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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PHYSICIAN PERSPECTIVE Viewpoint based on presentations from the 64th Annual Meeting of the Canadian Rheumatology Association

Kananaskis, Alberta / February 18-21, 2009

Editorial Review:

Dafna D. Gladman, MD, FRCPC

Senior Scientist, Toronto Western Research Institute, Centre for Prognosis Studies in the Rheumatic Diseases, UHN-Toronto Western Hospital

Professor of Medicine, University of Toronto, Toronto, Ontario

Patients who meet the Classification Criteria for Psoriatic Arthritis (CASPAR) for psoriatic arthritis (PsA) often represent a very challenging patient population, as there can be substantial variability in disease severity and historical course. Dedicated to improving patient care, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has recently published the first treatment recommendations based on a thorough review of the medical literature. According to GRAPPA, decisions on the management of PsA should be based on a thorough assessment of the different areas of disease involvement, including the peripheral joints, axial skeleton, dactylitis, enthesitis, skin and nails.

Recent clinical trials involving tumour necrosis factor (TNF) inhibitors have demonstrated greater degrees of disease control than ever before possible and this evidence has significantly altered current treatment paradigms. Indeed, for virtually all manifestations of PsA, anti-TNF agents figure prominently in the new GRAPPA treatment algorithm, especially in moderate to severe peripheral arthritis, skin disease, spinal disease, enthesitis, and (for infliximab) in dactylitis.

PRESTA Trial

As it is estimated that up to 30% of patients with psoriasis have PsA, dermatologists are in a unique position to prevent progression. PRESTA (Psoriasis Randomized Etanercept Study in Subjects with Psoriatic Arthritis) was a randomized, double-blind trial evaluating the safety and efficacy of etanercept in patients with psoriasis and PsA. Patients had moderate to severe plaque psoriasis and a <u>></u>10% body surface area of involvement. Physician Global Assessment (PGA) scores were also moderate or worse on study entry, and patients also had to have signs of active PsA, including two or more swollen/tender joints at baseline, joint pain for at least three months prior to screening and a negative serum rheumatoid factor within six months of screening. During the double-blind period, patients received either etanercept 50 mg twice a week or 50 mg once a week for 12 weeks. In the subsequent open-label period, patients received 50 mg once a week for another 12 weeks. A total of 379 patients received 50 mg twice a week, while 373 patients received 50 mg once a week.

As reported by Prof. Wolfram Sterry, Charité University Medicine, Berlin, Germany, at the 5th Annual Congress of the British Association of Dermatologists in December 2008, 46% of the twice-weekly group had achieved a PGA response of 0 or 1—namely, clear or almost clear at the end of 12 weeks vs. 32% of the once-weekly group (P<0.001). At the end of the open-label portion of the study, however, there was little difference between the two groups, with 56% in the twice-weekly group achieving a PGA response of 0 or 1 vs. 50% in the once-weekly group. For those who achieved a Psoriasis Area Severity Index (PASI)-75 or greater, the difference between the two treatment arms was significant at both week 12 (P<0.001) and at week 24 (P=0.026) (Figure 1).

Figure 1.

Significant improvement in joint symptoms in the majority of patients was also observed. At 24 weeks, 72% of patients treated with etanercept 50 mg q.w. and 77% of those treated with 50 mg b.i.w. for 12 weeks then q.w. for another 12 weeks had improvement in joint symptoms.

Serious adverse event rates were low at 4% vs. 3% for the twice-weekly vs. once-weekly groups, respectively, as were rates of serious infections at 0.5% vs. 0.8% for the same two respective groups.

The authors concluded that either etanercept dose regimen can be used safely and effectively in the treatment of psoriasis associated with PsA, allowing for individualized patient care.

Studies with other anti-TNF agents support the value of these agents in both skin and joint manifestations of inflammation. For example, as reported here at the CRA by Dr. Ernest Choy, King’s College, London, UK, and colleagues, ADEPT (Adalimumab Effectiveness in Psoriatic Arthritis Trial) findings showed that patients who achieved a PASI of at least 50 on the anti-TNF agent also showed signs of inhibition of radiographic progression vs. patients who achieved a PASI of less than 50 where there was more radiographic progression. ADEPT therefore confirms that patients who achieve a significant improvement in skin lesions in response to anti-TNF therapy are less likely to progress radiographically over the long term than those who do not respond as well to treatment.

The Canadian REPArE trial: A Real-World Experience

The importance of randomized clinical trials cannot be disputed. However, in clinical practice, the resulting effect of the therapeutic agent may vary greatly. Among the most recent trials demonstrating the efficacy of anti-TNF agents in PsA was an important observational study carried out in an all-Canadian setting. The REPArE (Rating Evaluations in Psoriatic Arthritis with Enbrel) study was designed as an open-label, prospective longitudinal trial. Entry criteria included the presence or previous evidence of psoriasis and active PsA with at least three swollen joints and at least three tender or painful joints.

The primary objective of this study was to describe the effectiveness of etanercept in patients with PsA, as measured by the change from baseline to month 24 on the Health Assessment Questionnaire Disability Index (HAQ-DI). Secondary objectives included the Psoriatic Arthritis Response Criteria (PsARC) at 24 months; the proportion of patients achieving at least a PASI-75 at 24 months; and various changes from baseline to study end point in measures of productivity, fatigue and arthritic disease activity. A total of 110 patients were enrolled in 22 Canadian centres and interim results at one year were released here during the CRA meeting.

When interpreting findings at 12 months, it is best to keep baseline patient characteristics in mind. Well over 80% of patients in REPArE had received prior treatment with NSAIDs and disease-modifying anti-rheumatic drugs (DMARDs), while the mean duration of PsA was 8.9 years, and roughly twice that for the mean duration of psoriasis alone. Importantly, only one out of the 110 patients enrolled in REPArE did not have fair, poor or very poor disease control as assessed by the PGA score at baseline.

The mean baseline PASI score was 4.8, the mean HAQ-DI was 1.5 and the mean joint-pain/tenderness score was 30.3. Patients also had a mean baseline joint-swelling score of 18.9. As reported here, the HAQ-DI declined from a mean of 1.5 at baseline to a mean of 0.91 after 12 months of treatment, with most of the improvement occurring within the first three months of receiving etanercept.

Between 62% and 69% of patients also achieved a <u>></u>30% improvement in the HAQ score between month 3 and 12, while between 51% and 62% of the cohort achieved a ³50% improvement in the HAQ score over the same follow-up period. Patients also experienced a 77% reduction in the mean joint-pain/tenderness score from 30.3 at baseline to 7.2 at 12 months, and a similar 83% reduction in the joint-swelling score from 18.9 at baseline to 3.3 at month 12. As assessed by the PsARC, 78% of patients had an improvement in PsA signs and symptoms at month 12.

The mean PGA score similarly declined from study outset to 12 months, from a mean of 3.23 at baseline to a mean of 2.2 at follow-up for a 31% reduction at interim assessment. Patient global assessment scores reflected the PGA scores, dropping from a mean of 3.28 at baseline to a mean of 2.72 at 12 months, for an approximately 16% reduction from study outset. The mean PASI score dropped from 4.8 to 2.0 at 12 months, while patients not on a DMARD at baseline had a remarkable response to treatment, dropping from a mean baseline PASI of 9.4 to a mean of 2.2 after 12 months of etanercept therapy.

Reductions in mean PASI scores for patients who were on DMARDs at baseline were less dramatic, from a mean of 4.2 at baseline to a mean of 2.0 at 12 months—still an improvement of over 52%. Noteworthy as well, 42% of the cohort achieved a PASI-75 at 12 months, which is a good measure of etanercept’s effectiveness in PsA, given the relatively low baseline PASI scores.

As can be expected, the mean baseline score for patients with more severe disease, PASI <u>></u>8, dropped by more than 65% from 17.9 to 6.2 at month 12 and experienced a greater absolute and relative improvement in cutaneous symptoms than the overall cohort with 52% achieving PASI-75.

In the overall cohort, 28% achieved a PASI-90 at 12 months and in those not taking a DMARD at baseline, PASI-90 responses were higher.

Work Productivity and Quality of Life

Patients also reported increased productivity with fewer days absent from work due to PsA, the mean number of missed work days declining from a mean of 20.8 days per year prior to study entry to a mean of 2.6 days per year at month 12. Importantly, patients reported a significant 25% decrease in mean fatigue scores at 12 months. Improvements in fatigue as measured by the Fatigue Severity Scale were actually more pronounced in those whose PsA had persisted for 10 years or more than in those with a shorter disease duration.

The impact of an anti-TNF agent on work productivity was also described in ACCLAIM (A Canadian Open-label Study to Evaluate the Safety and Effectiveness of Adalimumab when Added to Inadequate Therapy for the Treatment of Psoriatic Arthritis). After 12 weeks of treatment, statistically significant changes were reported in the Work Limitations Questionnaire (WLQ) from baseline in all four scales: the physical scale (-14.5 from baseline), time scale (-12.6), mental scale (-4.4) and output scale (-8.1). The WLQ Productivity Loss Score also dropped significantly from a mean of 8.0% at baseline to a mean of 5.4% at week 12 (P<0.001). Also at week 12, clinical response to treatment correlated with changes in work productivity outcomes, suggesting that the WLQ is a reliable and valid tool for evaluation of response to therapy in a PsA cohort.

Summary

Upwards of 30% of patients with psoriasis also develop arthritis, the majority experiencing skin lesions first followed by arthritis. Since TNF is intimately involved in the psoriatic cascade, blockade with anti-TNF agents has proven to be highly effective for the treatment of both skin lesions and rheumatic joints. In long-term use, etanercept has demonstrated clinically meaningful efficacy and safety and the interim analysis of REPArE supports its benef
tting.

Table 1.

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