The APPEAL trial compared efficacy, safety and PROs with ETN + MTX versus DMARD + MTX in patients from Asia-Pacific countries with moderate to severe RA, a mean disease duration of 6.7 years, and sub-optimal response to MTX monotherapy for a minimum of three months. Detailed results of primary clinical endpoints for ETN + MTX versus DMARD + MTX groups, reported by Kim and colleagues, showed significantly greater ACR response area under the curve, proportion of subjects achieving ACR 20, 50 and 70 responses at Week 16, numbers achieving low disease activity scores (DAS28 < 3.2), and improvements in DAS28 score, pain visual analogue scale, the health assessment questionnaire, and physician and patient global assessments. Results in the same subjects on health outcomes evaluations, presented here, demonstrate that in addition to improvements in objective clinical measures of disease activity, combination therapy with ETN + MTX provided statistically significant and clinically meaningful improvements in PROs compared to combination therapy using MTX and usual DMARDs.
The mean HAQ scores at baseline were not significantly different between the two groups and both groups of patients reported significant improvements. Slightly more than half (52%) of patients on ETN + MTX achieved a HAQ score lower than 0.5 at week 16, which is representative of the general population, compared to 39% of patients on DMARD + MTX. Furthermore, the ETN + MTX group improved their mean HAQ scores by 49% compared to 38% for the DMARD + MTX group. Two other trials reporting on HAQ scores with MTX/ETN combination therapy have reported percentage improvements in HAQ scores of approximately 50-60% over a period of 52 weeks [13, 14]. By way of comparison, Kosinski et al. concluded from a study of rheumatoid arthritis patients that an average percentage improvement of 27% in HAQ scores was clinically significant and could be correlated with meaningful changes in other disease severity indicators such as joint swelling and tenderness counts, patient and physician global assessments, and pain .
Rheumatoid arthritis patients generally report higher levels of severe fatigue that can exacerbate other symptoms of the disease, worsen physical and emotional well-being and interfere with employment, social and family opportunities and obligations [20, 21]. Fatigue is a common and debilitating symptom in RA patients and both the American College of Rheumatology and European League Against Rheumatism have highlighted the need for more information on fatigue from clinical trials, using validated fatigue scales . Both arms in this study reported a lessening of fatigue symptoms as measured using the FACIT-Fatigue instrument, however, the ETN + MTX arm showed a significantly larger reduction of fatigue symptoms after 16 weeks (8 points or 28% improvement) compared to the DMARD + MTX arm (3 points or 10.4% improvement). The clinical significance of this reduction can be understood through a comparison with other studies that have assessed the magnitude of changes in the FACIT-Fatigue scale that are associated with minimal clinically important differences in RA patients. Cella et al.  estimated a distribution-based minimally important difference in FACIT-Fatigue scores of 4.1, whereas Pouchot et al.  estimated a regression-based minimal clinically important difference of 8.3 points on the FACIT-Fatigue 52 point scale, which was used in our study.
The mean physical and mental health component summary scores derived from the SF-36 were not different between the two arms at baseline. However, after 16 weeks, both scores improved by a higher percentage for patients randomized to ETN + MTX compared to those on DMARD + MTX. Improvement in absolute score for the ETN + MTX group was higher by a magnitude of 2.7 points for the physical component summary, which is within the range of an accepted minimally clinically important difference (MCID) of 2.5-5 . The mean for mental component score, however, did not meet that threshold. Improvement for the ETN + MTX group was higher than the DMARD + MTX group for six of the eight domain scores by a magnitude within a range of what is considered a MCID for individual domains (5–10 points) . The two domains that did not meet the MCID threshold are mental health and physical functioning.
Not surprisingly, anxiety and depression coexist with RA and tend to be positively correlated with disease severity and duration . A previous study of patients with early RA indicated that anxiety and depression were improved, along with other PRO measures, with ETN + MTX and that these were associated with achieving clinical remission . The significantly greater improvements in the HADS measures for patients on ETN + MTX thus reflect the consistently more positive outcomes in this subject group seen in the other PRO measures. These improvements in functional ability and psychological well-being were further confirmed through a positive impact on work productivity and activity as measured by WPAI:GH. The percentage activity impairment due to health in all patients, as assessed by the WPAI:GH instrument, was improved more substantially in the ETN + MTX group compared to the DMARD + MTX group, by 49% compared to 29%, respectively. In a subgroup of patients who were employed upon enrollment, the WPAI:GH instrument showed an 81% improvement in missed time from work due to health in the ETN + MTX group, compared to a 22% improvement in missed time in DMARD+MTX arm.
There are limitations to this study and the analysis of PRO data. Since the APPEAL trial used an open-label study design, these PRO results may be considered less rigorous than a blinded study. However, this design allowed comparison of combination therapy approaches that incorporated the usual standard of care (synthetic DMARDs) versus ETN in routine clinical settings. The short-term follow-up period (16 weeks) may also be considered a limitation; however this is longer than the 3-month period recommended by EULAR for assessment of current treatment failure or success for RA. Thus, results from the 16 week follow-up period are valid in informing clinical decision making. Further, this study included patients who had not improved while on methotrexate for at least three months, thus the results may not be generally applicable to, for example, DMARD naïve patients. It is however interesting that similar improvements in HAQ and SF-36 scores were demonstrated over 52 weeks in patients from the COMET trial with early RA (mean disease duration of 9 months) . Lastly, the subject population comes from a limited number of countries in this region and may not be generalizable to the entire region or even to all countries studied due to the limited sample size.