Firstly, the prognostic ability of the criteria was analysed in the observational cohort. Patients in sustained MDA were compared to 200 controls who did not achieve the MDA criteria for >12 months. The average follow up time to assess progression of disease was matched at 34 months for both groups. The mean change in damaged joint counts over the study period was 0.93 (range 0 to 12) in the MDA group and 2.25 (range 0 to 17) in the controls (p<0.001). Of the MDA patients, 69% showed no progression of joint damage, compared to 51% in the control group. Reduced multivariate regression models looking at predictors for changes in damaged joint counts identified that those patients who achieved the MDA state had a lower rate of progression of clinical damage (p=0.03).
Prognosis was addressed in the trial data using radiographic evidence of progressive joint damage. In the IMPACT1 study, 96% of those patients who achieved MDA showed no progression of radiological disease at week 52 (increase in mS-vdH score of ≥0), compared to 67% of those who did not achieve MDA (p=0.012). At week 104 numbers were greatly reduced and 12/37 (30%) were in MDA. All patients who achieved MDA at week 104 showed no progression of radiological disease, compared to 58% of those who did not achieve MDA (p=0.03).
In the IMPACT2 study, 78% of those patients who achieved MDA showed no progression of radiological disease at week 52, compared to 57% of those who did not achieve MDA (p=0.009). There was a trend towards a reduced progression in total mS-vdH score and the erosion score at week 52 in patients who achieved MDA at this time (p=0.052, p=0.053 respectively) but no significant difference in progression of JSN. There was no significant difference seen at week 24 related to MDA.
Cumulative probability plots of changes in mS-vdH score through week 54 are shown (figure 7). The curve for patients consistently in MDA (at week 24 and 52) lies to the right of the control curve indicating less radiographic progression and a smaller amount of radiographic progression per patient in MDA patients.
Figure 7 - Probability plot for change in total mS-vdH score for those in MDA and those not.
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C h a n g e i n T o ta l M o d if ie d v d H -S S c o re Cumulative Frequency non-MDA MDA6.3.2.3 Responsiveness
Firstly, the number of patients achieving the MDA criteria in the observational cohort was studied. Of the 344 patients, 208 (61%) achieved MDA at one or more visit, and 116 (34%) achieved MDA on consecutive visits for a minimum duration of 12 months. The median duration of MDA was 28 months (range 12 to 48). The characteristics of the patients who met and sustained the MDA criteria are shown in Table 1. After the minimum 12 month period required for inclusion, twelve patients (10%) experienced a flare of their disease and ceased to fulfil the MDA criteria after an average of 34 months in MDA. The remainder were still in MDA at their most recent follow-up.
When considering the trial data, the responsiveness of the criteria was confirmed by comparing the proportion of patients achieving MDA in the placebo and treatment groups. In the IMPACT1 study data were available for 63 patients. Of those receiving infliximab, 48% (15/31) achieved MDA at week 16 compared to 3% (1/32) on placebo (p<0.0001). At week 52, when all patients were treated with infliximab, 42% were in MDA. In the IMPACT2 study data were available on 157 patients. At the primary endpoint (week 24), 52% (40/77) of the patients randomised to receiving infliximab achieved MDA compared to 21% (17/80) randomised to placebo (p<0.001). At week 52, when all patients were on infliximab, 40% were in MDA.
6.3.2.4 Reliability
The literature review identified previous evidence of reliability for each of the outcome measures included in the criteria. This had been assessed in previous studies including INSPIRE and IMPART (International Multicentre Psoriasis and Psoriatic Arthritis Reliability Trial) which analysed the reliability of TJC, SJC, PASI, BSA and a variety of enthesitis measures (Gladman et al. 2007a; Chandran et al. 2009). The HAQ-DI is self-administered by the patient and has been shown to be reliable in PsA without modification (Leung et al. 2008). The patient reported outcomes such as the VAS scales are again self-administered by the patients and they have been shown to be reliable in PsA (Cauli et al. 2007). Further reliability data are therefore not required.
6.3.3
Feasibility
All of these outcome measures included within the criteria are considered routine to researchers in this field. Three of the seven outcome measures are completed by the patient and can be done in the waiting room prior to their appointment. As part of the assessment, the assessor must complete a joint count,
PASI or BSA and enthesitis count all of which can be completed within 5-10 minutes in the clinic setting. Where doubt exists about the best outcome measure to apply, the criteria have been left open so that researchers can use the outcome measure that they are familiar with (eg PASI vs BSA and different enthesitis scores). None of the outcome measures included require any special equipment to perform, so the only significant cost to the assessor is of time. As stated above, the time needed to complete these measures is minimal.
6.4
Discussion
Until recently, there were no composite disease activity measures available to measure a “state” of disease in PsA. The proposed criteria for minimal disease activity in PsA encompass different aspects of this heterogeneous disease, and could provide a new outcome measure for future clinical trials in PsA (Coates et al. 2010b). Preliminary validation work, highlighted here, provides support for their further investigation and use.
The data in this study show that sustained MDA occurs in approximately one- third of the PsA population. The higher prevalence is not surprising as the criteria are less strict than those used for remission in previous studies. Low levels of disease activity are allowed in all domains and only five of the seven cut points must be met. As seen in the previous remission studies, flare of disease occurred after a significant duration of time in MDA in around 10% of the patients demonstrating the variable activity of disease both on and off therapy. The vast majority of patients in MDA stayed on stable therapy, but 15 did have an escalation of their treatment. This may represent specific treatment for a certain high domain (e.g. active skin psoriasis only) or an increasing focus by the PsA clinic on the target of remission.
Although there is a marked reduction in progression of joint damage, there is still evidence of some progression despite patients consistently achieving MDA. It must be noted that these criteria are not remission criteria but minimal disease activity and therefore a small amount of disease activity may be present. The patients achieving the MDA criteria can have active disease in one or two domains whilst still fulfilling the criteria and even in the other domains, low disease activity is considered acceptable by the criteria (e.g. 1 tender joint). This may account for the lower rate of joint damage. We also know that clinical examination does not identify all inflamed joints and it is particularly insensitive to low levels of inflammation (subclinical disease) (Wakefield et al. 2004). Even in patients with RA who are in remission (as defined by DAS), joint damage progression has been
shown to occur and is related to subclinical inflammation seen on imaging (Brown et al. 2006).
6.4.1
Truth
Face and content validity were carefully considered during the design and development phase of the MDA criteria. International consensus from members of GRAPPA provides support of this. Assessment of criterion validity in trial data has shown evidence of concurrent validity with other measures used to identify disease activity including composite disease activity measures such as ACR outcomes, laboratory tests such as CRP and physician assessments of disease activity. Ideally convergent and divergent validity should be assessed by comparing the new criteria to criteria measuring similar disease states (such as low disease activity/remission) and those measuring different disease states (such as active disease). The only criteria available for comparison are previous definitions of remission used in publications. Patients in remission should be encompassed within MDA, but the MDA criteria should also include patients who have some low disease activity. There is some evidence for convergent and divergent validity with remission criteria in PsA but direct comparisons with these cannot be used as they use distinct conceptual definitions. Therefore there is very limited evidence for construct validity at this time.
6.4.2
Discrimination
The ability of the criteria to classify patients as MDA seemed high in the initial development of the criteria when compared to physician opinion. However misclassification is always a risk. As stated previously, the risk to the patient of misclassification is particularly important when considering patients with active disease who are misclassified as MDA and potentially denied additional therapy. Observational cohort data has been reassuring in this regard as it has shown that none of the MDA patients had swollen joints and that very few had an escalation of therapy providing some reassurance that there was a low rate of misclassification in this cohort. Ideally further validation should be undertaken in a prospective cohort with borderline patients.
The impact of MDA on prognosis in terms of joint damage has been confirmed in both the observational (with regard to clinically damaged joint counts) and trial cohort data (with radiographic outcomes). It is clearly shown that patients can change states over time both in the observational cohort and in a randomised trial where drug and placebo groups are compared. There is a significant difference in the achievement of MDA between patients treated with anti-TNF therapy and
placebo, suggesting that this could be used as a trial outcome measure for new therapies.
Reliability of the individual outcome measures included in the criteria has been confirmed in a literature review. In this situation, the reliability of the MDA criteria are validated by the reliability of their constituent parts.
6.4.3
Feasibility
All of these outcome measures included within the criteria are quick and easy to perform with no equipment required, and three of the seven outcome measures are completed by the patient. The criteria are being used in further ongoing studies and have proved easy to integrate into a standard clinic visit.
6.5
Limitations
Although provisional data are available to address each of the constituents of the OMERACT filter, further data are required before they can be classified as valid. Ongoing use in prospective studies should provide further evidence towards their suitability as an outcome measure. Specifically, further evidence is required of their classification ability, construct and criterion validity. There is no confirmed gold standard of MDA limiting the assessment of criterion validity. Ideally a further study should be performed in an independent population comparing the criteria against physician and patient opinion. The assessments of convergent and divergent validity are also limited at present as no other criteria for minimal disease activity or low disease activity at present. If other criteria are developed, further testing could be done.
There are some limitations introduced by the type of datasets used to assess validity. Some of these are overcome by the use of two different data cohorts. The advantage of using observational data from a cohort such as the PsA program in Toronto is that it provides relevant information on real-life patients all treated according to their clinical need rather than any set trial protocol. However exactly because of this, there are some limitations on the conclusions that can be drawn from the data.
There is a significant potential for confounding in data from observational cohorts. PsA is known to be a heterogeneous disorder and the progression of joint damage is highly variable between individuals. Patients presenting with active disease and joint damage are highly likely to be prescribed biological therapies given their active disease, but also have a more severe disease phenotype and a higher potential for damage progression. Although we have shown an improved prognosis in those patients achieving a state of MDA, we cannot be sure what
proportion of this is due to the natural history of the disease and what impact successful treatment has on outcome. Also, in the observational study, a clinically damaged joint count was used, rather than assessment of joint damage on conventional radiography. This outcome measures has been validated against conventional radiography (Gladman et al. 1990; Gladman et al. 2004), but is probably less sensitive to early joint damage and to minor changes than radiography. Therefore the progression in both groups may be an underestimate of the progression of damage in PsA.
Analysis of interventional therapeutic trials can remove much of the potential for confounding and can provide stronger evidence for the prognostic ability of the MDA criteria. Data for prognosis in this study used radiological outcomes with a validated scoring system providing a more robust assessment of joint damage. However, the assessment of joint damage is only one aspect of prognosis. Further long term research is required to look at other measures of impact on patients’ long term outcome, such as functional ability, quality of life and work status.
Finally, the development of the criteria based on expert opinion represents current views and these may change in the future. The OMERACT definition of MDA is “that state of disease activity deemed a useful target of treatment by both the patient and physician, given current treatment possibilities and limitations”. This relationship to current treatment possibilities means that acceptable targets of treatment may drop further as additional therapeutic options are available.
6.6
Conclusion
Data from both observational and controlled clinical trial cohorts have provided initial evidence supporting the validity of the MDA criteria as an outcome measure. Although further work is required in some areas, initial assessments of the truth, discrimination and feasibility of the PsA MDA criteria are positive and the MDA criteria can be recommended for use in future research. Further use of these criteria in prospective studies will provide further validation evidence.
7
Tight Control of Psoriatic Arthritis
7.1
Introduction
Since the TICORA study highlighted the benefit of tight control in RA (Grigor et al. 2004), it has become standard of care in the majority of RA clinical trials and is gradually becoming adopted in clinical practice. The use of an objective target to guide treatment decisions has been shown to be associated with improved clinical and radiographic outcomes in RA.
Until recently, there were no objective targets designed specifically for PsA. With the development and validation of the MDA criteria (Coates et al. 2010a; Coates et al. 2010b; Coates and Helliwell 2010), a disease specific target for treatment has been established in PsA and it is possible to investigate the use of tight control in PsA. The aim of this study was to utilise the MDA criteria in a tight control protocol to treat newly diagnosed PsA.
7.2
Methods
The TICOPA study is a multicentre national trial currently running at 6 sites. It is designed as a randomised, controlled, parallel group, open label, clinical trial of 206 patients with recent onset PsA. Patients are randomised on a 1:1 basis to receive either standard care or tight control for a period of 48 weeks. The study was approved by national and local ethics committees and all patients gave written consent before inclusion.