Riesgos de los metales pesados a la salud y al medio ambiente

As discussed in previous sections, the majority of outcome measures used in PsA research have been “borrowed” from other diseases and have only been validated in subsets of disease. Recently, there have been increasing efforts in the development of a validated composite outcome measure which reflects disease activity in all of the domains in PsA and can be used in a variety of subsets of disease.

In recent years, work has been underway on two key composite measure initiatives, both led by members of Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). Professor Fitzgerald and colleagues proposed a composite outcome measure based on the GRAPPA treatment grid published by Ritchlin and Kavanaugh (Ritchlin et al. 2009). The Composite PsA Disease Activity Index (CPDAI) assigns a score of 0-3 to each of the five domains of PsA based on disease activity and impact of disease for this domain. These scores can then be added together to give a total score of 0-15 with an overall assessment of disease severity based on this total score (Mumtaz et al. 2010). One concern raised during the development of this measure was that patients with severe disease activity in only one domain may be disadvantaged by a relatively low total score. Two

solutions have been proposed for this. The first is that anyone with a single domain scored as severe would also be classified as severe overall. The second solution was the proposal of a modified CPDAI, with the total score being divided by the number of domains involved to give a mean CPDAI score.

Both of these CPDAI scores have undergone preliminary validation using data from observational cohorts and datasets from RCTs. Data from patients followed in rheumatology clinics in both Dublin and Leeds were used to relate CPDAI scores to patient and physician global disease activity VAS and to treatment decisions. The CPDAI score showed an excellent correlation with both patient and physician VAS and in multiple analyses, higher scores were found to be associated with treatment changes (Mumtaz et al. 2010).

A second initiative was started by GRAPPA following their annual meeting in 2008. In an attempt to develop an inclusive composite outcome measure based on real patient data, the GRAPPA Composite Exercise (GRACE) project was developed (Coates et al. 2010c). Based on the development of other composite outcome measures for both RA and AS (the DAS and ASDAS), observational longitudinal data are being collected on a large cohort of PsA patients across the world. Individual outcomes assessing disease activity in all of the domains of PsA, as well as patient reported outcome measures (PROMs) are being collected. Patients are classified by their treating physician in two groups: those requiring a treatment change (i.e. active disease) and those not (assumed to have a low disease activity). In this way, the two groups can be compared to see where significant differences exist between the two groups and which individual outcome measures account for this difference. To date, cross-sectional data has been collected on over 400 patients and these patients continue in follow up.

At the OMERACT10 meeting in 2010, the PsA working group (composed of key members of the GRAPPA group) presented a summary of the existing composite scores for PsA and preliminary work from the GRACE initiative. Professor FitzGerald presented data from the psoriasis randomised study in subjects with psoriatic arthritis (Psoriasis Randomised Etanercept STudy in subjects with Psoriatic Arthritis or PRESTA study) investigating the responsiveness of the CPDAI and other proposed indices including the DAREA or DAPSA. This study is particularly interesting as it is the only large RCT to include only patients with both significant joint disease activity and skin disease activity. The study compared standard dose etanercept (50 mg once weekly) with a higher dose of 50mg twice weekly to evaluate if higher doses were more effective in PsA. There was a significant difference seen between the treatment groups in terms of skin disease, but similar improvements were seen in joint disease activity (Sterry et al. 2010).

This differential response makes this database ideal for analysing proposed composite measures. The analysis showed that all measures performed well at discriminating between baseline and the primary endpoint, but none found a significant difference between the treatment groups related to the differential response in skin disease. Interestingly, the mean CPDAI score did show a trend between the two groups, possibly influenced by the skin disease activity but this did not reach significance.

Finally at OMERACT10, preliminary data were presented from the GRACE analysis. When considering individual domains of PsA, there was a clear differentiation between the two groups identified in the GRACE data collection for all outcome measures except those measuring nail psoriasis (mNAPSI), enthesitis (MASES), ESR and BASMI. The lack of a significant difference for these parameters is likely to be related to different factors. In some cases, particularly the nail disease, there is a relatively low prevalence of these features in the patient data. This lack of difference may also suggest that these features are less important to physicians when considering disease activity and potential changes in therapy. A PCA was performed for all variables included in disease activity measures with log transformation for PASI, LEI, dactylitis, joint counts and CRP, to identify which outcome measures best identified the variability in the data. The PCA identified five significant factors that were best represented by

1. Global disease activity VAS

2. Skin disease activity (BSA and PASI) 3. TJC and enthesitis count

4. SJC and dactylitis count

5. CRP

Regression analysis was then applied showing that nearly 80% of the variability (adjusted R2) was contributed by the global disease activity VAS, and over 90% of the variance can be summarised with just three VAS scores (patient global, patient skin, and physician global). Therefore the PsA disease activity score (PASDAS) was proposed as a composite of three VAS scales (Coates et al. 2010c).

A preliminary analysis of a modular approach to disease assessment rating each domain (peripheral arthritis, skin, dactylitis, enthesitis and spine) in terms of an intention to treat was also presented at the OMERACT 10 conference. Each domain would be rated from A to E on a five point scale where E represents no involvement of that domain and A severe involvement requiring DMARD therapy.

This method of using PCA and regression analysis was used in the development of both the RA DAS and the ASDAS. However, precisely because of the nature of PsA, this methodology has some disadvantages. The most significant issue is that any potential formula is based on a particular sample of patients’ data, and their disease pattern influences the resulting formula. For example, the majority of the GRACE participants were recruited from rheumatology clinics where skin disease is usually mild. Therefore skin disease may have less of an impact in these patients on their total disease activity. However patients seen in dermatology clinics are likely to have greater skin disease activity, and the disease activity score may not accurately reflect their pattern of disease. In a more homogenous condition, this is less of an issue as the sample is likely to be representative of most of the patients it will be utilised in. However in PsA, basing disease activity scores on “average” rheumatology patients may severely disadvantage those with other patterns of disease.