As mentioned above, CLE is multidimensional and it is our impression that the different dimensions of the disease have to measured and assessed separately. The cutaneous aspects of the disease can be measured by the CLASI, the pain with visual analogue scales, the quality of life with different quality of life measures, preferably those focused on skin symptoms like the Skindex, rather than with other instruments like the SF-36 (39
) which are likely to underestimate the specific quality of life issues related to skin diseases. What actually constitutes a meaningful clinical difference is notoriously difficult to assess.
Based on experience with a pain scale it seems that on a 0–10 visual analogue scale a change of 2 points is clinically meaningful (40
). For most important instruments there is a body of evidence that facilitates the interpretation of study outcomes, which are then taken up by the FDA. However, still the translation of what is generally considered a clinical meaningful outcome is often conceptually difficult. Is a score of 50 of the OSAAD (Objective Severity Assessment of Atopic Dermatitis) twice as bad as a score of 25 (i.e. is the score linear)? What does a 75% reduction of the Psoriasis Activity and Severity Index (PASI), short PASI 75, mean for the patient? The answer for the individual patient will depend on the location of the lesions and their visual prominence as much as on the restrictions that the patient feels in his normal life due to them. Some patients will always wear long sleeves if any skin blemish can be noted and restrict their leisure activities, while others are largely unfazed by clearly obvious and prominent lesions. Thus the answer for clinical trials is an evaluation that correlates quality of life instruments with clinical outcome instruments.
A general criticism of outcome instrument is that they do not adequately reflect the improvement of the patients. This is correct, but misleading because the criticism assumes that the disease process is a measurable conceptual entity that can be expressed as a clinical summary score. Even taking into account the differences of disease perception between patients, instruments are designed to measure only limited aspects of a disease. A thermometer measures body temperature but not what it feels like to have fever, or whether the fever is dangerous; similarly an instrument like the PASI reflects the affected skin area but not the psychological or the physiological effect of psoriasis. This is due to the nonlinear nature of many disease processes, which resists summarization in one number. A frequently used solution in therapeutic research is to express change in terms of differential, i.e. the relative reduction of the score. Again however, this is no panacea. The same PASI 75 may signal dramatic improvement in some patients while others feel that their disease has hardly changed because hand and facial lesions are still present. Thus dramatic improvement in Quality of Life instruments may be associated with changes in the disease activity based on the location of the lesions. As a consequence HRQL often does not parallel clinical disease severity as assessed by the clinician, though it may arguably be one of the most important clinical guides to treatment choice (41
). HRQL, however, cannot be the only measure for clinical trials for several reasons, amongst them
- For early trials during clinical development, it is important to show that a treatment is physiologically active and can change the disease process, i.e. to demonstrate efficacy. For these trials the utilization of HRQL outcomes as a primary outcome may be far too early.
- Particularly for scarring diseases treatment that halts the disease process is tremendously important. However, if scarring cannot be completely avoided, the patient may be traumatized by the wounds s/he has suffered and quality of life may not return to normal. Quality of life may not improve or even worsen with development of more damage, even when the activity of the disease has improved.
- The diagnosis of a severe skin disease may be life altering in itself and lead to changes, like strict sun avoidance, which in themselves can be life altering.
However, when used to assess the final effectiveness of treatment, HRQL is an important outcome. That treatment may not be successful in changing HRQL by itself is not necessarily a sign of treatment failure. We validated the CLASI to demonstrate clinical responsiveness in small group of nine patients with CLE (5 DLE, 2 SCLE, 2 DLE/SLE). The results of our study were surprising in that complete resolution of the disease in two SCLE patients in particular was only associated with minimal improvement in their Skindex scores as they dropped from 68 to 67 and 77 to 70. Combined we only found moderate correlation (Spearman r=0.55) between improvements of the CLASI activity scale and the Skindex scores. In 3 DLE patients we found mild to moderate improvement of the Skindex even though the skin condition as measured by the CLASI did not improve. In three patients the Skindex and the CLASI correlated, in one the skin condition got worse and the patients Skindex increased, in another the skin remained unchanged as did the Skindex and in the third the skin improved as did the Skindex.(42
) These results of a small study with a single investigator are only preliminary. But they confirm the clinical experience that arrest of the activity, particularly in scarring conditions, while preventive, does not solve the HRQL problems that the patients face. In order to address these problems the therapeutic approach has to include reconstructive and cosmetic treatment. The patient may also continue to be faced with limitations like sun avoidance that can seriously restrict social and leisure activities like sports. In addition CLE may be only part of the patient’s affliction that is compounded by the systemic symptoms that the patient may have.
As with the CLASI itself it would be desirable if investigators in this relatively rare disease could try to use the same HRQL instrument throughout. We have used the Skindex, but others may find other instruments more responsive and helpful. Ideally those interested in clinical research of lupus would come together to try to establish a standard that does not need to be the Skindex to facilitate comparison between studies. This has been done successfully in oncology.