Early improvement in the HRQoL of RA patients during their first

The HRQoL of our RA patients had already improved significantly after 12 weeks of treatment with etanercept or adalimumab. Improvement in HRQoL with both biologicals was equal and paralleled clinical outcome variables.

Several RCTs have assessed the HRQoL of RA patients in subgroup

analyses. In an RCT of etanercept, HRQoL was measured with the SF-36 in a

subgroup of 48 RA patients, with the scores for physical and mental

components calculated. Both scores improved significantly after 26 weeks of treatment with etanercept 25 mg twice weekly (Mathias et al. 2000). Exactly the same follow-up time was used in RCT of adalimumab, where again significant improvement in HRQoL was observable (Mittendorf et al. 2007). A recent study of patients with early RA treated with adalimumab already showed improvement in physical domains of the SF-36 after 12 weeks of treatment (Kimel et al. 2008). In our study of adalimumab and etanercept, our follow-up time was identical, but the patients had long-standing severe RA and were treated in routine practice. Despite this we were able to demonstrate rapid improvement in HRQoL as measured by RAND-36.

In longitudinal studies of RA patients treated with DMARDs, the HAQ has shown a tendency toward a slight increase with time. In a 5-year follow-up study of 863 RA patients and 1176 population controls, the increase in HAQ in both groups was 0.01 units per year, an increase primarily attributable to the age-group over 70 (Sokka et al. 2006). In our study of RA patients treated with biologicals, their HAQ scores improved statistically significantly in the

etanercept group with a median (IQR) change of 0.25 (0.12 to 0.5). In the adalimumab group the improvement of the HAQ by 0.25 (0.13; 0.6) was not statistically significant, but the change was clinically important. In a study of pooled data of 36 trials (Aletaha and Ward 2006), authors showed that patients with late RA show less improvement in the HAQ as response to treatment than do patients with early RA. They explained the lesser

improvement in disability by the irreversible nature of joint damage. Therefore, we assume that the HAQ results of our study of patients with long-standing RA would have been even better had biologicals been started during its early phase.

Etanercept and adalimumab were equally effective in our RA patients in improving their HRQoL and clinical variables. The best way to compare the efficacy of two biologicals would be a randomized head-to-head study. Until now, no such study has been performed, so observational studies may be the

compared the effectiveness and medication costs of three biologicals:

infliximab, etanercept, and adalimumab given in routine settings (Kievit et al.

2008). The authors concluded that improvements in the physical component scale of SF-36 and in DAS-28 were statistically more pronounced in patients treated with adalimumab and etanercept than in those treated with infliximab.

One possible reason for the worse outcome of patients treated with infliximab was the use of the lowest possible dose, 3 mg/kg, in 80% of these patients.

At the same time, treatment with infliximab resulted in higher medication costs. Etanercept and adalimumab were equally effective in improving the SF-36 physical scale, paralleling our own results.

6.3 Clinical outcome and costs of treating chronic arthritis patients with infliximab

We showed that treatment with infliximab improves the clinical outcome of patients with chronic arthritis significantly in routine clinical practice. On the other hand, infliximab raised medical costs substantially, and work disability costs failed to decrease.

Only a few studies have analysed the costs of using biological drugs in routine practice. Our results differ from those of a study conducted in southern

Sweden (Kobelt et al. 2004) with 160 RA patients treated either with

etanercept or infliximab in which the direct costs fell by 40% during the first year. Several differences between our studies should be noted. First of all, in the Swedish study the costs of those 44 patients who discontinued before completing one year of treatment were excluded from the direct costs, as were also the costs of biologicals. In our study both of those costs are included in the analyses. In addition, in the Swedish study, 70% of patients were treated with etanercept, which is associated with lower administration costs than is infliximab. All of our patients were treated with infliximab. The total costs increased in the Swedish study by €12 183 (44%), rising from a mean of €27 447 to €39 630; this is comparable to our figures. As expected, in neither of the studies did the indirect costs change during one year of

follow-up. This can be explained by severity of RA, long disease duration, short follow-up, and by the fact that approximately 50% of the Swedish patients and ours were already on long-term sick-leave (Kobelt et al. 2004). A recent study by Kievit et al (2008) evaluated the clinical outcome and medication costs of patients treated with infliximab, etanercept, and adalimumab. This register-based study showed that the medication costs of patients treated with

infliximab were significantly higher than in patients treated with etanercept and adalimumab (Kievit et al. 2008).

Another approach to study the costs of biologicals is to use various models in the calculations. Such is the Dutch study by Nuijten et al (2001), in which the medical costs of patients treated with etanercept or infliximab were compared in a model. They concluded that etanercept was, from a health economics standpoint, superior to infliximab. But we have to take into account that the perspective of this study was that of Dutch society, and results of economic modeling studies cannot be easily transferred to other societies (Welte et al.

2004).

The reasons for higher costs for patients treated with infliximab can be the route of administration and the loading dose. Administration of infliximab intravenously requires visits to a medical specialist, while etanercept and adalimumab can be injected at home. In addition, infliximab treatment is started with a loading dose that raises the costs in the first year of use. For us, as well, costs for infliximab administration in addition to the price of infliximab raised the medical costs substantially.

6.4 Clinical impact of switching from infliximab to etanercept in patients with RA

In 49 RA patients, treatment with infliximab was discontinued and etanercept started for three reasons: infliximab failure, adverse event, or non-medical reasons. We were able to demonstrate that switching from established

tolerated, and the good response was maintained. A similar result occurred with switching from infliximab to adalimumab in RA patients who have

responded well to infliximab in a small open-label study in Ireland (Walsh et al.

2007). This was a study of 19 patients who were treated with infliximab for at least 12 weeks and responded to the treatment well; they were willing to switch to treatment with self-administered injections of adalimumab. The authors concluded that switching to adalimumab was safe and well tolerated and no significant changes in the HRQoL or physical function were detectable after the switch.

Although switching between etanercept, adalimumab, and infliximab has not been studied in any RCTs, several small observational studies have shown that, in the case of infliximab failure or adverse event, switching RA patients between biologicals can be an effective and safe option (Buch et al. 2007, Nikas et al. 2006, van Vollenhoven et al. 2003, Haraoui et al. 2004, Sanmarti et al. 2004, Hansen et al. 2004, Wick et al. 2005, Cohen et al. 2005). In our study, as well, the DAS28 score improved significantly in those whose reason to switch from infliximab to etanercept was infliximab failure or adverse event.

Several large register-based studies on treatment of RA patients with TNF-inhibitors have appeared lately. A recent study from the South Swedish Arthritis Treatment Group Register demonstrated that the response rates of the first-time TNF switchers were lower than the response rates in anti-TNF-naïve patients, and furthermore, that the response rates of second-time switchers were markedly lower. They also showed that younger age, lower HAQ score, and higher DAS28 at baseline predicted better response to second-line treatment (Karlsson et al. 2008).

In a large prospective cohort study, 73% of patients who switched to a second anti-TNF agent had remained on the new therapy by the end of the mean follow-up of 6 months (Hyrich et al. 2007). Another register-based study reported that the drug survival rate after the switch to a second anti-TNF is significantly lower than for the first course of anti-TNF, and that drug survival was statistically significantly lower for infliximab (34%) than for etanercept

(76%), or adalimumab (67%) (Gomez-Reino et al. 2006). The second anti-TNF survival in our study was significantly lower than in the earlier studies. In the group of infliximab failure, the 1-year drug survival was 43% (95% CI, 26 to 70) and in the adverse event group 50% (95% CI, 33 to 100). Only in the group involving non-medical reasons was the 1-year drug survival after the switch higher, 77% (95% CI, 62 to 97).

A new approach for treating patients with an inadequate response to TNF-inhibitors is to switch to B-cell-depleting therapy with rituximab (RTX). This was assessed in a cohort study of 116 RA patients who had an inadequate response to at least 1 TNF-inhibitor and in whom switching to an alternative TNF-inhibitor was compared with switching to RTX (Finckh et al. 2007).

Compared to those 66 patients who received another course of TNF-inhibitor, the evolution of DAS28 in those 50 patients who received RTX was more favourable (p=0.01). The authors concluded that treatment with RTX could be a better alternative in patients with a first or second inadequate response to a TNF-inhibitor than the use of all other alternative TNF-inhibitors. In addition, that study showed that one of the predictors of favourable outcome was the use of concomitant DMARDs.

In Studies I and II, we used the questionnaires RAND-36, 15D, and HAQ to measure patient-reported outcomes of treatment. Patient questionnaires have proven better than any laboratory test or imaging method in predicting

important clinical outcomes of RA such as mortality and work disability

(Pincus et al. 1984, Wolfe & Hawley 1998). They could therefore prove useful not only in clinical research but also for patient follow-up in routine practice.

However, these questionnaires are so long and complicated that in the busy schedule of routine visits they are rarely used. Several shorter and easier questionnaires based on the HAQ have been developed in recent years such as the modified HAQ (MHAQ), multidimensional HAQ (MDHAQ), HAQ-II, and Routine Assessment of Patient Index Data 3 (RAPID3) that could be

incorporated into the routine follow-up of individual patients (Pincus et al.

2005, 2008, Wolfe et al. 2004).