Over the past decade, the management of RA has changed dramatically as a result of the development of the TNF inhibitors, which have resulted in improved long-term outcomes. Initially, improved clinical responses achieved by the use of TNF inhibitors were the primary focus of clinicians. Now the RA burden as reported by patients has come to be recognized as a significant and treatable component of the disease. Utilized together, clinical and patient-reported outcomes reflect the spectrum of patients' disease and best reflect the overall effectiveness of TNF inhibitor therapy in RA.
Concepts that have traditionally been shown to be among the most important to RA patients are physical function, pain, and tiredness (fatigue). However, it is now well-documented that mental health disturbance is an important consequence of RA and a central component of the assessment of HRQoL. Therefore in RAPID 1, the concepts that were assessed as reported by the patients were HRQoL (including emotional, social and physical components), fatigue, physical function, arthritis pain, and global assessment of disease activity.
Patients in this trial (RAPID 1) had substantially diminished HRQoL at baseline compared with age- and gender-matched US population norms (particularly in Vitality, Role Emotional, Physical Function, Role Physical and Bodily Pain), as illustrated by the spydergram of SF-36 scores at baseline (Figure ). The US population norms were used only as a benchmark to allow comparisons between RA patients with available general population data. Following treatment with either dose of CZP plus MTX, patients reported improvements in HRQoL, or 'multidimensional function', at first assessment (week 12), with large improvements in both the physical and mental domains of HRQoL that exceeded MCID. In particular, energy (Vitality) and emotional state (mental health) domain scores approached normative values of the general population in the US, and the significant improvement in SF-36 MCS scores observed with CZP plus MTX treatment in this trial, which approached levels of improvement in PCS scores, is novel among studies of TNF inhibitors in RA [31
]. The negative psychological effects of RA are well documented; many patients with RA have mood and anxiety disorders [36
], and it has been reported that 21% to 39% of patients with RA experience significant depressive symptoms [37
], although treatment of these aspects of the disease is often suboptimal. The improvements in SF-36 MCS and mental health scores following CZP treatment are thus particularly relevant for patients because they may help them return to normal levels of emotional functioning.
Patients treated with CZP plus MTX also reported significant improvements in global assessment of disease activity and physical function, as well as relief of pain and fatigue, as early as week 1 of treatment. Although there was a small decrease in the percentage of patients reporting clinically meaningful reductions in fatigue from week 4 to week 52, this is likely because of protocol-mandated withdrawal at week 16 for failure to achieve ACR20 responses at weeks 12 and/or 14, as well as imputation of withdrawn subjects with the conservative approach of non-responders after week 16. Reductions in fatigue and all other PROs with CZP plus MTX remained highly significant throughout the trial, with approximately 50% of patients reporting clinically meaningful reductions by week 52. In general, the effect of CZP on the patient-reported outcomes described herein are comparable with those reported with other TNF inhibitors in clinical studies [31
] as well as in studies in clinical practice [19
]. However, the rapid improvements in patient-reported outcomes in CZP-treated patients, particularly those reflecting improved mental health, which have not previously been observed, are a particularly interesting characteristic of this new anti-TNF.
Patient's daily burden of disease and their poor HRQoL directly limit their everyday activities as well as productivity at work and within the home with negative consequences for society. Results from the RAPID 1 trial have demonstrated that CZP treatment improves productivity at work and at home, including fewer number of days lost engaging in family, social and leisure activities [44
]. Furthermore, a post hoc
analysis demonstrated that these improvements in productivity were closely reflected by similar changes in pain, physical function and fatigue (unpublished observations).
The data presented in this paper demonstrate that the CZP-treated patients experience early improvements in all patient-reported outcomes over PBO. In addition, there have been data suggesting that rapid improvements in disease activity are associated with better long-term outcomes [45
]. Patients have a greater chance of avoiding long-term disability, allowing them to regain their normal levels of physical, emotional and social participation and greatly improving overall HRQoL.
Previously reported results from the RAPID 1 trial have demonstrated that treatment with CZP plus MTX rapidly and significantly reduces disease activity (as assessed by DAS28 scores) and improves the clinical signs and symptoms of RA (as assessed by ACR20 response rates) [15
]. The improvements in patient-reported outcomes following CZP treatment reported herein thus support and complement these previously reported clinical improvements. In addition, the analyses correlating responses as assessed by improvements in PROs with clinical (ACR and DAS) responses demonstrate that patient-reported outcomes correlate well with physician-reported, clinical indices. Not surprisingly, because the HAQ-DI and pain are components of the ACR20 response rate criteria, physical function and pain were highly correlated with ACR20 response rates. In contrast, changes in SF-36 PCS and MCS scores had the lowest correlation with ACR20 and DAS responses. These results illustrated that although clinical measures and PROs are generally well correlated, assessment of only clinical measures does not capture all aspects of RA and its impact on patients' physical and mental health. Assessment of both clinical (physician-reported) and patient-reported outcomes is thus necessary to fully elucidate treatment benefit.