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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Objective

New criteria for minimal disease activity (MDA) in psoriatic arthritis (PsA) have been developed. The aim is to provide further validation of these criteria using data obtained in interventional trials with infliximab, a drug with proven efficacy in PsA.

Methods

The data were obtained from patients in phase II and III infliximab studies of PsA. In both studies, patients with active PsA were treated with infliximab (5 mg/kg) or placebo followed by a period of treatment with infliximab. Between-group comparisons in terms of those achieving MDA and the relationship of MDA to American College of Rheumatology outcomes, C-reactive protein levels, and radiologic progression were performed.

Results

In the Infliximab Multinational Psoriatic Arthritis Controlled Trial, 48% (15 of 31) of infliximab-treated patients achieved MDA at week 16, compared with 3% (1 of 32) taking placebo (P < 0.0001). At week 50, 96% of those patients who achieved MDA showed no progression of radiologic disease (increase in the modified Sharp/van der Heijde score of ≤0), compared with 67% of those who did not achieve MDA (P = 0.012). In the Induction and Maintenance Psoriatic Arthritis Clinical Trial 2, 52% (40 of 77) of infliximab-treated patients achieved MDA at week 24, compared with 21% (17 of 80) receiving placebo (P < 0.001). At week 54, 78% of those patients who achieved MDA had no radiologic progression, compared with 57% of those who did not achieve MDA (P = 0.009).

Conclusion

Patients with active PsA achieving MDA with effective therapy have a significant reduction in radiographic progression. Aiming for low levels of disease activity can improve the outcome of patients with PsA even in a disease-modifying antirheumatic drug–resistant cohort. The new MDA criteria could provide an objective target for treatment in trials and clinical practice.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with significant impact on quality of life and progressive joint damage. There is some evidence of the link between inflammation and damage in PsA, where observational studies have shown that active inflammatory disease predicts future outcome (1). New therapies, such as the tumor necrosis factor α blockers, have shown a reduction in disease activity and a corresponding reduction in radiographic progression of damage (2–4). Ongoing joint damage can cause significant functional impairment and disability, which raises the possibility that controlling disease activity could improve outcome. Similar research in rheumatoid arthritis (RA) has identified that treating to an objective target can improve long-term outcome (5).

Minimal disease activity (MDA) is defined by the Outcome Measures in Rheumatology Clinical Trials (OMERACT) as “that state of disease activity deemed a useful target of treatment by both the patient and physician, given current treatment possibilities and limitations,” and encompasses both remission and low disease activity (6). New criteria for MDA in PsA have been developed (7), which provide an objective target for therapy. However, use in clinical trials cannot be recommended until the measure has been validated and ongoing validation work is underway. The OMERACT filter of truth, discrimination, and feasibility (8) provides a framework for assessing the validity of an outcome measure, and this study aims to provide further evidence of validation.

The PsA MDA criteria are a composite of 7 outcome measures used in PsA. As individual outcome measures, there are significant data to support their validity, but validity must be ascertained for the composite measure of MDA.

The first application of the criteria was within the Toronto Psoriatic Arthritis Clinic, which is an ongoing observational cohort with regular prospective data collection (9). These data were analyzed to see if patients who consistently achieved MDA on consecutive visits for >12 months had less progression in joint damage. Unfortunately, radiologic data are collected only every 2 years, and therefore an analysis of radiologically-assessed joint damage was not possible. Progression of joint damage in this study used a clinical damaged joint count performed at each visit. This measure has been validated against radiographs in 2 independent studies (10, 11), but is likely to be less sensitive to early or subtle changes than radiography or other imaging. Despite this limitation, the analysis did confirm a reduction in joint damage progression over a 3-year period, with an increase in damaged joint count of 0.9 in patients persistently in MDA and an increase of 2.4 in controls.

Although this finding provides a suggestion that achieving MDA can reduce joint damage, this analysis is based on an observational cohort, which may cause a significant bias. The analysis confirms an association between MDA and lower joint damage but does not allow assessment of whether intervention in active disease with effective therapy to achieve MDA can improve outcome. The aim of this study was to assess whether intervention with effective therapy to achieve MDA was related to an improved outcome in terms of radiologic damage.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

The study was an analysis of most patients in the previously published phase II and III of the randomized placebo-controlled trials of infliximab in PsA (Infliximab Multinational Psoriatic Arthritis Controlled Trial [IMPACT] and the Induction and Maintenance Psoriatic Arthritis Clinical Trial 2 [IMPACT 2]) (12, 13). In both studies, patients with active PsA were treated with infliximab (5 mg/kg) or placebo followed by blinded infliximab treatment through week 46 and open-label infliximab treatment from weeks 50–98 in IMPACT. The data from a randomly-selected 80% of the patients from both studies were made available for analysis by the company concerned. Patients were then excluded if it was not possible to ascertain their MDA status due to missing data.

The IMPACT study recruited 104 patients with established PsA who had active arthritis (≥5 tender and swollen joints and raised inflammatory markers or significant early morning stiffness) and had failed at least 1 disease-modifying antirheumatic drug (DMARD). Patients received infliximab or placebo infusions at weeks 0, 2, 6, and 14 before switching to blinded infliximab therapy up to week 46. In a subset of patients followed in an open-label study, further data were available up to week 98.

The IMPACT 2 study recruited 200 patients with very similar inclusion criteria, except that these patients had to have failed either ≥1 DMARD or ≥1 nonsteroidal antiinflammatory drug, meaning that some of the patients had never taken DMARDs. Patients in the IMPACT 2 study received infliximab or placebo infusions at weeks 0, 2, 6, 14, and 22, but were eligible for “early escape” in a blinded manner to infliximab at week 16 if they had <10% improvement in both tender and swollen joint counts.

Patients were classified as achieving MDA if they fulfilled 5 of 7 outcome measures: tender joint count ≤1; swollen joint count ≤1; psoriasis activity and severity index ≤1 or body surface area ≤3; patient pain visual analog scale (VAS) score of ≤15; patient global disease activity VAS score of ≤20; Health Assessment Questionnaire (HAQ) score ≤0.5; and tender entheseal points ≤1. A comparison was made of the proportion of patients achieving MDA in treatment and placebo groups at the primary end point (week 16 for IMPACT and week 24 for IMPACT 2) using intent-to-treat analysis. Long-term outcome was also analyzed by assessing the proportion of all patients achieving MDA at the end of 1 year in both studies.

Radiologic progression was assessed using modified PsA Sharp/van der Heijde scores (SHS) for the hands and feet (14). Radiographs were performed at baseline, weeks 50 and 98 (IMPACT), or weeks 24 and 54 (IMPACT 2). For this study, baseline, 1-year, and 2-year radiographs were analyzed where available. Progression was defined as an increase in the SHS score of ≥0. All analysis was on an intent-to-treat basis, including the analysis of those patients who entered the early escape arm of the IMPACT 2 study and were treated with infliximab from week 16. Significance testing was performed using chi-square tests for categorical variables and Mann-Whitney U tests for continuous variables. All analyses were performed using SPSS, version 12.0 (SPSS).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

IMPACT data.

In IMPACT, data were available for 63 patients. Of those receiving infliximab, 48% (15 of 31) achieved MDA at week 16, compared with 3% (1 of 32) taking placebo (P < 0.0001). At week 50, when all patients were treated with infliximab, 42% were in MDA.

At week 50, 96% of those patients who achieved MDA showed no progression of radiologic disease (increase in SHS score of ≥0), compared with 67% of those who did not achieve MDA (P = 0.012). At week 98, data from only 37 subjects were available for analysis and 12 (30%) of 37 were in MDA. All patients who achieved MDA at week 98 had no change in their radiologic score, compared with 58% of those who did not achieve MDA (P = 0.03).

IMPACT 2 data.

In IMPACT 2, data were available for 157 patients. At the primary end point (week 24), 52% (40 of 77) of the patients randomized to receiving infliximab achieved MDA, compared with 21% (17 of 80) randomized to placebo (P < 0.001). Of the 100 patients randomized to placebo in the original trial, 47 entered the early escape arm at week 16 and received infliximab, possibly accounting for the relatively high placebo MDA rate. At week 54, when all patients were receiving infliximab, 63 (40%) of 157 were in MDA. Those patients who achieved MDA were significantly more likely to achieve all of the American College of Rheumatology (ACR) outcome measures (ACR 20% improvement criteria, ACR 50% improvement criteria, and ACR 70% improvement criteria; P < 0.001) (15) (Figure 1).

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Figure 1. Percentages of minimal disease activity (MDA; blue) and non-MDA (red) patients who achieved American College of Rheumatology (ACR) 20% improvement criteria (ACR20), 50% improvement criteria (ACR50), and 70% improvement criteria (ACR70) responses at week 24 (A) and week 54 (B).

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In addition to the relationship with composite measures, there was an association seen between achievement of MDA and the levels of systemic inflammatory response. There was a significant difference between the levels of C-reactive protein (CRP) at week 52 in patients who achieved the MDA criteria and those who did not (median CRP level 0.4 mg/dl, interquartile range [IQR] 0.4–0.6 versus median CRP level 0.5 mg/dl, IQR 0.4–1.3; P = 0.019). There was also an association seen with the physicians' assessment of disease where there was a significant difference in the physicians' global assessment of disease in patients who achieved the MDA criteria and those who did not (median VAS score 0.5 cm, IQR 0.1–1.0 versus median VAS score 2.4 cm, IQR 0.8–5.4; P < 0.001).

At week 54, 78% of those patients who achieved MDA had no change in radiologic score, compared with 57% of those who did not achieve MDA (P = 0.009). There was a trend toward a reduced progression in total SHS score and the erosion score at week 54 in patients who achieved MDA at this time (P = 0.052 and P = 0.053, respectively), but no significant difference in progression of joint space narrowing (Table 1). No significant difference was seen in radiologic outcome at week 24 related to MDA status.

Table 1. Changes in modified Sharp/van der Heijde (SHS) scores from baseline to week 54 for MDA and non-MDA patients in IMPACT 2*
Change in SHS scoreNon-MDAMDAP
  • *

    MDA = minimal disease activity; IMPACT 2 = Induction and Maintenance Psoriatic Arthritis Clinical Trial 2.

Total   
 Mean ± SD0.38 ± 2.54−0.40 ± 3.100.052
 Median0.00.0 
 Range−3.50, 12.1−12.5, 9.68 
Erosion   
 Mean ± SD0.33 ± 2.07−0.23 ± 2.100.053
 Median0.00.0 
 Range−3.00, 12.1−7.00, 9.00 
Joint space  narrowing   
 Mean ± SD0.05 ± 0.75−0.17 ± 1.370.239
 Median0.00.0 
 Range−1.86, 3.00−5.50, 6.01 

Cumulative probability plots of changes in SHS scores through week 54 are shown in Figure 2. The curve for patients consistently in MDA (at week 24 and 54) lies to the right of the control curve indicating less radiographic progression and a smaller amount of radiographic progression per patient in MDA patients.

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Figure 2. Probability plot of change in total modified Sharp/van der Heijde (S-vdH) score at week 54 for the group consistently in minimal disease activity (MDA; squares) and the non-MDA group (diamonds).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

The new MDA criteria for PsA provide an objective target for therapy in clinical trials and this study provides further validation of these criteria within the framework of the OMERACT filter of truth, discrimination, and feasibility (8).

The truth domain assesses how well the outcome measure represents what it seeks to measure. Face validity assesses whether the criteria make sense to those who will use them. The design of the criteria is based partially on the development of similar measures in RA by the OMERACT group (6). The development of the PsA criteria was discussed and debated within the Executive Committee of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), who are an international panel of experts in psoriatic disease (16). This expert input into the criteria's developmental phase provided face validity for the criteria.

Content validity assesses whether the content is sufficient to measure the outcome and whether all of it is required. The content of the MDA criteria is based on the psoriasis PsA core measures, which were agreed on at OMERACT VIII (17). The criteria encompass all of the core measures of disease (joint disease, skin disease, patient's assessment of disease activity, pain, and function) with the exception of quality of life. Measures of acute-phase response such as CRP levels were excluded from the core measures in PsA (and therefore the MDA criteria), since they are often normal in PsA and therefore may not accurately reflect disease activity at the individual patient level (17). After discussion within GRAPPA, a measure of entheseal disease was added to ensure that no disease domains were excluded (7).

Although other composite disease activity measures have been proposed for use in PsA, including composite measures developed for RA (18) and reactive arthritis (19), none included evaluation of joints, skin, enthesitis, and patient-reported outcomes. When considering criteria that can be used as a target for treatment, it is imperative that all aspects of disease are considered to ensure that patients are not undertreated.

Criterion validity assesses how well a new outcome measure performs in relation to a gold standard or to other available measures. There is no agreed gold standard for assessing disease activity states in PsA. Therefore, by comparing the outcome measure with other measures of disease activity, concurrent validity must be assessed instead. These data show a significant association between MDA and composite outcome measures, such as the ACR response measures, and with other markers of active disease, such as inflammatory markers.

Discrimination encompasses classification, prognosis, responsiveness, and reliability. The reliability of the MDA criteria can be considered using data from the individual outcome measures included within it. These outcome measures have been assessed in PsA and have been shown to be reliable (20–22). Previous research investigating the MDA criteria within the Toronto PsA observational database has shown evidence of the responsiveness of the MDA criteria with patients moving in and out of an MDA state over time (23).

As part of the discrimination domain, the question of prognosis is raised. Does achieving a better short-term outcome affect longer-term prognosis? Previous data from the Toronto cohort have suggested a reduced clinical damage progression for patients in MDA, but corresponding radiologic data were unavailable. There is also a significant potential bias in observational cohorts, a bias that is avoided by using data from clinical trials. The data in this report support the prognostic value of the PsA MDA criteria, since they have clearly shown that patients achieving MDA are more likely to have a better radiologic outcome.

Although the MDA criteria require the assessment of 7 individual outcome measures, these are all familiar instruments to those researching PsA and are not time consuming to perform. Patients only have to complete 2 VAS and the HAQ, which takes a few minutes and can be done prior to the consultation. The physician then completes a joint count, enthesitis index, and skin assessment. This clinical examination takes ∼10 minutes to complete. Indeed, it could be argued that this assessment of arthritis, enthesitis, and skin disease constitutes a reasonable review of disease activity for patients with PsA in a rheumatology clinic. Results of all of these measures can be calculated immediately, and there is no requirement to await blood tests for acute-phase reactants. Therefore, the MDA criteria can be used in clinical settings to contemporaneously guide treatment decisions.

In summary, preliminary validation work supports the use of the MDA criteria in both observational cohorts and now in interventional trial cohorts. The PsA MDA criteria have evidence supporting their use within the OMERACT filter of truth, discrimination, and feasibility. Application of these criteria in prospective studies will provide additional validation for their use in PsA disease assessment.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Helliwell had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Coates, Helliwell.

Acquisition of data. Coates, Helliwell.

Analysis and interpretation of data. Coates, Helliwell.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Centocor and Schering-Plough were responsible for the original data collection in the IMPACT and IMPACT 2 studies and kindly provided the data for this analysis. They played no role in the study design or data analysis. Centocor and Schering-Plough reviewed the submitted manuscript but publication was not contingent on their approval.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

The authors thank all of the patients, investigators, and study personnel involved in the IMPACT and IMPACT 2 studies.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES
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