Clinical Outcome Measurements VIII

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Clinical Outcome Measurements VIII

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^Psoriasis

Kenneth B. Gordon

Contents

1 Introduction 125

2 Psoriasis Area and Severity Index (PASI) 125 3 Physician’s Global Assessment (PGA) 127 4 Combination Outcome Measures 127 5 Conclusion 128

References 128

1 Introduction

Measuring improvement in psoriasis, while seemingly straightforward, remains a perplex- ing problem. It is relatively easy to estimate the amount of the body covered with psoriatic plaques; however, this measurement does ac- count for the severity of the lesions involved.

Moreover, the severity of the disease can be dis- tinct from the number or size of lesions. A re- cent consensus conference of the American Academy of Dermatology emphasized that any determination of the severity of psoriasis re- quires special attention to the impact of the disease on the patient’s quality of life [1]. Since the impact of psoriasis may differ from one patient to the next, any physical measurement of psoriasis will necessarily be an incomplete assessment of the severity of the disease. In this chapter, the commonly used techniques for measur-

ing the clinical severity of psoriasis will be dis- cussed. The critically important measures of quality of life are reviewed in Chap. VIIA.

2 Psoriasis Area and Severity Index (PASI)

The most commonly used outcome measure for the extent and severity of psoriasis in clinical trials today is the PASI. The PASI is a complex formula (Table A1) that was introduced in studies of systemic retinoids in 1978 [7]. The PASI incorporates the elements in the clinical pres- entation of psoriasis that are readily visible on the skin: erythema, scaling, and desquamation.

Each element is assessed separately on a 5 point (0–4) scale for each of the sections of the body:

the head and neck, the trunk, the upper extremities, and the lower extremities. Scores for each of the three different factors are added, along with the score from a 6 point scale (1–6) repre- senting the surface area involved on that body region. This number is multiplied by a correc- tion factor that accounts for the area encom- passed by that body region (0.1 for the head and neck, 0.2 for the upper extremities, 0.3 for the trunk, and 0.4 for the lower extremities). Fi- nally, the scores for the 4 body regions are added to give the PASI score. The highest possible PASI is 72 though this number is generally considered impossible to attain. Scores in the 20’s and 30’s are considered to represent very severe disease.

Given the complexity of the PASI, it is not surprising that it is almost never used as a clinical measurement in dermatology offices. It is exclusively a tool for research purposes. The PASI can be manipulated in a number of ways as an outcome measurement. In clinical trials,

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the percentage change in PASI may be used as an endpoint. More commonly, however, the clinical endpoint of therapy is defined as the number of patients who reach a minimum percentage improvement in the PASI. The United States Food and Drug Administration (FDA) has used a 75% improvement in PASI as repre- senting the clinically significant hurdle to de- fine a patient response. Many researchers, however, believe that the PASI underestimates the clinical response to therapy and that a 50% improvement in PASI is a more reasonable endpoint [2]. Large changes in the quality of psoriasis lesions, without concomitant changes in surface area, is a common clinical scenario, and would result in a change in PASI that would be defined as non-responsive by the FDA criteria, but may be quite significant to the patient [2, 3].

Other difficulties with the PASI stem from the difficulty measuring it, as well as its lack of correlation with patient reported outcomes.

Measurement of body surface area is inconsis- tent among researchers, leading to significant inter-observer variability [14]. More important- ly, the PASI does not clearly predict the impact of the disease on patients. Studies examining the correlation of quality of life with PASI scores have demonstrated that there is little consistency [10]. On the positive side, PASI im- provements do seem to correlate to improve- ments in quality of life in placebo controlled trials.

Several variations of the PASI have been proposed to improve upon these weaknesses, as well as to decrease the time and effort needed to perform this complex measurement. One particularly interesting variation is to have the

Chapter VIII Clinical Outcome Measurements 126

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Table A1.Measurement of the Psoriasis Activity and Severity Index [7]

Head and neck Upper extremities Trunk Lower extremities

1 Erythema 2 Induration 3 Scale 4 1+2+3 5 Area 6 4× 5

7 Body Segment Factor 0.1 0.2 0.3 0.4

8 6× 7 A B C D

Total PASI=A+B+C+D

Ratings for Erythema, Induration, and Scale:

0 – none 1 – mild 2 – moderate 3 – severe 4 – very severe

Ratings for Regional Surface Area:

1 – 1–<10%

2 – 10%–<30%

3 – 30%–<50%

4 – 50%–<70%

5 – 70%–<90%

6 – 90%–100%

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patient perform a modified PASI on him-/her- self. This measurement is called the Self Ad- ministered PASI (SAPASI) [4]. The SAPASI cor- relates well with PASI [6] and is responsive to therapy [5]. The SAPASI may be a particularly useful instrument in large, epidemiologic studies, where physician examination of all patients may be impractical [5].

3 Physician’s Global Assessment (PGA) Other measures of psoriasis severity have developed that are simpler to calculate than the PASI. One approach is to examine the overall quality of the lesions and assign a general severity score. This physician’s global assessment (PGA) is most similar to the criteria used in a clinician’s office to assess response. There are a number of different scales for the PGA and they are identified by many different names [8, 15].

The most important distinction is whether the PGA represents a static measure of disease severity at a single point in time, or as a dynamic measure of improvement following an inter- vention. Samples of each approach are shown in Table A2 [8, 13].

The primary endpoint used in static global assessments is the number of patients who reach the categories of “clear and almost clear.”

This is generally considered the point where almost all patients will be satisfied with their therapy. Interestingly, in studies where both a PASI 75 and static PGA have been measured, these numbers are generally very similar. Im-

portantly, the PGA seems to have greater intra- rater and inter-rater reproducibility than the PASI, making it potentially a more effective research tool [14].

A variation of the PGA that has been studied as a possible outcome measure is the Lattice System PGA (LS-PGA). This system relies on global ratings of scale, erythema, and lesion thickness to determine an overall rating for the patient. Particular emphasis is placed on le- sional thickness with this instrument. In a small study, this measure had better intra-rater reproducibility than the PGA with similar inter-rater concordance [14].

4 Combination Outcome Measures As noted above, measures of physical disease burden often do not represent the full impact of psoriasis on the patient. On the other hand, quality of life measures do not always indicate the full physiological effect of a medication.

Combination outcome measures, incorporating both physical measures of disease burden and quality of life outcomes, have been proposed.

This type of approach is commonly used in other areas of clinical research; the American College of Rheumatology (ACR) response criteria reviewed in Chap. VIIIB is a good example.

Two different combination criteria have been developed and validated in clinical trials, the National Psoriasis Foundation Psoriasis Score (NPF-PS) and the Salford Psoriasis Index (SPI). The NPF-PS incorporates elements of the PASI, and global assessments of both disease extent and symptoms. It has been compared to the PASI and the PGA in a small clinical trial and seems to correlate well [9]. Use of the NPF- PS has been limited by its complexity.

The SPI was developed to combine disease severity with the impact of psychosocial pres- sures faced by the patients. It is based on cancer staging methods, and incorporates separate scales for the amount of disease (PASI), a psychosocial instrument, and a record of disease treatment over time [11]. By combining these separate elements, it may be possible to better categorize the impact of disease on patients and to direct therapy based on this impact.

Kenneth B. Gordon

A Psoriasis 127

Table A2.Samples of the Physician’s Global Assessment (PGA) [8]

Static Global Dynamic Global

Assessment Assessment

Very severe Worse

Severe Unchanged

Moderate Slight improvement

Mild Fair improvement

Minimal Good improvement

Clear Excellent improvement

Cleared

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While this approach is still being developed, it seems a promising compromise for both research and clinical use [12].

5 Conclusion

Measuring the amount of psoriasis as well as its impact remains a significant challenge for clinical research in psoriasis. While the PASI and the physician’s global assessment re- main the standards, new criteria, including the NPF-PS and SPI are being developed that incorporate the impact of psoriasis on patients, not simply the physical amount of disease. Over time, evidence of the value of these types of outcome measures in other specialties, such the ACR criteria, will likely lead to greater acceptance of combination measures by dermatology researchers.

References

1. Callen JP, Krueger GG, Lebwohl M, McBurney EI, Mease P, Menter A, Paller AS, Pariser DM, Weinblatt M, Zimmerman G (2003) AAD consensus statement on psoriasis therapies. J Am Acad Dermatol 49 : 897–899

2. Carlin CS, Feldman SR, Krueger JG, Menter A, Krueger GG (2004) A 50% reduction in the Psoria- sis Area and Severity Index (PASI 50) is a clinically significant endpoint in the assessment of psoriasis.

J Am Acad Dermatol 50 : 859–866

3. Feldman SR (2003) The design of clinical trials in psoriasis: lessons for clinical practice. J Am Acad Dermatol 49 : S62–S65

4. Feldman SR, Fleischer AB Jr, Reboussin DM, Rapp SR, Exum ML, Clark AR, Nurre L (1996) The self-ad- ministered psoriasis area and severity index is valid and reliable. J Invest Dermatol 106 : 183–186 5. Fleischer AB Jr, Feldman SR, Dekle CL (1999) The

SAPASI is valid and responsive to psoriasis disease

severity changes in a multi-center clinical trial.

J Dermatol 26 : 210–215

6. Fleischer AB Jr, Rapp SR, Reboussin DM, Vanarthos JC, Feldman SR (1994) Patient measurement of psoriasis disease severity with a structured instrument.

J Invest Dermatol 102 : 967–969

7. Fredriksson T, Pettersson U (1978) Severe psoriasis – oral therapy with a new retinoid. Dermatologica 157 : 238–244

8. Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, Bresnahan BW, Menter A (2003) Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial.

JAMA 290 : 3073–2080

9. Gottlieb AB, Chaudhari U, Baker DG, Perate M, Dooley LT (2003) The National Psoriasis Founda- tion Psoriasis Score (NPF-PS) system versus the Psoriasis Area Severity Index (PASI) and Physician’s Global Assessment (PGA): a comparison. J. Drugs Dermatol 2 : 260–266

10. Heydendael VM, de Borgie CA, Spuls PI, Bossuyt PM, Bos JD, De Rie MA (2004) The burden of psoriasis is not determined by disease severity only. J In- vest Dermatol Symp Proc 9 : 131–135

11. Kirby B, Fortune DG, Bhushan M, Chalmers RJ, Griffiths CE (2000) The Salford Psoriasis Index: an holistic measure of psoriasis severity. Br J Dermatol 142 : 728–732

12. Kirby B, Richards HL, Woo P, Hindle E, Main CJ, Griffiths CE (2001) Physical and psychologic measures are necessary to assess overall psoriasis severity. J Am Acad Dermatol 45 : 72–76

13. Krueger GG, Papp KA, Stough DB, Loven KH, Gul- liver WP, Ellis CN (2002) A randomized, double- blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 47 : 821–833

14. Langley RG, Ellis CN (2004) Evaluating psoriasis with psoriasis area and severity index (PASI), psoriasis global assessment (PGA), and lattice system physician’s global assessment (LS-PGA). J Am Acad Dermatol (in press)

15. Weinstein GD, Koo JY, Krueger GG, Lebwohl MG, Lowe NJ, Menter MA, Lew-Kaya DA, Sefton J, Gibson JR, Walker PS (2003) Tazarotene cream in the treatment of psoriasis: Two multicenter, double-blind, randomized, vehicle-controlled studies of the safety and efficacy of tazarotene creams 0.05% and 0.1%

applied once daily for 12 weeks. J Am Acad Derma- tol 48 : 760–767

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