic therapies for psoriasis and psoriatic arthritis and made recommendations based upon evidence of symptom control, size of effect, and side-effect profile of these therapies.21 The group then graded each class of therapy, giving an A to the biologics (eg, adalimumab, etanercept, infliximab) because of their superior efficacy and low side-effect profile; the group assigned grades of B, B, and A to methotrexate, cyclosporine, and gold compounds, respectively.
Although small-molecule compounds still must undergo considerable testing before they are approved for clinical use by the FDA, they remain an interesting concept in treating inflammatory diseases. In fact, they may represent a new class of therapeutic agents 510 years down the road.
AEB071 is an orally administered selective inhibitor of protein kinase C. In a small study, 32 patients with moderate-to-severe plaque psoriasis were randomized to receive one of four different doses of the drug or placebo for 14 days; the cohort was followed for another 2 weeks after treatment ended. Although this study was very short, it was interestingthe group that received the highest dose level showed a nearly 70% reduction in PASI from baseline during the treatment period as compared with a 5% reduction seen in the placebo group (B. Strober, personal communication). Side effects were mild and included abdominal pain and nausea. However, gastrointestinal (GI) distress occurred in three of six patients given the higher dose; this effect, therefore, may be a limiting factor for this drug.
CC-10004 is an orally available, small-molecule drug that inhibits the production of multiple proinflammatory mediators that may be involved in the pathogenesis of psoriasis (eg, phosphodiesterase-4, TNF-a, IL-2, interferon-γ, and nitric oxide synthase).22 In a phase II clinical trial, 257 patients were randomized to receive 20 mg/d of the drug, 20 mg twice daily, or placebo. Investigators noted a modest efficacy in PASI-75 among patients given 20 mg twice daily (25%) when compared with those using placebo (10%; P < 0.05); no difference was noted between patients treated with 20 mg/d and the placebo group. Once again, GI symptoms were the most common side effects reported among the treatment group.
These small-molecule drugs represent a novel class of therapeutics that target key inflammatory mediators of such conditions as psoriasis. However, identifying molecules that are more specific to the disease processes themselves is of paramount importance. These drugs have yielded modest clinical efficacy and have caused a relatively high frequency of GI side effects. With further refinement and design, small-molecule compounds may offer clinical benefit within 510 years.
Psoriasis has a profound impact on both the physical and mental health of affected patients. Fortunately, many treatment options are available for patients with moderate-to-severe psoriasis or psoriatic arthritis. The biologic agents continue to show excellent clinical efficacy and safety profiles when used appropriately in patients with moderate-to-severe disease. Advances in knowledge about the pathogenesis of psoriasis have led to the development of two new biologic therapies, ustekinumab and ABT-874. These drugs have shown promising results in clinical trials; they likely will be approved in the near future by the FDA to treat psoriasis.
Treatment of childhood psoriasis with biologic agents is likely to become more common in the future. However, use of these drugs has been associated with a high risk of infections in this patient population. Therefore, young patients given these drugs must be followed closely for signs of serious infection that would require cessation of therapy.
For patients with psoriatic arthritis, imaging modalities such as ultrasonography and MRI may help to predict subclinical signs of inflammation. Such early identification of the disease may allow quicker treatment with systemic therapies to modify or prevent disease progression.
Finally, with further refinement, such novel therapeutic agents as the small-molecule compounds may offer clinical benefit in the years ahead. Ongoing research into these drugs may reveal more information about their effectiveness and may lead to future psoriasis and psoriatic arthritis therapies.
1. Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol Clin. 1996;14:485496.
2. Schön MP, Boehncke WH. Psoriasis. N Engl J Med. 2005;352:18991912.
3. Mease PJ. Cytokine blockers in psoriatic arthritis. Ann Rheum Dis. 2001;60:iii37iii40.
4. Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol. 1999;41:401407.
5. Yawalkar N, Karlen S, Hunger R, Brand CU, Braathen LR. Expression of interleukin-12 is increased in psoriatic skin. J Invest Dermatol. 1998;111:10531057.
6. Hong K, Chu A, Lúdviksson BR, Berg EL, Ehrhardt RO. IL-12, independently of IFN-g, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder. J Immunol. 1999;162:74807491.
7. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo: Mosby Elsevier; 2008.
8. Kimball AB, Gordon KB, Langley RG, Menter A, Chartash EK, Valdes J. Safety and efficacy of ABT-874, a fully human interleukin 12/23 monoclonal antibody, in the treatment of moderate to severe chronic plaque psoriasis: results of a randomized, placebo-controlled, phase 2 trial. ABT-874 Psoriasis Study Investigators. Arch Dermatol. 2008;144:200207.
9. Leonardi C, Langley RG, Lebwohl M, et al. CNTO 1275 (anti-Il-12/23p40) treatment of psoriasis: phase 3 trial results. Presented at the World Congress of Dermatology 2007; September 30 to October 5, 2007; Buenos Aires, Argentina. Abstract 1543.
10. Burmester GR, Pease PJ, Dijkmans BAC, et al. Adalimumab clinical trial safety in multiple indications and reduction in mortality in rheumatoid arthritis Presented at the American College of Rheumatology Annual Meeting; November 1115, 2006; Washington, DC. Poster 467.
11. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48:3545
12. Mease PJ. Adalimumab: an anti-TNF agent for the treatment of psoriatic arthritis. Expert Opin Biol Ther. 2005;5:14911504.
13. Saurat JH, Stingl G, Dubertret L, et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol. 2008;158:558566.
14. Heydendael VM, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med. 2003;349:658665.
15. Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomized trial. Lancet. 2000;356:385390.
16. Nanda S, Bathon JM. Etanercept: a clinical review of current and emerging indications. Expert Opin Pharmacother. 2004;5:11751186.
17. Paller AS, Siegfried EC, Langley RG, et al. Etanercept treatment for children and adolescents with plaque psoriasis. Etanercept Pediatric Psoriasis Study Group. N Engl J Med. 2008;358:241251.
18. Jackson JM. TNF-alpha inhibitors. Dermatol Ther. 2007;20:251264.
19. Gisondi P, Tinazzi I, El-Dalati G, et al. Lower limb enthesopathy in patients with psoriasis without clinical signs of arthropathy: a hospitalbased casecontrol study. Ann Rheum Dis. 2008;67:2630.
20. McGonagle D, Gibbon W, O’Connor P, Green M, Pease C, Emery P. Characteristic magnetic resonance imaging entheseal changes of knee synovitis in spondylarthropathy. Arthritis Rheum. 1998;41:694700.
21. Soriano ER, McHugh NJ. Therapies for peripheral joint disease in psoriatic arthritis. A systematic review. J Rheumatol. 2006;33:14221440.
22. Bäumer W, Hoppmann J, Rundfeldt C, Kietzmann M. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007;6:1726.