Health-related quality of life in patients with giant cell arteritis treated with tocilizumab in a phase 3 randomised controlled trial

The GiACTA RCT (ClinicalTrials.gov, NCT01791153) design and enrolment criteria have been published [16, 17]. Briefly, patients ≥ 50 years of age with newly diagnosed or relapsing active GCA confirmed by temporal artery biopsy or cross-sectional imaging and a history of elevated erythrocyte sedimentation rate attributable to GCA were randomly assigned (2:1:1:1) to one of four 52-week regimens: (1) weekly subcutaneous TCZ 162 mg plus a 26-week prednisone taper (TCZ-QW + Pred-26), (2) every-other-week subcutaneous TCZ 162 mg plus a 26-week prednisone taper (TCZ-Q2W + Pred-26), (3) weekly subcutaneous placebo plus a 26-week prednisone taper (PBO + Pred-26) or (4) placebo plus a 52-week prednisone taper (PBO + Pred-52). The trial was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. All patients provided written informed consent as approved by the institutional review board or ethics committee. The primary outcome (sustained disease remission to week 52) and secondary and exploratory PRO outcomes (SF-36, FACIT-Fatigue and PtGA) were analysed at 1 year.

We analysed data by SF-36 PCS and MCS and all eight individual domains. These domains are physical function, role physical, bodily pain, general health, vitality, social function, role emotional and mental health. We also analysed PtGA by visual analogue scale (VAS) and FACIT-Fatigue score. We used MCIDs previously validated in patients with rheumatoid arthritis and systemic lupus erythematosus because such values have never been defined in GCA.

Least square mean (LSM) changes from baseline to week 52 in SF-36 PCS and MCS scores were assessed using a range of 0 to 50, with normative scores of 50 and a standard deviation of ± 10; higher scores indicate better HRQOL [18]. Change ≥ 2.5 in PCS and MCS was considered the MCID [19]. SF-36 domain scores ranging from 0 to 100 were compared with A/G norms matched to the study population. LSM changes from baseline to week 52 were depicted using spydergrams [20]. An MCID of 5.0 was used for changes in domain scores [19]. Overall changes in SF-36 scores in spydergrams were quantified using the SF-6D utility score based on mean scores across all eight domains [21, 22] and the previously defined minimally important difference (MID) for an SF-6D utility score of 0.041 [23]. Changes from baseline to week 52 in PtGA, ranging from 0 to 100, were assessed by VAS using the generally accepted MCID of 10.0 [19]. FACIT-Fatigue was assessed on a scale of 0 to 52, with higher scores representing less fatigue, using an MCID of 4.0 [24].

The current analyses compared PROs between the TCZ-QW + Pred-26 group and the PBO + Pred-26 and PBO + Pred-52 groups. These comparisons were selected to correspond with the primary and key secondary analyses of sustained remission from baseline to week 52 in the GiACTA trial [16]. Comparisons of SF-36 PCS and MCS scores between the TCZ-Q2W + Pred-26 group and the two PBO + Pred groups were not statistically significant at the pre-specified 1% level. Therefore, data from that group were not assessed further. Our analyses focused on the TCZ-QW + Pred-26 group, the PBO + Pred-26 group and the PBO + Pred-52 group.

All patients in the intent-to-treat (ITT) population, including those who experienced disease flare, were included in the current analyses. This approach contrasts with the analytical approach used previously, in which data obtained after use of escape therapy were censored [16]. Statistical significance was set as p < 0.01. All analyses presented were performed after unblinding and are considered exploratory.

One hundred patients were randomly assigned to TCZ-QW + Pred-26, 50 to TCZ-Q2W + Pred-26, 50 to PBO + Pred-26 and 51 to PBO + Pred-52. One patient assigned to the TCZ-Q2W group did not receive any study treatment and was not included in the ITT population. Baseline demographics and disease characteristics for all patients have been reported [16, 25] and are shown for the TCZ-QW + Pred-26, PBO + Pred-26 and PBO + Pred-52 groups in Table 1. In the ITT population, patients in both PBO + Pred groups received approximately twice the cumulative dose of prednisone as patients receiving TCZ-QW + Pred-26 over 52 weeks. The median (minimum–maximum) cumulative prednisone doses were 1862.0 mg (630.0–6602.5) for TCZ-QW + Pred-26, 3296.0 mg (932.0–9777.5) for PBO + Pred-26 and 3817.5 mg (822.5–10,697.5) for PBO + Pred-52 (p < 0.001 for comparisons). Among patients in the escape population who remained in the study until week 52, the median (minimum–maximum) cumulative prednisone doses over 52 weeks were 3129.8 mg (2009.0–5680.5, n = 18) for TCZ-QW + Pred-26, 4023.5 mg (2583.5–8695.0, n = 29) for PBO + Pred-26 and 5389.5 mg (2700–10,697.5, n = 24) for PBO + Pred-52. In summary, in the ITT and escape populations, cumulative prednisone doses were far higher in both PBO + Pred groups than in the TCZ-QW + Pred-26 group.

At baseline, PCS and MCS scores were similar across treatment groups and approximately 1 standard deviation (SD) below the A/G-matched normative scores of 50. Patients in the TCZ-QW + Pred-26 group reported greater LSM improvements from baseline to week 52 in PCS scores than patients in both PBO + Pred groups (p < 0.01). LSM improvement in MCS was significant in the TCZ-QW + Pred-26 group compared with the PBO + Pred-52 group (p < 0.01). Changes from baseline exceeded the MCID in both PCS and MCS scores in the TCZ-QW + Pred-26 group. Change from baseline in MCS score to week 52 exceeded the MCID in the PBO + Pred-26 group (Table 2).

Baseline domain scores reflected impaired HRQOL, which was the most impacted in the role physical, vitality, social function, role emotional and mental health domains. Scores were lowest in the PBO + Pred 52 group, reflecting decrements of 16–25 points below A/G norms (Table 3, Fig. 1). At week 52, LSM changes from baseline with TCZ-QW + Pred-26 treatment exceeded those in the PBO + Pred-26 group in four domains (physical function, role physical, general health and vitality; p < 0.01 for all) and exceeded those in the PBO + Pred-52 group in six domains (role physical, bodily pain, general health, vitality, social function and mental health; p < 0.01 for all) (Table 3, Fig. 1). Reported improvements across all domains exceeded the MCID in the TCZ-QW + Pred-26 group compared with five of eight domains in the PBO + Pred-26 group and none in the PBO + Pred-52 group (Table 3).

The SF-6D utility score (a quantitative measure of SF-36) was low in each treatment group at baseline, reflecting impaired HRQOL. Changes in SF-6D utility scores from baseline to week 52 exceeded the MID of 0.041 in the TCZ-QW + Pred-26 group (0.080) but in neither of the two PBO + Pred groups (0.034 for PBO + Pred-26 and 0.029 for PBO + Pred-52) (Table 3).

Reported improvements in LSM PtGA scores from baseline to week 52 with TCZ-QW + Pred-26 treatment were not statistically significantly different from those of either PBO + Pred group. LSM changes exceeded the MCID [19] only in the TCZ-QW + Pred-26 group (Fig. 2).

LSM increases in FACIT-Fatigue scores from baseline to week 52 in the TCZ-QW + Pred-26 group were significantly greater than in both PBO + Pred groups (p < 0.001) and exceeded the MCID [24] (Fig. 2).

The proportions of patients who reported improvements that met or exceeded the MCID from baseline to week 52 in SF-36 PCS and MCS, PtGA and FACIT-Fatigue scores ranged from 43 to 72% in the TCZ-QW + Pred-26 group and were numerically higher than in either PBO + Pred group with the exception of PBO + Pred-52 for FACIT-Fatigue (Fig. 3a). Statistically significant differences in the percentages of patients reporting clinically meaningful improvements in PtGA (p = 0.0029) and SF-36 MCS (p = 0.0012) scores were observed in the TCZ-QW + Pred-26 group compared with the PBO + Pred-26 group, resulting in numbers needed to treat (NNTs) of 3.5 and 3.15, respectively. NNTs represent the number of patients who required treatment with an intervention, in this case TCZ-QW + Pred-26, to effect a clinically meaningful improvement in HRQOL (met or exceeded MCID) for one patient. Across SF-36 domain scores, 31 to 61% of patients receiving TCZ-QW + Pred-26 reported improvements that met or exceeded the MCID compared with 12 to 49% receiving PBO + Pred-26. The difference was statistically significant in the general health domain (40 vs 12%, p = 0.0010, NNT = 3.53) (Fig. 3b).

The proportions of patients reporting clinically meaningful improvements in SF-36 domain scores were numerically higher with TCZ-QW + Pred-26 than with PBO + Pred-52 (Fig. 3b). These differences were statistically significant in role physical (57 vs 27%, p = 0.0016, NNT = 3.42) and general health (40 vs 16%, p = 0.0053, NNT = 4.11) domains.

Impaired HRQOL at baseline compared with A/G norms was evident across SF-36 PCS, MCS, domain and FACIT-Fatigue scores across all treatment groups, and few patients in any treatment group reported baseline scores that met or exceeded A/G norms across these PROs (Table 3, Figs. 1 and 3c, d).

The proportions of patients reporting scores that met or exceeded A/G norms in SF-36 PCS, MCS and FACIT-Fatigue increased from baseline to week 52 in the TCZ-QW + Pred-26 group, with generally smaller improvements in both PBO + Pred groups (Fig. 3c). The TCZ-QW + Pred-26 group demonstrated statistically significant differences in the proportions of patients reporting scores that met or exceeded A/G norms compared with the PBO + Pred-26 group in FACIT-Fatigue score (p = 0.008, Fig. 3c). Week 52 domain scores exceeded A/G norms in five of eight domains with TCZ-QW + Pred-26 (physical function, role physical, bodily pain, vitality and social function; Fig. 1) and met A/G norms in the remaining three domains. The proportions of patients reporting SF-36 physical function domain scores that met or exceeded A/G norms was significantly higher in the TCZ-QW + Pred-26 group than in the PBO + Pred-26 group (p = 0.002). The proportions of patients reporting bodily pain, general health, vitality, social function and mental health domain scores that met or exceeded A/G norms were lowest in the PBO + Pred-52 group. The patients in the PBO + Pred-52 group actually reported deterioration in the bodily pain and general health domains at week 52 (Fig. 3d).