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PRIORITY PRESS - 19th International Congress of the European Academy of Dermatology and Venereology

Gothenburg, Sweden / October 6-10, 2010

To a large extent, psoriasis comorbidity is thought to be linked to underlying systemic inflammation. “The skin is merely a window into the psoriasis condition,” explained Dr. Wayne P. Gulliver, Memorial University of Newfoundland, St. John’s, during a presentation of data from 1494 patients hospitalized for acute psoriasis symptoms. The analysis showed that >27% of these patients had some form of gastrointestinal comorbid condition, >25% had comorbidities relating to the circulatory system and >20% had genitourinary comorbidities. Some 45% of patients with psoriasis had 1 comorbidity and 55% present with 2 or more comorbid conditions (J Cutan Med Surg 2010, accepted for publication). “When we see patients with psoriasis in our clinics, we really must think about associated morbidity,” commented Dr. Gulliver.

In psoriasis, the risk of developing metabolic syndrome is 5 times more likely compared with the general population (Arch Dermatol Res 2006;298(7):321-8). In severe psoriasis, the risk is 70% higher relative to mild psoriasis (J Am Acad Dermatol 2006;55(5):829-35). The metabolic syndrome is a manifestation of a state of chronic inflammation, in which pro-inflammatory cytokines IL-6 and tumour necrosis alpha (TNF-a) trigger an inflammatory cascade that results in elevated C-reactive protein (CRP) levels, a hepatic acute-phase protein known to be associated with increased cardiovascular (CV) mortality (Arterioscler Thromb Vasc Biol 1999;19(4):972-8, Circulation 2003;107(3):391-7). This inflammation is thought to contribute to the overall CV risk in patients with metabolic syndrome (Am J Physiol Endocrinol Metab 2005;288(4):E741-E747).

Depending on the age of the patient and the psoriasis severity, comorbid conditions may have a detrimental effect as the risk of death is more than doubled for those under the age of 45 with severe psoriasis, compared with the average risk for all psoriasis patients (Arch Dermatol 2007;143(12):1493-9). It has been estimated that comorbid conditions may reduce the life expectancy by up to 10 years in patients who develop psoriasis as adults, and by as much as 20 years in patients who develop psoriasis before the age of 25 (Clin Dermatol 2007;25(6):529-34). “Psoriasis really does affect life expectancy and mortality, and young patients are at particular risk,” Dr. Gulliver informed delegates.

Outlook on Long-term Management

Psoriasis requires life-long treatment and underlying systemic inflammation is increasingly recognized as a viable target for long-term treatment. Clinical data showed that as the skin improves during treatment, the levels of CRP, a highly sensitive indicator of systemic inflammation, dropped (J Eur Acad Dermatol Venereol 2004;18(2):180-3). Treatment with the anti-TNF-a adalimumab has been shown to normalize CRP in patients with moderate to severe psoriasis (Abramovits et al. EADV 2008, Poster FP1307).

TNF inhibitors are now widely used for the management of several inflammatory conditions, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis. While the evidence linking anti-TNF treatment with CV outcomes is limited in psoriasis patients, data obtained in RA patients show that anti-TNF agents are associated with a significant reduction in the incidence of first CV events, including myocardial infarction (adjusted HR 0.46; 95% CI, 0.25-0.85), and a significantly lower mortality (HR 0.65; 95% CI, 0.46-0.93) (J Rheumatol 2005;32(7):1213-8). Therefore, there may be more risks in not treating patients and with “appropriate assessment and screening of the individual CV risk and maintaining early disease control over a prolonged period of time, it should be possible for us to give our psoriasis patients those 10 to 20 missing years back,” Dr. Gulliver stated.

Prof. Kristian Reich, Dermatologikum Hamburg, Germany, highlighted some of the practical challenges that dermatologists will face when endeavouring to control inflammation for prolonged periods of time for a large number of patients. “Our patients will be asking us what they can expect from their treatment,” remarked Prof. Reich. “We lack studies that correlate a specific Psoriasis Area and Severity Index (PASI) score to levels of comorbidity. Until data like this become available, we need to know exactly what is going on not just during the induction phase but in the longer term as well.”

In study findings, one key to interpreting long-term psoriasis data is to understand how missing data are treated. The most conservative approach is the intent-to-treat (ITT) analysis with non-responder imputation (NRI) whereby all drop-outs, regardless of reason, are treated as non-responders. Last-observation-carried-forward (LOCF) analyses allow data from drop-outs to remain in the study and be included in the end point analysis; as-observed analyses only take into account the patients who actually complete the study.

This was clearly illustrated in a recent publication of 3-year data for infliximab in patients with psoriasis. PASI 75 responses ranged from 41% using the ITT-NRI approach to 75% with the as-observed approach (Dermatology 2010;221(suppl 1):43-7). “Different methods may yield widely differing results,” explained Prof. Reich. “This is not because they are designed to cheat; different methods are simply used to consider different aspects of the intervention. As-observed data provide us with a probability of success for a patient who remains on the therapy for the duration of treatment, whereas the ITT-NRI approach gives us a worst-case scenario.”

Prof. Reich also advised caution as the statistical methodology may actually get in the way of providing useful information, for example, by defining arbitrary cutoff points and excluding non-responders which make it very difficult to interpret the study results. Examples of this include REVEAL (The Randomized Controlled Evaluation of Adalimumab Every Other Week in Moderate to Severe Psoriasis Trial), which included cut-off points at 16 and 33 weeks after which only patients fulfilling pre-defined response criteria were analyzed (J Am Acad Dermatol 2008;58(1):106-15); and the PHOENIX (Efficacy and Safety of CNTO 1275 in the Treatment of Subjects with Moderate to Severe Plaque-type Psoriasis Followed by Long-term Extension) study of ustekinumab which included a cut-off point at 12 weeks (Lancet 2008;371(9625):1665-74). In contrast, EXPRESS (European Infliximab for Psoriasis Efficacy and Safety Study) employed strictly-defined, pre-specified ITT and per-protocol analyses which proved highly conservative with only a modest difference between the 2 methods: the proportion of patients achieving PASI 75 at week 50 was 61% in the ITT population and 71% in the pre-specified per-protocol population (Lancet 2005;366(9494):1367-74). “We all know that loss of efficacy is an issue with biological therapies, and missing data will be a problem when interpreting clinical trials over prolonged periods of time. Different statistical methods have their pros and cons; the important thing is to know what is going on,” concluded Prof. Reich.

Achieving Treatment Goals

The long-term treatment goals for psoriasis are largely the same as those that have been established for short-term management, i.e. to achieve a PASI score of 75 or alternatively a Physician Global Assessment (PGA) score of clear or almost clear and a Dermatology Life Quality Index (DLQI) score of 0 or 1 (J Eur Acad Dermatol Venereol 2009;23(suppl 2):1-70). Achieving and sustaining such responses may require dosing adjustments or switching to another TNF inhibitor.

In PSUNRISE (Prospective Study Using Remicade in Psoriasis Patients With an Inadequate Response to Etanercept), patients with significant psoriasis despite treatment with etanercept for =4 months were switched to infliximab 5 mg/kg infusions at weeks 0, 2, 6, 14 and 22. As reported previously, 65.4% (72.5% as observed) of patients achieved a PGA score of 0 (clear) or 1 (minimal) at week 10. PGA scores of clear or minimal were observed as early as week 1 and increased throughout the study to 72.4% at week 26. In the latest analysis of PSUNRISE, the global reduction of disease activity was paralleled by regional responses in high-impact areas. By modified ITT, overall psoriasis improvements were reported in 64.6% and 51.7% of patients according to the Visual Analogue Scale (VAS) and PASI 75. VAS improvements observed included the scalp (84.9%), face (72.0%), palms and soles (72.1%) and nails (70.1%). PASI 75 improvements were reported for head (69.3%), trunk (72.7%), upper extremities (56.4%) and lower extremities (52.2%). No new safety signals were detected.

Summary

Managing psoriasis in the longer term constitutes a challenge for dermatologists, both in terms of maintaining efficacy of anti-inflammatory therapy and preventing the development of debilitating comorbidities. TNF inhibitors have advanced the management of psoriasis and other severe inflammatory conditions such as RA and IBD, and well-designed clinical trials indicate that it is possible to maintain clinical efficacy for prolonged treatment periods. However, when interpreting published trial data, it is important to bear in mind that the statistical methodology may have a dramatic impact on the outcome of the analyses. Consequently, great caution should be exercised when managing patient expectations on the basis of clinical trial findings.