Psoriasis assessment tools in clinical trials
- 1Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
- 2Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, UT, USA
- Correspondence to:
Dr S R Feldman
Wake Forest University School of Medicine, Department of Dermatology, Medical Center Boulevard, Winston-Salem, NC 27157-1071, USA;
In clinical practice, broad global assessments of psoriasis disease activity and its effect on patients’ quality of life are used to assess the severity of patients’ disease and their response to treatment. In clinical trials, more objective, validated instruments are required. Several such instruments have been developed and continue to be developed to provide an assessment of the severity of the skin lesions. Because a lesion’s impact on patients’ lives varies widely among patients, there has been growing recognition of the need to measure the quality of life impact of the disease along with the severity of the lesions.
- DLQI, Dermatology Life Quality Index
- NPF-PS, National Psoriasis Foundation Psoriasis Score
- PASI, Psoriasis Area and Severity Index
- PGA, physician global assessment
The measurement of psoriasis disease activity in clinical practice is very straightforward. Physicians ask their patients how they are doing, and patients report their perceptions of the severity of their disease. By combining this subjective report with the physician’s global assessment of the severity of the lesions, the physician makes a determination of how severe the disease is and how well the patient is progressing with therapy.
Clinical trials of psoriasis present a greater challenge for measurement of psoriasis disease activity/severity. Objective measures are needed that are reliable, valid, and consistent from investigator to investigator. Fortunately, psoriasis lesions are quite visible and therefore relatively easy to quantify; unfortunately, simple quantitation of the lesions is not a complete assessment of severity, as the impact of the lesions is experienced differently by different patients. As discussed below, tools now exist to measure the character and extent of psoriasis lesions and there are other measures used to assess the effect of psoriasis on patients’ quality of life.
TRADITIONAL ASSESSMENT TOOLS
The basic characteristics of psoriasis lesions—redness, thickness, and scaliness—provide a means of assessing the severity of psoriasis. The current gold standard for assessment of extensive psoriasis has been the Psoriasis Area and Severity Index (PASI).1 The PASI is a measure of the average redness, thickness, and scaliness of the lesions (each graded on a 0–4 scale), weighted by the area of involvement (table 1). While the PASI has been the most widely used measure, it does have a number of limitations, one of which is its poor sensitivity to change for relatively small areas of involvement (table 2). In studies involving treatment for localised plaques of psoriasis, target lesion assessments are generally performed that also measure the redness, thickness, and scaliness of target plaques.
Another key measure used in clinical trials of psoriasis is the physician global assessment (PGA; table 3). Global assessments can be done for extensive disease as well as localised plaques. There are two primary forms: a static form, which measures the physician’s impression of the disease at a single point, and a dynamic form in which the physician assesses the global improvement from baseline. Because the latter requires the dubious assumption that physicians can remember the severity of psoriasis at baseline over the course of the trial, the static PGA has become the standard. Although the PASI is probably the gold standard for assessment of severe psoriasis (and PGA is also widely used), there have been few validation studies, and the construct validity, face validity, and sensitivity to change are not well characterised.2
When conducting a clinical trial for treatment for psoriasis, a predetermined primary endpoint is required on which the efficacy of the drug will be assessed.3 This endpoint must demonstrate that more patients achieve clinically meaningful success with the drug treatment than with placebo. Determining a definition for “clinically meaningful success” is somewhat problematic in psoriasis. For patients with severe psoriasis, clinicians typically consider at least 75% improvement in disease to be a clinically meaningful improvement indicative of success. This has been translated into 75% improvement in the PASI score; however, it is clear that patients with far lower improvements in the PASI score also can have clinically meaningful improvement in their disease. Quality of life measures are helpful for demonstrating that changes in the severity of the skin lesions correspond to improvement in patients’ lives. One advantage of the PASI score is that it is now well established that 75% improvement in PASI (PASI 75) is a clinically meaningful endpoint for clinical trials, and there is strong evidence demonstrating that 50% improvement in PASI (PASI 50) is also a clinically meaningful endpoint.4 A major limitation of the PASI is that it is not routinely used by clinicians and therefore is poorly understood by both clinicians and patients (see table 2). Physician global assessments that are used in trials are far easier to understand and are more similar to the assessments physicians actually perform in clinical practice.
MORE RECENT ASSESSMENT TOOLS
Other important psoriasis measurement tools are being developed. The lattice system provides a global psoriasis score that ranges over eight steps from clear to very severe.5 The investigator rates the elevation (also termed induration or thickness in other measures), erythema, and scaliness of the lesion, each on a none to mild, moderate, marked scale. The percentage of body surface area involved is also measured in categories of 0%, 1–3%, 4–9%, 10–20%, 21–29%, 30–50%, and 51–100%. By combining these areas of involvement with the character of the plaques, the psoriasis can be categorised into one of eight categories on the clear to very severe scale. This system shows a good correlation with both physician global assessment and PASI scores and provides better intrarater and interrater reliability than PASI.5 Although it first appears difficult to use, with experience the lattice system actually becomes quite easy to use and provides a static step score that has meaning for both doctors and patients. Still, determining what endpoint is clinically significant will need to be addressed. Is a one step change meaningful (for example, going from very severe to severe), or should a change of two or more steps be required? It is to be appreciated that the Food and Drug Administration (FDA), at this time, prefers a step score endpoint as it is believed to be more reflective of a physician’s assessment in non-study settings.
The National Psoriasis Foundation (NPF) has developed the NPF Psoriasis Score (NPF-PS), a responder index, that include six subdomains: induration at two target sites, current and baseline body surface area, physician global assessment, patient global assessment, and patient assessment of itch (table 4).6,7 To help improve intrarater and interrater reliability of the induration score, the NPF-PS utilises a reference card embossed with elevations that increase at 0.25 mm intervals.
Two other quantitative ways of measuring psoriasis are biopsies and photographs. Biopsies are attractive because they are objective—however, their major limitation is that psoriasis does not resolve in a uniform fashion, and therefore biopsies may not provide a representative sampling of lesions. Nevertheless, histological changes, decrease in epidermal thickness, and loss of K16 in biopsies taken after 30 days of therapy will predict outcome weeks to months later.8 Histological evaluations can be objective and are useful for assessing biomarkers of improvement as well as following pharmacodynamic endpoints. In theory, photography could be used to confirm real time assessments of disease severity. It is not clear, however, if thickness/induration or even scaliness of lesions can be accurately assessed using the photographs. Nevertheless, photographs do make a strong impact in educating physicians and are therefore commonly incorporated into clinical trials.
A major component of the assessment of psoriasis now is the measurement of quality of life. Measures of quality of life do not directly measure the impact of a drug on disease, however, they do measure the impact of the disease and the ability of treatment to improve patients’ lives. Because improving patients’ lives is the primary goal of therapy, quality of life measures are very important.9,10 Nevertheless, the primary outcome in clinical trials almost certainly will remain the relatively more objective measures of disease severity. The tools listed in tables 2 and 3, with the exception of the NPF-PS, do not assess this impact. Some patients have lots of lesions but are not bothered by them, and some patients have very few lesions and are greatly bothered by them. Treatments that improve lesions but do not improve quality of life are not providing a clinically meaningful benefit. In general, there is correlation between quality of life measures and changes in the more objective measures such as PASI and PGA; however, the correlation is far less than 1:1 (see table 2).
Quality of life can be measured at different levels. Non-specific measures such as the Medical Outcome Survey Short Form 36 (SF-36), the Euro QoL, and utility measures assess patients’ overall quality of life.11,12 There are more specific instruments that focus on aspects of quality of life that are affected by skin disease. These include the Dermatology Life Quality Index (DLQI) and the Skindex.13,14 There are even psoriasis specific measures. The generic measures, such as the SF-36, are useful for showing the impact of psoriasis relative to other medical diseases. The SF-36 was used to show that the impact of psoriasis was as great or greater than many other serious medical conditions.15 The DLQI has been most widely used measure for assessing quality of life related to skin disease in psoriasis trials.13 This instrument consists of 10 questions covering six domains (symptoms and feelings, daily activities, leisure, work and school, personal relationships, and bother with psoriasis treatment). The response options range from 0, not affected at all, to 3, very much affected. This gives an overall range of 0–30 where lower scores mean better quality of life. The reliability, construct validity, and sensitivity to change of the DLQI have all been demonstrated in psoriasis patients.16 Another score that includes psychological impact along with the severity of the skin lesions is the Salford Psoriasis Index (SPI).17 This measure includes the extent of psoriasis, the psychosocial impact of the disease, and the intensity of previous psoriasis treatments. The psychosocial impact component showed good correlation (r = 0.59) with the Psoriasis Disability Index, and the extent of psoriasis component showed good interrater reliability (r = 0.70).17
Trials of new agents—such as alefacept, efalizumab, and tumour necrosis factor α (TNFα) inhibitors such as etanercept and infliximab—have demonstrated that patients’ quality of life clearly improves with treatment.18–23 Detailed examination of some of these trials has shown that even in those patients who achieve only 50% improvement in the PASI, but not 75% improvement in the PASI, have significant improvement in their DLQI scores, meaning that patients with this level of improvement in the skin lesions are achieving clinical significant improvement in their quality of life.4
An important feature of the quality of life score is that it is complementary to the lesion severity scores. For example, mean PASI scores may show statistically significant improvement early in clinical trials, and quality of life measures can be used to confirm that these changes are clinically meaningful. For example, in etanercept trials, quality of life measured by DLQI was improved four weeks into the course of treatment, confirming the clinical significance of early PASI changes.21
A final assessment that may be of value in the future is genomics. These studies may lead to better mechanistic understanding of psoriasis. For treatment purposes, genomics may also be particularly helpful for providing prognostic information and for guiding treatment recommendations that may provide patients the maximum benefit with the fewest side effects.24
In conclusion, there is no one “best” measure for use in clinical trials. The PASI, along with physician global assessment and quality of life measures, provide a complement of measures for studies of moderate to severe psoriasis that offer objectivity, are understandable to clinicians, and yield a comprehensive view of the impact of disease. Radically changing psoriasis measurement in future trials would have the further disadvantage of making it difficult to compare the efficacy of new agents to established agents that had been tested under the previous measurement paradigm. However, recent clinical trials in psoriasis have clearly shown that the PASI was not a way to measure therapeutic response in those patients who had a PASI <3; a standardised assessment tool that effectively measures small amounts of psoriasis is needed. Target lesion severity score, supplemented by physician global assessment and quality of life measures, is the current standard, but the NPF-PS may prove to be an effective approach. If it works well in clinical trials, the NPF-PS would have the advantage of assessing response or natural history of all forms of plaque psoriasis.