ReportA 50% reduction in the Psoriasis Area and Severity Index (PASI 50) is a clinically significant endpoint in the assessment of psoriasis☆
Section snippets
Emergence of PASI 75 as a primary endpoint
In recent years, the US Food and Drug Administration (FDA) and pharmaceutical companies have used a reduction from baseline PASI score of ≥75%, termed PASI 75, as the benchmark of primary endpoints in assessing therapies for psoriasis.14, 15, 16 This endpoint stemmed from 1998 deliberations between the FDA and the Dermatology Advisory Council.17 No formal conclusions were reached at this meeting, and the FDA has not offered formal guidelines on the matter. Patients reaching PASI 75 experience
Consideration of PASI 50 as a primary endpoint
After assessment of PASI and QoL data, it is our consensus that PASI 50, or a reduction in PASI score of ≥50%, consistently demonstrates clinically meaningful improvement and represents an appropriate primary endpoint for clinical trials. This position is supported by several lines of evidence: (1) the PASI score is not linearly reflective of psoriasis severity, and thus PASI 50 can represent far greater than 50% improvement in disease activity; (2) treatment with methotrexate, a very effective
Improvements in PASI score do not linearly reflect improvement in psoriasis
An improvement in PASI score does not correlate in a 1:1 ratio with improvement in disease and can underestimate improvement. Consider how the PASI scoring system works.8 Erythema, induration, and scale are each measured on a 0-4 scale: 0 is none, 1 is barely perceptible, 2 is slight, 3 is moderate, and 4 is severe. Area is nonlinear and is measured using a 1-6 scale (1 is <10% body surface area (BSA) involvement, 2 is 10%-<30% BSA, 3 is 30%-<50% BSA, 4 is 50%-<70% BSA, 5 is 70%-<90% BSA and 6
PASI improvement with a known effective therapy
Improvement of psoriasis with methotrexate provides additional evidence that PASI 50 equates to clinically meaningful improvement. Methotrexate is currently the established “gold standard” of therapy when considering systemic agents for this disease. While it is recognized as having considerable side effects, there is no question that it is a highly effective psoriasis treatment. In a past survey of dermatologists that ranked reasons for using ultraviolet B (UVB) versus psoralen plus
Improvements in quality of life measures exist at PASI 50
In addition to a statistical differentiation from placebo using an objective measure, the Medical Advisory Board of the National Psoriasis Foundation affirms that a therapeutic agent that predictably enhances QoL for patients with psoriasis provides clinically meaningful improvement.31 With large enough sample sizes, very small changes in lesion severity between drug and placebo can reach statistical significance. It is acknowledged that if enough patients were entered into a clinical trial,
Patients who achieved high PASI scores delay re-treatment to levels below PASI 50
Evaluating re-treatment desires of patients gives additional evidence that PASI 50 is a clinically meaningful endpoint. In two phase II trials of alefacept, patients who had achieved an improvement in PASI of 75% from their original baseline and who had been taken off active medication were given the option to restart alefacept at their discretion (S. Ertel, personal communication, Sept 12, 2002). With this freedom, the patients allowed their PASI score to drop to an average of 20% improvement
Effective medications are differentiated from placebo at PASI 50
A clinically significant treatment must provide an improvement that has a statistically significant P value (<.05), compared to placebo, in a properly blinded and powered, placebo-controlled clinical trial.31 Additionally, an objective endpoint that measures the clinically meaningful treatment would be useless if it could not differentiate active drugs from placebos.
In 3 recent placebo-controlled trials of alefacept,19 efalizumab,* and etanercept,50 statistical differences from placebo were
Governing agencies, physicians, insurance carriers, and patients should embrace PASI 50 as clinically meaningful improvement
Reduction in the PASI score of at least 50% affords improvement in QoL, provides statistical differentiation from placebo, and represents true improvement. If a particular therapy is developed that consistently helps patients achieve a PASI 50 response but not a PASI 75 response, such a therapy could be highly beneficial to patients even though it would not meet current regulatory requirements for FDA approval. It is our position that regulatory bodies wanting to use a reduction in PASI as a
Acknowledgements
The Medical Advisory Board of the National Psoriasis Foundation has been interested in determining whether a reduction in PASI of 50% from baseline as a result of therapeutic intervention is clinically meaningful. After due deliberation the Board voted to direct a writing committee to generate an evidence-based assessment of this issue. The position represented herein is the completion of this assignment.
The members of the Medical Advisory Board of the National Psoriasis Foundation are Jerry
References (52)
- et al.
The impact of psoriasis on the quality of life of patients from the 16-center PUVA follow-up cohort
J Am Acad Dermatol
(1997) - et al.
Psoriasis causes as much disability as other major medical diseases
J Am Acad Dermatol
(1999) - et al.
Quantifying the harmful effect of psoriasis on health-related quality of life
J Am Acad Dermatol
(2002) - et al.
Psoriasiscurrent perspectives with an emphasis on treatment
Am J Med
(1999) - et al.
The self-administered psoriasis area and severity index is valid and reliable
J Invest Dermatol
(1996) - et al.
Etanercept in the treatment of psoriatic arthritis and psoriasisa randomised trial
Lancet
(2000) - et al.
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
(2002) - et al.
Two considerations for patients with psoriasis and their clinicianswhat defines mild, moderate, and severe psoriasis? What constitutes a clinically significant improvement when treating psoriasis
J Am Acad Dermatol
(2000) - et al.
The outcomes movement and new measures of the severity of psoriasis
J Am Acad Dermatol
(1996) - et al.
Quality of lifea valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn's Relapse Prevention Trial Study Group
Gastroenterology
(1994)
Rederived values of the eight coefficients of the Crohn's Disease Activity Index (CDAI)
Gastroenterology
Physical and psychologic measures are necessary to assess overall psoriasis severity
J Am Acad Dermatol
Linkage disequilibrium analysis of familial psoriasisidentification of multiple disease-associated MHC haplotypes
Tissue Antigens
Quality of life measures in psoriasisa critical appraisal of their quality
J Clin Pharm Ther
The impact of psoriasis on quality of liferesults of a 1998 National Psoriasis Foundation patient-membership survey
Arch Dermatol
Severe psoriasis—oral therapy with a new retinoid
Dermatologica
The Salford Psoriasis Indexan holistic measure of psoriasis severity
Br J Dermatol
The SAPASI is valid and responsive to psoriasis disease severity changes in a multi-center clinical trial
J Dermatol
Clinical measures of disease severity and outcome in psoriasisa critical appraisal of their quality
Br J Dermatol
Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes
N Engl J Med
Anti-E-selectin is ineffective in the treatment of psoriasisa randomized trial
Br J Dermatol
Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cells
J Exp Med
Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells
J Exp Med
Cited by (0)
- ☆
Funding sources: none.
Disclosure: The commercial associations, current or over the past 5 years, that might pose a conflict of interest including consultant arrangements, honoraria, stock or other equity ownership, research grants and support are the following: Christopher S. Carlin, MD—Roche Pharmaceuticals; Steven R. Feldman, MD, PhD—Amgen, Bristol-Meyers Squibb Dermatology, Connetics Corporation, Novartis, Dermatology Foundation, American Society of Dermatologic Surgery, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, Photomedex, Genetech, Biogen, Galderma, and 3M; James G. Krueger, MD—Amgen, Biogen, Boehringer, Centocor, Genentech, Pfizer, and Protein Design Labs; Alan Menter, MD—Abbott, Amgen, Biogen, Centocor, Corixa, Genentech, Otsuka, Roche, and Serona; and Gerald Krueger, MD—Allergan, Amgen, Biogen, Centocor, Fujisawa, Genetech, Isis, Roche Pharmaceuticals, Serona, and Watson.
A portion of the information contained in this manuscript was presented in poster form at the International Investigative Dermatology meeting of the Society of Investigational Dermatology from April 30-May 4, 2003.
Accepted for publication September 13, 2003.
Reprints not available from authors.