In the context of routine clinical practice, deviations from a T2T strategy according to predefined DMC for a cohort of patients with recent onset RA occurred in approximately 25% of clinical visits. Of these deviations, 43.3% were justifiable on clinical grounds. The most common type of protocol deviation was failure to escalate dose when indicated, which accounted for more than half of deviations.
The need for early referral and commencement of DMARDs followed by close monitoring of disease activity requires frequent patient visits, which may be a barrier to the T2T approach in clinical practice [20]. In our cohort, patients attended an average of 6.2 and 9.8 visits in the first 6 and 12 months following DMARD initiation respectively, and as such, the need for frequent visits did not appear to be an issue. However, 21 individuals were lost to follow up. The concordance with T2T may have been different in these patients for the same reasons they failed to continue attending the clinic. As the aim of this article was to evaluate ongoing issues with implementing T2T strategy, we excluded these patients from current analysis.
Frequent dose intensification shortly after DMARD initiation was particularly common in the DAS28-based DMC group, which may have been due to increased physician awareness of the importance of early intensive management in recent years and/or the greater conviction imbued by a well-recognised composite measure of disease activity. Furthermore, compared with the criteria-based DMC cohort, approximately 20% more visits fulfilled the criteria for increasing therapy when the DAS28-based DMC was used (data not shown). These latter patients, therefore, progressed through the algorithm more quickly, reaching the less attractive drug options (that is, gold, cyclosporine and azathioprine) earlier, which may be associated with more deviations (see Figure 1) due to a reluctance to initiate medications that were perceived to be more toxic, particularly after the first year. Also, with more prolonged treatment there may be a greater likelihood that the patient and possibly the physician will be more tolerant of the status quo and less demanding in their quest for solutions. Protocol deviation was also higher among patients with HDA at baseline. These patients experienced more continuation rather than escalation of therapy, which may have been due to their experiencing more side effects from medications (data not shown). The higher rate of deviation in patients with HDA at baseline was contrary to our expectation that there would be a high incidence of (rapid) intensification instead of continuation when compared to patients with LDA/MDA. This impact of baseline disease activity, however, declined over time. This was in line with the influence of baseline disease activity on treatment outcome, which also declined as treatment progressed. The higher prevalence of deviation and the lower rate of remission in patients with baseline HDA indicate the extent to which protocol deviation translates into treatment outcome.
In the DREAM remission-induction cohort, deviation in at least one clinic visit was similar to our cohort (91.0 versus 90.4%), but the overall prevalence of deviations in our cohort was lower (24.5% versus 30.7%) [9]. Furthermore, the rate of deviations in those who achieved remission was 13.1% in this cohort compared to 19.0% in the DREAM cohort, while in those who did not achieve remission the corresponding rates were 30.9% and 42.1% [9]. Difference in clinical settings, the nature of protocol used (for example, biological DMARDs were used more commonly in the DREAM cohort), patient characteristics or cultural reasons may have resulted in differences in the prevalence rate. Furthermore, the fact that there were stable personnel in our cohort (for example, physicians and a metrologist with standardisation of application of the T2T protocol), may also explain the lower rate of deviation in this study.
This study differs from earlier reports in three major respects. First, long-term (up to three years) follow up in compliance with the T2T approach is reported, which allowed identification of the stages of therapy when deviation is more likely to occur, and the impact of duration of therapy on the type of deviation that is likely to occur.
Second, we studied the pattern of protocol deviations, which appears to have an important relationship with outcome. For example, delaying a suggested recommended change to therapy to the next visit (that is, temporary deviations) may have little impact on the overall treatment outcome. Furthermore, the prevalence of persistent/recurrent deviations was low among patients in remission compared with those in non-remission whose disease activity dictated more frequent adjustments in treatment (Figure 3E). Deviations due to comorbidity, toxicity or patient-related factors were more likely to have persistent deviations, whilst physician-related factors did not differ between temporary and persistent deviations. Interestingly, these relations also extended to treatment outcome; DAS28 remission was less likely among patients experiencing deviations due to toxicity, comorbidity, patient-related factors or other factors, whereas physician-related factors did not have any impact on long-term treatment outcome.
Finally, we also explored whether baseline characteristics would predict the occurrence of protocol deviations, but the only objective baseline factor associated with protocol deviation was BMI. This has potential long-term clinical implications. Increased BMI is correlated with physical inactivity and greater risk of comorbid conditions including diabetes, hypertension, cardiovascular disease and other musculoskeletal symptoms, which may also affect how RA is treated [21,22]. Other objective measures such as baseline radiographic scores, laboratory values as well as socio-demographic variables, including gender, age and smoking habits, did not predict protocol deviation. Most of the factors correlating with protocol deviations in a univariate analysis, albeit weakly, were patient-reported outcomes, which may not directly measure the pathophysiological status of disease and can be biased by other comorbid conditions [23]. On the other hand, decisions about dose modification could be influenced by patient-reported outcomes to the extent that they provide an indication of the life impact of disease and personal factors such as illness behaviours. Furthermore, the effect of patient reported outcomes such as helplessness could be mediated through several factors. For example, patients with high levels of helplessness are known to experience higher levels of anxiety, depression, low self-esteem, impaired activities of daily living, low socioeconomic status and more symptoms such as fatigue, pain and stiffness [24-26]. This may in turn lead to poor concordance with therapy and/or reduce patient motivation to comply with a physician’s recommendation.
Toxicities and comorbidities
Toxicity can restrict long-term utilization of DMARDs [27] and accounted for 16.6% of total deviations in this cohort (Table 6). After DMARD-induced toxicity, judicious re-challenge or addition of new drugs should be a gradual and individualised process to avoid recurrence of unwanted effects. Gastrointestinal side effects, such as nausea, vomiting, abdominal pain/cramps, anorexia and diarrhea, were the leading drug-related safety issues responsible for deviations. These side effects are common with all conventional DMARDs [28], in particular sulfasalazine, which has been previously reported in this cohort [29]. In addition, comorbidities are very common in patients with RA [30], and can impact on physical function [31]. These comorbidities may be independent of or related to RA and its treatment, and it is often difficult to discriminate between these causes [32], but regardless of this, withholding or reducing DMARDs until these conditions have resolved was considered to be a justifiable reason for protocol deviation.
Patient and physician point of view
In the current study, both patients and physicians contributed equally to failure of adherence to a strict T2T strategy. According to international T2T taskforce recommendations [6], the management of RA should be based on a ‘shared decision between patient and physician’, and effective implementation is based on patients’ long-term commitment to therapy. However, full commitment was not demonstrated in this study, as about one quarter of all deviations (24.7% of total visits associated with deviations) were associated with patient-related reasons, including unwillingness to escalate their current treatment and poor concordance with previously agreed therapy. While concordance was not evaluated systematically in this study, patient self-reported concordance with therapy was used as a rough estimate of concordance rate, although this is likely to overestimate the true concordance level [19]. Poor concordance occurred when patients remained on the same dose regardless of a recommendation to intensify at the previous visit, or when all or part of the medication regimen was ceased or tapered by the patient. If this occurred, the physician had no choice but to reinstate the earlier regimen instead of intensifying, even when dose escalation was indicated. Systematically assessing the extent of concordance with therapy in the context of T2T and implementing tailored approaches to improving concordance with therapy is almost certainly critical to the success of this strategy.
Reluctance to modify therapy when indicated is a common phenomenon in RA. Wolfe and Michaud [11] reported that a common preference of patients undergoing long-term treatment for RA was maintenance of their current status and treatment, rather than striving for longer-term benefits with more intensive treatment, with attendant risks of new toxicities [11]. Van Hulst et al. [33] reported that factors that patients use to inform this decision are different from those used by clinicians. Current disability status, motivation to get better, belief in their physician, satisfaction with their current medications, and current number of painful joints affect patients’ decision to modify therapy [33]. Patients may make their own risk-benefit assessment before making decisions about their therapy, and therefore may need to be educated about the importance of short-term disease control in improving long-term treatment outcomes.
It may be difficult in practice to strictly comply with rigid T2T principles given the heterogeneity of patient populations and a tendency to individualise the approach. For example, sometimes therapy was intensified if there was a belief that disease was still active, even if a DMC was not fulfilled. Similarly, components of DAS28 such as ESR are not specific for RA disease activity, and disease may be considered inactive if elevated ESR was thought to be due to an unrelated cause. Such decisions based upon clinical judgement rather than composite disease activity measures are common practice [9,34,35], and may be considered rational and acceptable by physicians, but were considered unacceptable protocol deviations in this study. Another common approach practised by physicians is the so-called wait-and-see policy, where the physician thinks more time is needed for the drug to deliver optimal benefit and dose escalation is delayed until the next visit and beyond so as to minimise potential overtreatment. This was considered an unacceptable deviation in this study, and was especially common with leflunomide and gold injections, although the latter can take up to 6 months to produce maximal benefit [36].
The results of the current study should be interpreted within the following methodological limitations. The data for this analysis were compiled from various sources including physicians’ correspondence, a database containing information on patient characteristics, treatments and outcomes and from other medical records, but complete information from all visits may not be available. The frequency of clinic visits varied between patients depending on disease activity, and if patients failed to attend scheduled visits. In the case of the latter, non-concordance with the T2T protocol could have been underestimated. Our assessment of reasons for deviations was subjective and sometimes reasons for deviations were overlapping/inter-related, and as a result there is a potential for misclassification bias, including categorisation as permissible or non-permissible deviations. While we explored comorbidities as a reason for deviation, patient baseline comorbidities and their impact were not systematically assessed. For example, we did not evaluate the extent to which the treatment protocol was difficult to follow among patients with multiple comorbidities. Various clinical guidelines that utilise T2T differ from each other in certain aspects [10]. Because this study was conducted in the context of local T2T guidelines, which are based on parallel triple DMARD therapy, the findings may not be generalizable to other treatment approaches such as step-down, step-up or monotherapy. Despite these limitations, the study addressed important issues concerning the extent of deviation from T2T recommendations, reasons for deviations, whether deviations are justifiable or not and baseline factors affecting deviation. Further work towards understanding how T2T operates in daily practice and the relationship between compliance with treatment guidelines and short- and long-term treatment outcomes is required. Other unanswered questions in the setting of DMC being fulfilled include whether either a new medication or increasing the dose of an existing drug is more likely to be associated with protocol deviation, the type of medication most likely to contribute to deviations and whether strict adherence to treatment guidelines, particularly early in the course of disease, will prevent patients from requiring expensive biological agents.
