Treatment of rheumatoid arthritis (RA) has undergone remarkable changes over the last few years, following introduction of biologic therapies, such as tumor necrosis factor (TNF) blockers and interleukin-1 receptor antagonists. Several randomized controlled clinical trials (RCTs) have provided documentation of the effectiveness of these drugs (1–14). However, these trials have limitations compared with observational studies. Due to the strict inclusion criteria frequently used, RA patients enrolled in RCTs are often limited to those with disease of moderate severity and without any significant comorbidity. Thus, results obtained in RCTs cannot be uncritically applied to clinical practice, since RA patients are heterogeneous regarding disease severity, duration, and comorbidity prior to therapy initiation (15–17). RCTs therefore have limitations in terms of external validity.
Moreover, RCTs are often restricted in duration and in the number of patients included, which in turn reduces the power for detecting long-term efficacy and tolerability. In addition, rare or comorbidity-associated side effects are difficult to detect. Finally, comparisons of different biologic therapies are mainly indirect, since RCTs often compare new drugs with conventional therapy.
Conversely, by using open observational studies according to a clinical protocol, it is possible to include patients continuously and without limits regarding number or comorbidity. Furthermore, observational studies allow the inclusion of different treatments in heterogeneous patient groups independent of industry support.
Previously, the concept of “adherence to therapy,” i.e., the number of patients continuing treatment with a drug, has been used to compare different drugs in observational studies (18–20). However, the adherence-to-therapy fraction provides information only about the proportion of patients receiving a drug, regardless of clinical response. Thus, only the subgroup of patients adhering to a treatment actually experiences a considerable clinical effect. To address these limitations, we developed the LUNDEX, which is an index of the proportion of patients who not only remain on a particular therapeutic regimen but also fulfill certain response criteria, such as the American College of Rheumatology 20% response criteria (ACR20) (21).
This study was observational in design and used a structured clinical protocol developed by the South Swedish Arthritis Treatment Group for monitoring new biologic therapies in RA (19). Herein we present the LUNDEX and describe its application in the evaluation of long-term efficacy and tolerability of etanercept and infliximab in RA patients treated in clinical practice.
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- PATIENTS AND METHODS
This report introduces the LUNDEX as a suitable index for comparing biologic therapies in observational studies. As illustrated in Figures 2A–D, the LUNDEX yields considerably lower values compared with the per-protocol technique. Previously, evaluation of response rates at fixed times of followup using intent-to-treat analyses with last observation carried forward (LOCF) has been used to compare biologic treatments (1–10). Both LOCF and completer (per-protocol) analyses inflate the apparent proportions of responses in clinical studies. In observational investigations, study of patients fulfilling particular response criteria, in isolation (Table 2), does not yield information about the true fraction of patients actually responding to a particular therapy, since not all patients adhere to the different therapeutic regimens. Therefore, the response rates observed in such studies reflect drug performance in selected groups of patients, but without accounting for differences in dropout among the treatment groups.
In many RCTs this problem is solved by using intent-to-treat analysis with carry forward techniques. In observational studies this type of analysis is inappropriate. Patients are continuously entering and exiting the study, and some patients switch to different treatment groups during the observation period.
In addition, clinical information necessary for calculating response criteria is sometimes missing for dropouts. To address this problem we developed the LUNDEX for assessment of drug efficacy in RA patients. The LUNDEX provides a unifying concept of the fraction of patients, among those adhering to therapy, who truly achieve a specific response criterion after a defined followup time. It is easy to utilize, and is calculated by multiplying the proportion of patients adhering to therapy by the proportion fulfilling a particular response criteria set (Figure 1). In this way, the LUNDEX can be applied without having to use intent-to-treat analysis, which thus facilitates the process of evaluating therapies in clinical observational studies in which specific treatments are continuously being initiated and discontinued in individual patients. Furthermore, the concept of the LUNDEX is not limited to RA and to ACR or EULAR response criteria. It is a universal index that can be applied to evaluate drug efficacy in other well-defined diseases with validated response criteria.
In this study, the treatment groups were not precisely matched because of the observational design. Therefore, several significant differences were noted at baseline. From a clinical perspective, however, the groups were quite similar. Both groups were dominated by patients with long disease duration, unsuccessful treatment with several previous DMARDs, and marked disability as well as high disease activity. Therefore, we believe limited comparisons of the different treatments are justifiable. The present comparison is not hampered by inclusion of patients previously treated with biologic agents, and the indications for anti-TNF therapy as well as concomitant DMARD therapy remained stable throughout the study period.
It is therefore reasonably clear from the results of this study that patients treated with etanercept have higher LUNDEX values than those treated with infliximab. The main reason for this finding is the lower level of drug adherence in patients treated with infliximab. In turn, this lower adherence in the infliximab group was explained mostly by withdrawals because of adverse events, but there also seemed to be more instances of lack of efficacy with this treatment. However, the lower degree of disease activity at baseline in the infliximab group (lower CRP level, DAS28 score, and HAQ score [Table 1]) may account, to some extent, for the lower rate of adherence to therapy and lower LUNDEX values observed among patients in this group, since their potential for improvement was lower. Conversely, the infliximab group also included a significantly higher proportion of patients receiving concomitant methotrexate at baseline, and concomitant treatment with anti-TNF therapy and methotrexate has been reported to be a more efficacious regimen compared with monotherapy (14).
In accordance with previous reports (29, 30), we did not observe any consistent differences in per-protocol response rates between the therapies. Etanercept showed significantly better responses at some followup points for ACR20, ACR50, and EULAR (moderate) response when compared with infliximab. However, the lack of consistency combined with the heterogeneity of the baseline population makes it less likely that etanercept truly yields a better clinical response than infliximab.
The open, nonrandomized nature of this study may introduce bias, both in the process of collecting data and during the selection of patients for particular treatments (17, 31). In order to minimize observational bias, all data entries were centralized, thereby ensuring uniform interpretation of information in registration forms. Possible confounding by indication cannot be excluded in this study. However, data directly comparing the different biologic drugs are sparse (31), thus giving no obvious reason for favoring prescription of one over another.
A placebo effect, improving the response to the drugs, may be expected. However, there is no reason to believe that this effect is distributed unevenly between treatment groups. In fact the rates of response to the treatments in this study were lower compared with findings of previous controlled clinical trials (1, 2, 6–10, 13, 14). This can be explained by the variation of glucocorticoid usage and the inclusion in this study of patients encountered in the clinical setting. Also, the long observation period of this study better reflects the chronic course of RA, and thus dilutes the bias that occurs in many RCTs, which focus on treatment of disease during flares (17).
We expect that the LUNDEX will become a valuable tool for evaluating results of observational studies. It is a practical measure with potentially universal application, independent of diagnosis and response criteria.