Joerg Albrecht, Victoria P. Werth*
Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA
1. Introduction to outcome measures in cutaneous autoimmune disease
The ability to measure, to describe, to classify and to diagnose diseases is the prerequisite for successful clinical research. Diagnosis and classification of cutaneous autoimmune diseases have made enormous progress during the latter half of the last century. In general, we now have a solid frame of reference for clinical research even though some of the diagnostic criteria are still being refined, and we are likely to see new and important markers of autoimmune diseases that will be introduced into clinical practice. However, comparative trials depend on outcome instruments that measure the extent and severity of a disease and can be used to compare the baseline status with the condition of the disease after treatment has been initiated. These are largely missing for the skin.
The success of any therapy for the skin can always be assessed by comparing the proportion of patients in each treatment group who have completely cleared their skin disease. While this basic comparison is readily available and likely to be reliable, this approach is not suitable for all diseases. It works only for diseases for which undisputed cure can be achieved, such as acute cutaneous bacterial infections, or for those diseases for which the
Department of Dermatology, University of Pennsylvania, 2, Rhodes Pavillion, 3600 Spruce Street, Philadelphia, PA 19119, USA.
Tel.: +1-215-823-4439; Fax.: + 1-215-823-5994 E-mail address: [email protected] (V.P. Werth).
study's baseline comparisons are likely to focus on secondary patient characteristics. The extent and activity of the disease in question cannot be measured without appropriate instruments.
The assessment of treatment success or the natural history of chronic skin diseases, particularly autoimmune diseases, has to allow measurement of subtle, gradual changes that are still clinically significant. Total permanent clearance is rarely achieved and patients who have been successfully treated may still have some lesional activity or suffer permanent damage from the disease. In addition, studies using binary outcome of total clearance and failure are likely to be prohibitively large for diseases that are as rare as many autoimmune diseases. Therefore, sensitive and clinically meaningful outcome instruments are a critical prerequisite for clinical research. Unfortunately, to date, the number of outcome instruments available to study autoimmune diseases is quite limited.
In this chapter, we will first describe some general experiences with outcome instruments in dermatology and then describe in detail the development of outcome instruments based on the experience in cutaneous lupus erythematosus (CLE) and dermatomyositis (DM).
During the last three or four decades there have been numerous attempts to develop instruments to measure skin disease. Unfortunately, several of these instruments are not reliable and therefore lack the precision that is necessary to conduct trials in rare diseases (Charman and Williams, 2000). As a good approximation of the available scores, the medical algorithm project lists 111 medical algorithms in dermatology (www.medal.com, accessed 06/02/2005). Roughly, 30 of these can be used to grade the severity of diseases or were designed to be used as outcome instruments in clinical trials.
There have been attempts to develop general scores for dermatology, e.g. the dermatology index of disease severity (DIDS) (Faust et al., 1997), but the validation of general scores is challenging. The DIDS was validated in psoriasis patients and was helpful in the population studied. However, while it may work well in psoriasis, this score is not the solution for autoimmune diseases for various reasons. An accompanying editorial by Williams (1997) pointed out that the measure of extent of body surface area (BSA) involved was inappropriately crude for other diseases like acne—or indeed CLE or DM. These disease have a different distribution and involvement of BSA than psoriasis (Williams, 1997) and may hugely affect patients' lives while they only affect a small percentage of BSA. Also, the score tries to assess dermatological disease severity in terms of functional disability. This is helpful if the functional disability is the consequence of the skin disease alone. However, autoimmune diseases, particularly systemic LE and DM, can lead to functional disability due to systemic involvement or muscle disease, even though the skin lesions are improving on treatment, thus blurring or obstructing the treatment effect.
The desirable qualities of an outcome instrument for clinical trials have been summarized very succinctly by Finlay (1996):
1. The method should be simple enough to use in a busy clinical setting.
2. The method should clearly separate scores derived from the observer and from the patient.
3. The signs chosen to be recorded should be amenable to change and should be unambiguous in their meaning and proven to be so. If the presence of two signs is highly correlated only one needs to be recorded.
4. Recording of area of involvement should be based on an assessment of the site of involvement rather than the virtually impossible task of determining an accurate total percentage involvement.
5. Validity testing, including repeatability testing by the same and different observers, must be carried out.
Unfortunately, most of the developed scores in dermatology are disease specific and many have not been properly evaluated. Often they were developed for specific clinical trials, which can skew the instrument to fit the therapeutic mechanism of the treatment rather than the needs of the patient population. For skin diseases with a large population burden like psoriasis, atopic dermatitis and acne there are a number of scoring systems, some of which have been validated and are used frequently by a number of researchers. The number of instruments varies widely, e.g. there are 10 scores for atopic eczema but only 3 for psoriasis on the medal.org website. Even though it is likely that not all psoriasis instruments were captured on the website, this difference reflects the dominance of the PASI (Psoriasis Activity and Severity Index) for psoriasis research. For atopic dermatitis even the more elaborately evaluated instruments like the scoring atopic dermatitis (SCORAD) have not reached this level of dominance, which can make the comparison of trial results very difficult and certainly hinders the conduction of meta-analysis (Kunz et al., 1997).
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Rosacea and Eczema are two skin conditions that are fairly commonly found throughout the world. Each of them is characterized by different features, and can be both discomfiting as well as result in undesirable appearance features. In a nutshell, theyre problems that many would want to deal with.